Conditions: Healthy Volunteers hATTR Amyloidosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: yes

Brief summary:
To evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of Eplontersen administered subcutaneously to healthy volunteers and patients with Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).

Detailed description:
This will be a Phase 1/2, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center for the healthy volunteer cohorts in up to 56 participants. It will consist of 1 single-dose cohort and 3 multiple-dose cohorts (n = 12 per cohort, 10 active:2 placebo). The open-label, hATTR patient cohort portion of the study will be conducted at multiple centers.

Arms:
arm 1: Participants received ION-682884 matching placebo, subcutaneously (SC) once every 4 weeks \[Q4W\] (total of 4 doses) along with daily oral supplemental doses of the recommended daily allowance (RDA) of vitamin A during the 13-week Treatment Period. arm 2: Participants received ION-682884, 45 milligrams (mg), SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. arm 3: Participants received ION-682884, 60 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. arm 4: Participants received ION-682884, 90 mg, SC, Q4W (total of 4 doses) along with daily oral supplemental doses of the RDA of vitamin A during the 13-week Treatment Period. arm 5: Participants received single dose of ION-682884 matching placebo, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1. arm 6: Participants received single dose of ION-682884, 120 mg, SC along with daily oral supplemental doses of the RDA of vitamin A on Day 1.

Interventions: intervention 1: ION-682884 intervention 2: Placebo intervention 3: Vitamin A
Intervention descriptions: intervention 1: ION-682884 administered SC intervention 2: Placebo comparator calculated volume to match ION-682884 administered SC intervention 3: Oral supplement

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
This Was a Phase 1/2, Double-blind, Randomized, Placebo-controlled, Dose- 
escalation Study Conducted at a Single Center for the Healthy Volunteer 
Cohorts in up to 56 Participants. It Consisted of 1 Single-dose Cohort and 3 
Multiple-dose Cohorts (n = 12 Per Cohort, 10 Active:2 Placebo). The Open- 
label, hATTR Patient Cohort Portion of the Study Was Conducted at Multiple 
Centers. 
 
 
NCT03728634 
06 April 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Official Title: 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy Volunteers 
and Patients with Hereditary Transthyretin-Mediated Amyloidosis 
NCT Number: 
NCT03728634 
Document Date: 
Protocol Amendment Version 2: 12-June-2019 


1 of 103 
 
Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc. 
Study Number: ION-682884-CS1 
 
 
11 November 2021 
 16. Appendices 
 
 
 
 
1. 
STUDY INFORMATION 
1.1. 
Protocol and Protocol Amendments 
The protocol was amended 2 times. The latest version of the protocol (Protocol Amendment 2) 
is provided along with the change summary for the revision. 
 
Protocol Version 
Date 
Document Provided 
Original 
05 September 2018 
None 
Protocol Amendment 1 
26 October 2018 
None 
Protocol Amendment 2 
12 June 2019 
Protocol and change summary 


2 of 103 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS1 
 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy 
Volunteers and Patients with Hereditary Transthyretin-Mediated 
Amyloidosis 
 
 
Protocol Amendment 2 – 12 June 2019 
 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 760-931-9200 
Fax: 760-603-2700 
 
Key Sponsor Contact: 
 
Ionis Pharmaceuticals Inc. 
Phone: 
 
Sponsor Signatory: 
Ionis Pharmaceuticals Inc. 
Phone: 


ION-682884-CS1 
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, MD 
 
 
ION-682884-CS1 
 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy 
Volunteers and Patients with Hereditary Transthyretin-Mediated 
Amyloidosis 
 
Protocol Amendment 2 – 12 June 2019 
 
 
Protocol History: 
Original Protocol: 
5 September 2018 
Protocol Amendment 1: 
26 October 2018 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 See electronic signature and date attached at end of document  
 
 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. 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. 
 
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Protocol Signature Page 
 
 
Protocol Number: 
ION-682884-CS1 
Protocol Title: 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of ION-682884, an Antisense Inhibitor of 
Transthyretin Production, in Healthy Volunteers and Patients with 
Hereditary Transthyretin-Mediated Amyloidosis 
Amendment: 
Amendment 2 
Date: 
12 June 2019 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled 
“A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of ION-682884, an antisense inhibitor of Transthyretin Production, in 
Healthy Volunteers and Patients with Hereditary Transthyretin-Mediated Amyloidosis,” dated 
12 June 2019, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
Date (DD Month YYYY) 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS  
Page 
PROTOCOL AMENDMENT ...................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 18 
Schema for Single-Dose Cohort C ............................................................................................. 18 
Schema for Every 4 Week, Multiple-Dose Cohorts (A, B and E) .............................................. 19 
Schema for Every 4 Week, Multiple-Dose Cohort D ................................................................. 20 
STUDY GLOSSARY .................................................................................................................. 21 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................... 23 
1.1 
Objectives ...................................................................................................................... 23 
1.1.1 
Primary Objectives ................................................................................................. 23 
1.1.2 
Secondary Objectives ............................................................................................. 23 
1.1.3 
Exploratory Objectives ........................................................................................... 23 
1.2 
Study Endpoints ............................................................................................................. 23 
1.2.1 
Primary Endpoints .................................................................................................. 23 
1.2.2 
Secondary Endpoints .............................................................................................. 23 
1.2.3 
Additional/Exploratory Endpoints .......................................................................... 23 
2. 
BACKGROUND AND RATIONALE ........................................................................... 24 
2.1 
Overview of Disease ...................................................................................................... 24 
2.1.1 
Disease Background ................................................................................................ 24 
2.1.2 
Overview of Target – Transthyretin ....................................................................... 25 
2.1.3 
Current Therapies .................................................................................................... 26 
2.2 
Therapeutic Rationale ..................................................................................................... 26 
2.3 
ION-682884 ................................................................................................................... 28 
2.3.1 
Mechanism of Action ............................................................................................. 28 
2.3.2 
Chemistry ............................................................................................................... 28 
2.3.3 
Preclinical Experience ............................................................................................ 29 
2.3.4 
Clinical Experience ................................................................................................. 29 
2.4 
Rationale for Dose and Schedule of Administration ...................................................... 31 
2.5 
Benefit-Risk Assessment ............................................................................................... 32 
2.5.1 
Healthy Volunteer Benefit Assessment .................................................................. 32 
2.5.2 
Patient Benefit Assessment ..................................................................................... 33 
2.5.3 
Healthy Volunteer and Patient Risk Assessment .................................................... 33 
2.5.4 
Overall Assessment of Benefit:Risk ....................................................................... 34 
3. 
EXPERIMENTAL PLAN .............................................................................................. 34 
3.1 
Study Design.................................................................................................................. 34 
3.1.1 
Healthy Volunteers (Cohorts A, B, C and E) .......................................................... 34 
3.1.2 
hATTR Patients (Cohort D) ................................................................................... 36 
3.2 
Number of Study Centers ............................................................................................... 36 
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3.3 
Number of Subjects ........................................................................................................ 36 
3.4 
Overall Study Duration and Follow-up .......................................................................... 36 
3.4.1 
Screening and Baseline Assessments...................................................................... 37 
3.4.2 
Treatment ............................................................................................................... 37 
3.4.3 
Post-Treatment ........................................................................................................ 38 
3.5 
End-of-Study ................................................................................................................... 38 
3.6 
Safety Committee .......................................................................................................... 38 
3.7 
Data and Safety Monitoring Board or Independent Data Monitoring Committee .......... 40 
3.8 
Dose Escalation ............................................................................................................. 40 
4. 
SUBJECT ENROLLMENT ........................................................................................... 40 
4.1 
Screening ....................................................................................................................... 40 
4.2 
Randomization/Registration ........................................................................................... 41 
4.3 
Replacement of Subjects ................................................................................................ 41 
4.4 
Unblinding of Treatment Assignment ............................................................................ 41 
5. 
SUBJECT ELIGIBILITY ............................................................................................... 42 
5.1 
Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) ............................... 42 
5.2 
Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) .............................. 42 
5.3 
Inclusion Criteria for hATTR Patients (Cohort D) ......................................................... 44 
5.4 
Exclusion Criteria for hATTR Patients (Cohort D) ........................................................ 44 
6. 
STUDY PROCEDURES ................................................................................................. 46 
6.1 
Study Schedule ............................................................................................................... 46 
6.1.1 
Study Schedule for the Healthy Volunteers (Cohorts A, B, C and E) ..................... 46 
6.1.1.1 
Screening Period .............................................................................................. 46 
6.1.1.2 
Treatment Period .............................................................................................. 47 
6.1.1.3 
Post-Treatment Period ...................................................................................... 47 
6.1.2 
Study Schedule for hATTR Patients (Cohort D) .................................................... 48 
6.1.2.1 
Screening and Baseline .................................................................................... 48 
6.1.2.2 
Treatment Period .............................................................................................. 48 
6.1.2.3 
End-of-Treatment Efficacy Assessment Period ................................................ 49 
6.1.2.4 
Post-Treatment Period ...................................................................................... 49 
6.2 
Study Assessments ......................................................................................................... 49 
6.2.1 
Laboratory Assessments ......................................................................................... 49 
6.2.2 
Congestive Heart Failure ........................................................................................ 49 
6.2.3 
Arrhythmias ........................................................................................................... 49 
6.2.4 
Myocardial Ischemia ............................................................................................... 50 
6.3 
Restriction on the Lifestyle of Subjects .......................................................................... 50 
6.3.1 
Contraception Requirements .................................................................................. 50 
6.3.2 
Other Requirements ................................................................................................ 50 
7. 
STUDY DRUG ................................................................................................................ 51 
7.1 
Study Drug Description ................................................................................................. 51 
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7.1.1 
ION-682884 ............................................................................................................ 51 
7.1.2 
Placebo ................................................................................................................... 51 
7.2 
Packaging and Labeling ................................................................................................. 51 
7.3 
Study Drug Accountability .............................................................................................. 51 
8. 
TREATMENT OF SUBJECTS ..................................................................................... 51 
8.1 
Study Drug Administration ............................................................................................ 51 
8.2 
Other Protocol-Required Drugs ...................................................................................... 52 
8.3 
Other Protocol-Required Treatment Procedures............................................................. 52 
8.4 
Treatment Precautions ................................................................................................... 52 
8.5 
Safety Monitoring Rules ................................................................................................ 52 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ............................................... 52 
8.5.2 
Safety Monitoring Rules for Platelet Count Results ............................................... 53 
8.5.3 
Safety Monitoring for Minor Bleeding Events ....................................................... 55 
8.6 
Stopping Rules ............................................................................................................... 55 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ..................................................... 55 
8.6.2 
Stopping Rules for Renal Function Test Results .................................................... 55 
8.6.3 
Stopping Rule for Platelet Count Results ............................................................... 56 
8.6.3.1 
Healthy Volunteers (Cohorts A, B, C and E) ................................................... 56 
8.6.3.2 
hATTR Patients (Cohort D) ............................................................................. 56 
8.7 
Adjustment of Dose and/or Treatment Schedule ............................................................ 58 
8.8 
Discontinuation of Study Drug ...................................................................................... 58 
8.9 
Withdrawal of Subjects from the Study Procedures ....................................................... 58 
8.10 
Cohort and Study Stopping Rules ................................................................................... 59 
8.11 
Concomitant Therapy and Procedures ........................................................................... 59 
8.11.1 
Concomitant Therapy .............................................................................................. 59 
8.11.2 
Concomitant Procedures ......................................................................................... 60 
8.12 
Treatment Compliance ................................................................................................... 60 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ........................ 60 
9.1 
Sponsor Review of Safety Information .......................................................................... 60 
9.2 
Regulatory Requirements ................................................................................................ 61 
9.3 
Definitions ..................................................................................................................... 61 
9.3.1 
Adverse Event ........................................................................................................ 61 
9.3.2 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ......... 62 
9.3.3 
Serious Adverse Event (SAE) ................................................................................. 62 
9.4 
Monitoring and Recording Adverse Events ................................................................... 63 
9.4.1 
Serious Adverse Events .......................................................................................... 63 
9.4.2 
Non-Serious Adverse Events .................................................................................. 64 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ..................................... 64 
9.4.3.1 
Relationship to the Study Drug ........................................................................ 64 
9.4.3.2 
Severity ............................................................................................................ 64 
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9.4.3.3 
Action Taken with Study Drug......................................................................... 65 
9.4.3.4 
Treatment Given for Adverse Event ................................................................ 65 
9.4.3.5 
Outcome of the Adverse Event ........................................................................ 65 
9.4.3.6 
Follow-up of Adverse Event ............................................................................ 66 
9.5 
Procedures for Handling Special Situations ................................................................... 67 
9.5.1 
Abnormalities of Laboratory Tests ......................................................................... 67 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............. 67 
9.5.3 
Dosing Errors ......................................................................................................... 67 
9.5.4 
Contraception and Pregnancy .................................................................................. 68 
10. 
STATISTICAL CONSIDERATIONS ........................................................................... 69 
10.1 
Study Endpoints, Subsets, and Covariates ..................................................................... 69 
10.1.2 
Secondary Endpoints .............................................................................................. 69 
10.1.2.1 
Pharmacokinetic Endpoints .............................................................................. 69 
10.1.2.2 
Pharmacodynamic Endpoints ........................................................................... 69 
10.1.3 
Additional/Exploratory Endpoints .......................................................................... 69 
10.2 
Sample Size Considerations ........................................................................................... 69 
10.3 
Populations .................................................................................................................... 70 
10.4 
Definition of Baseline .................................................................................................... 70 
10.5 
Interim Analysis ............................................................................................................ 70 
10.6 
Planned Methods of Analysis ......................................................................................... 70 
10.6.1 
Demographic and Baseline Characteristics ............................................................. 70 
10.6.2 
Safety Analysis ....................................................................................................... 70 
10.6.3 
Pharmacokinetic Analysis ...................................................................................... 71 
10.6.4 
Pharmacodynamic Analysis .................................................................................... 72 
10.6.5 
Additional Analyses ............................................................................................... 72 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................................................ 72 
11.1 
Informed Consent .......................................................................................................... 72 
11.2 
Ethical Conduct of the Study .......................................................................................... 72 
11.3 
Institutional Review Board ............................................................................................ 72 
11.4 
Subject Confidentiality .................................................................................................. 73 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 73 
12.1 
Protocol Amendments ................................................................................................... 73 
12.2 
Study Termination ......................................................................................................... 73 
12.3 
Study Documentation and Storage ................................................................................. 74 
12.4 
Study Monitoring ........................................................................................................... 74 
12.5 
Language ....................................................................................................................... 75 
12.6 
Compensation for Injury ................................................................................................ 75 
13. 
REFERENCES ............................................................................................................... 76 
 
 
 
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14. 
APPENDICES ................................................................................................................. 79 
Appendix A 
Schedule of Procedures .................................................................................... 80 
Appendix B 
List of Laboratory Analytes ............................................................................. 90 
Appendix C 
PK Sampling Schedule for Single- and Multiple-Dose Cohorts ....................... 92 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ....... 95 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Dosing Information ............................................................................. 51 
Table 2 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 ............................................................................................................................................................ 54 
Table 3 
Actions in Patients with Low Platelet Count ..........................................................57 
TABLE OF FIGURES 
 
 
 
 
 
Page 
Figure 1 
On-Treatment Percent Change from Baseline in TTR over Time .......................... 30 
Figure 2 
On-Treatment LSM Change from Baseline in mNIS+7 Composite Score ............. 31 
Figure 3 
On-Treatment LSM Change from Baseline in Norfolk QoL-DN Total 
Score ...................................................................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL AMENDMENT 
 
Protocol Number: 
ION-682884-CS1 
Protocol Title: 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy 
Volunteers and Patients with Hereditary Transthyretin-Mediated 
Amyloidosis 
Amendment Number: 
2 
Amendment Date: 
12 June 2019 
Following a review of the data from the completed treatment period of the planned healthy 
volunteer portion of this study (Cohorts A, B and C), the Sponsor intends to run an additional 
multiple-dose cohort to better assess the safety, tolerability, pharmacokinetics and 
pharmacodynamics of ION-682884. 
Protocol ION-682884-CS1 already contained a provision for an additional healthy volunteer 
cohort, Cohort E, to be enrolled and dosed at ≤ 120 mg per dose using the same dosing schedule 
as the other 2 multiple-dose, healthy volunteer cohorts (Cohorts A and B). 
The purpose of this amendment is to confirm the Sponsor’s intent to perform Cohort E and to 
identify the intermediate dose level of 60 mg per dose throughout the protocol for this cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of ION-682884, an Antisense Inhibitor of 
Transthyretin Production, in Healthy Volunteers and Patients with Hereditary 
Transthyretin-Mediated Amyloidosis 
Study Phase 
1/2 
Indication 
Hereditary Transthyretin-Mediated Amyloidosis (hATTR) 
Primary Objectives 
To evaluate the safety and tolerability of single and multiple doses of 
ION-682884 administered subcutaneously (SC) to healthy volunteers and 
patients with hATTR. 
Secondary Objectives 
To evaluate the pharmacokinetic and pharmacodynamic profiles of single and 
multiple doses of ION-682884 administered subcutaneously to healthy 
volunteers and patients with hATTR. 
Exploratory Objectives 
To evaluate the effects of ION-682884 subcutaneous injection on the 
mNIS+7, Norfolk QoL, 6MWT, 10MWT, EQ-5d, SF-36, COMPASS, and 
Amyloidosis-specific QoL. 
Study Design 
Healthy Volunteers (Cohorts A, B, C and E) 
Blinded, placebo-controlled, dose-escalation, single-center study 
For each dose cohort, the first 2 sentinel subjects will be dosed on the same 
day. If no major safety concerns are observed following 48 hours of 
observation, as determined by the Safety Committee, (comprised of the 
Investigator, the Sponsor Medical Monitor and an Independent Safety 
Monitor), dosing of the remaining subjects in that cohort may proceed. 
hATTR Patients (Cohort D) 
Open-label, multi-center study. At the end of the Treatment Period, eligible 
patients may elect to enroll in an open-label extension (OLE) study pending 
study approval by the IRB/IEC and the appropriate regulatory authority. 
Patients not participating in the OLE will enter the 13-week Post-Treatment 
evaluation portion of this study. 
Number of Subjects 
Healthy Volunteers (Cohorts A, B, C and E) 
Approximately 36 healthy volunteers are planned to be enrolled in the study. 
Additional subjects may be added to better assess the safety, tolerability, 
pharmacokinetic and pharmacodynamic of ION-682884 to meet study 
objectives. Maximum enrollment of healthy volunteers will be limited to 
60 subjects. 
hATTR Patients (Cohort D) 
Approximately 20 hATTR patients are planned to be enrolled in the study. 
Additional patients may be added to better assess the safety, tolerability, 
pharmacokinetic and pharmacodynamic of ION-682884 to meet study 
objectives. Maximum enrollment will be limited to 30 hATTR patients. 
Study Population 
Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
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. Healthy males or females of non-childbearing potential, aged 18 to 
65 inclusive at the time of informed consent. 
 
 
 
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Study Population Continued 
Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
Continued 
3. Females must be non-pregnant and non-lactating, and either surgically 
sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or post-menopausal (defined as 12 months of 
spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved. 
Males must be surgically sterile or abstinent*, if engaged in sexual 
relations with a female of child-bearing potential, the subject must be 
using an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until at least 91 days 
(single-dose cohorts) or 13 weeks (multiple-dose cohorts) after the last 
dose of Study Drug (ION-682884 or placebo) 
*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. 
4. Willing to refrain from strenuous exercise/activity (for example heavy 
lifting, weight training, intense aerobics classes etc.) for at least 
72 hours prior to study visits 
5. Weight ≥ 50 kg and body mass index (BMI) < 32 kg/m2 
6. Willingness to take vitamin A supplements 
Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
1. 
Clinically-significant abnormalities in medical history (e.g., previous 
acute coronary syndrome within 6 months of Screening, major surgery 
within 3 months of Screening) or physical examination 
2. 
Screening laboratory results as follows, or any other 
clinically-significant abnormalities in screening laboratory values that 
would render a subject unsuitable for inclusion 
• 
Random spot urine protein/creatinine (P/C) ratio 
(UPCR) ≥ 200 mg/g. In the event of P/C ratio (UPCR) above 
this threshold eligibility may be confirmed by a repeat random 
spot UPCR ≥ 200 mg/g or a 24-hr urine ≥ 200 mg/24 hr 
• 
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 
• 
ALT, AST, bilirubin, alkaline phosphatase, serum creatinine, 
BUN > upper limit of normal (ULN) 
• 
Fasting blood glucose > ULN 
• 
Platelet count < lower limit of normal (LLN) 
3. 
Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
4. 
Unwillingness to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the 
Investigator 
5. 
Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
6. 
Uncontrolled hypertension (blood pressure [BP] > 160/100 mm Hg) 
 
 
 
 
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Study Population Continued 
Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
Continued 
7. 
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 
8. 
Treatment with another investigational drug, biological agent, or device 
within 1 month of Screening, or 5 half-lives of investigational agent, 
whichever is longer 
9. 
Previous treatment with an oligonucleotide or other RNA therapeutic 
(including siRNA) within 4 months of Screening if single-dose received, 
or within 12 months of Screening if multiple doses received 
10. History of bleeding diathesis or coagulopathy 
11. Regular use of alcohol within 6 months prior to screening 
(> 7 drinks/wk for females, > 14 drinks/wk for males (1 drink = 
5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 
1.5 ounces (45 mL) of hard liquor), or use of soft drugs (such as 
marijuana) within 3 months prior to screening, or hard drugs (such as 
cocaine and phencyclidine) within 1 year prior to screening, or positive 
urine drug screen at Screening 
12. Concomitant medication restrictions including over-the-counter and 
herbal remedies, other than occasional acetaminophen (paracetamol) 
or ibuprofen unless authorized by the Sponsor Medical Monitor 
13. Use of oral anticoagulants, unless the dose has been stable for 
4 weeks prior to the first dose of Study Drug (ION-682884 or placebo) 
and regular clinical monitoring is performed 
14. Smoking limitations: smoking >10 cigarettes a day 
15. Blood donation of 50 to 499 mL within 30 days of Screening or of 
> 499 mL within 60 days of Screening 
16. Have any other conditions, which, in the opinion of the Investigator or 
Sponsor would make the subject unsuitable for inclusion, or could 
interfere with the subject participating in or completing the Study 
Inclusion Criteria for hATTR Patients (Cohort D) 
To be eligible to participate in this study cohort candidates must meet the 
following eligibility criteria within 6 weeks of Study Day 1, or at the time 
point specified in the individual eligibility criterion listed. 
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. Aged 18 to 82 years at the time of informed consent 
3. Females must be non-pregnant and non-lactating, and either surgically 
sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or post-menopausal (defined as 12 months of 
spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved. 
Males must be surgically sterile or abstinent*, if engaged in sexual 
relations with a female of child-bearing potential, the subject must be 
using 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 ION-682884 
 
 
 
 
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Study Population Continued 
Inclusion Criteria for hATTR Patients (Cohort D) Continued 
*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. 
4. hATTR-PN as defined by: 
a. 
Polyneuropathy Disability (PND) Stage I-III 
b. 
Documented genetic mutation in the TTR gene 
c. 
Symptoms consistent with polyneuropathy as measured by 
NIS score ≥ 10 
d. 
Willingness to take vitamin A supplements 
5. 
BMI > 16 kg/m2 
Exclusion Criteria for hATTR Patients (Cohort D) 
1. 
Clinically-significant abnormalities in medical history (e.g., previous 
acute coronary syndrome or major surgery within 3 months of 
Screening) or physical examination 
2. 
Screening laboratory results as follows, or any other 
clinically-significant abnormalities in screening laboratory values that 
would render a subject unsuitable for inclusion 
a. 
ALT/AST > 1.9 x ULN 
b. 
Bilirubin ≥ 1.5 x ULN (patients with bilirubin ≥ 1.5 x ULN may be 
allowed on study following discussion with the Study Medical 
Monitor if indirect bilirubin only is elevated, ALT/AST is not greater 
than the ULN and genetic testing confirming Gilbert’s disease) 
c. 
Platelets < 125 x 109/L 
d. 
Urine protein/creatinine (P/C) ratio (UPCR) ≥ 1000 mg/g. In the 
event of P/C ratio (UPCR) above this threshold eligibility may be 
confirmed by by a repeat random spot UPCR ≥ 1000 mg/g or a 
24-hr urine ≥ 1000 mg/24 hr 
e. 
Renal insufficiency as defined by estimated creatinine clearance 
calculated according to the formula of CKD-EPI < 45 mL/min/ 
1.73 m2 at Screen. If the calculated creatinine clearance is thought 
to be artificially low, a 24-hr urine creatinine clearance can be 
completed with prior Sponsor approval 
f. 
TSH values outside normal range (unless approved by the Study 
Medical Monitor) 
3. 
Serum retinol level at Screen < LLN 
For patients with a TTR mutation at position 84 (e.g., Ile84Ser or 
Ile84Asn) and retinol < LLN the exclusion criterion is signs or 
symptoms of vitamin A deficiency (such as dry eye, bitots’ spot 
observed in the ophthalmology exam, that in the opinion of the 
ophthalmologist is consistent with vitamin A deficiency) 
4. 
Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
5. 
Unwillingness to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the 
Investigator 
6. 
Known history of or positive test for HIV, hepatitis C or chronic 
hepatitis B 
 
 
 
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Study Population Continued 
Exclusion Criteria for hATTR Patients (Cohort D) Continued 
7. 
Uncontrolled hypertension (BP > 160/100 mm Hg) 
8. 
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. Patients with a history of other malignancies that 
have been treated with curative intent and which have no recurrence 
within 5 years may also be eligible if approved by the Sponsor Medical 
Monitor 
9. 
Treatment with another investigational drug, biological agent, or device 
within 1 month of Screening, or 5 half-lives of investigational agent, 
whichever is longer. Does not apply to tafamidis, diflunisal, 
doxycycline or TUCA if subject has been on a stable dose of drug for 
≥ 4 weeks and continues receiving the same dose for the duration of 
the study 
10. Previous treatment with an oligonucleotide or other RNA therapeutic 
(including siRNA) within 3 months of Screening 
11. Karnofsky performance status ≤ 50 
12. Diagnosis of type 1 or type 2 diabetes for equal or more than 5 years; 
Screening HbA1c > 9.5%; or history of severe peripheral neuropathy 
due to diabetes 
13. Other causes of sensorimotor or autonomic neuropathy 
(e.g., autoimmune disease) 
14. Prior liver transplant or anticipated liver transplant within 1 year of 
Screening 
15. New York Heart Association (NYHA) functional classification of ≥ 3 
16. NT-proBNP > 3000 pg/mL 
17. Known Primary Amyloidosis (AL amyloidosis) 
18. Known Leptomeningeal Amyloidosis 
19. Known Multiple Myeloma 
20. Monoclonal gammopathy of undetermined significance (MGUS) unless 
serum M protein level of < 3 g/dL, < 10% clonal plasma cells in the 
bone marrow, urine monoclonal protein < 500 mg/24 hrs and no 
evidence of end-organ damage 
21. Have any other conditions, which, in the opinion of the Investigator or 
Sponsor would make the subject unsuitable for inclusion, or could 
interfere with the subject participating in or completing the Study 
Treatment Groups 
Healthy Volunteers (Cohorts A, B, C and E) 
There are 3 planned cohorts in healthy volunteers, 2 multiple-dose cohorts 
(Cohorts A and B) and 1 single-dose cohort (Cohort C) and 1 additional 
multiple-dose cohort (Cohort E). Cohorts A, B, C and E are comprised of 
12 subjects, randomized 10:2, active:placebo. Subjects in the multiple-dose 
cohorts will receive SC doses of Study Drug once every 4 weeks for a total of 
12 weeks (total of 4 doses). Subjects in the single-dose cohort will receive 
1 SC dose of Study Drug on Day 1. For each dose cohort, the first 
2 (sentinel) subjects (randomized 1 active:1 placebo) will be dosed on the 
same day. If no major safety concerns are observed following 48 hours of 
observation, as determined by the Safety Committee, dosing of the remaining 
10 subjects (randomized 9 active:1 placebo) in that cohort may proceed. 
 
 
 
 
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Treatment Groups Continued 
Healthy Volunteers (Cohorts A, B, C and E) Continued 
Following the administration of the 1st dose of Study Drug in each 
multiple-dose cohort, individual subjects must have completed their Day 15 
safety evaluations with an acceptable safety profile, as determined by the 
Safety Committee, before receiving additional doses of Study Drug. 
Cohort 
Number 
Total 
of Doses 
ION-682884 
Cohort A: 45 mg ION-682884 or placebo 
4 
180 mg 
Cohort B: 90 mg ION-682884 or placebo 
4 
360 mg 
Cohort C: 120 mg ION-682884 or placebo 
1 
120 mg 
Cohort E: 60 mg ION-682884 or placebo 
4 
240 mg 
The additional multiple-dose, healthy-volunteer cohort with 4 once-every- 
4-week doses of 60 mg ION-682884 or placebo, was added to further 
elucidate safety or PD effects of ION-682884. 
hATTR Patients (Cohort D) 
There is 1 planned, open-label, multiple-dose cohort (Cohort D) comprised of 
up to 20 patients with hATTR. Patients in this cohort will receive SC doses of 
ION-682884 once every 4 weeks for a total of 12 weeks (total of 4 doses). 
The dose level in this cohort will not exceed doses planned for Healthy 
Volunteers (120 mg) and will be selected after reviewing the safety and 
pharmacodynamic data obtained in the healthy volunteer portion of this study. 
Following the administration of the 1st dose of ION-682884 patients must 
have completed their Day 15 safety evaluations with an acceptable safety 
profile, as determined by the Safety Committee, before receiving additional 
doses of Study Drug. 
Cohort 
Number of 
 
Total 
Doses 
ION-682884 
Cohort D: ≤ 120 mg ION-682884 
4 
≤ 480 mg 
Study Drug Dosage and 
Administration 
The Sponsor will provide ION-682884 (150 mg/mL, 0.8 mL) and the site will 
provide Placebo (0.9% sterile saline). All doses will be given by SC injection. 
Dose Escalation 
Healthy Volunteers (Cohorts A and B) 
Dosing of Cohort B (4 x 90 mg ION-682884 or placebo) can only proceed 
when at least 8 subjects in Cohort A have completed Day 29 safety 
evaluations and have demonstrated an acceptable safety profile as 
determined by the Safety Committee. 
Healthy Volunteers (Cohorts C) 
Dosing of Cohort C (1 x 120 mg ION-682884 or placebo) can only proceed 
when at least 8 subjects in Cohort A have completed Day 57 safety 
evaluations and have demonstrated an acceptable safety profile as 
determined by the Safety Committee. 
Additional Multiple-Dose Cohort in Healthy Volunteers (Cohort E) 
Dosing of the additional multiple-dose cohort (4 x 60 mg ION-682884 or 
placebo), can only proceed when at least 8 subjects in Cohort B have 
completed Day 29 safety evaluations and have demonstrated an acceptable 
safety profile as determined by the Safety Committee. 
 
 
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Dose Escalation Continued 
hATTR Patients (Cohort D) 
Enrollment in Cohort D (4 x ≤ 120 mg ION-682884) can only proceed when at 
least 8 subjects in Cohort B (4 x 90 mg ION-682884 or placebo) have 
completed the Treatment Period and have demonstrated an acceptable 
safety profile as determined by the Principal Investigator and the Safety 
Committee. 
The dose level for Cohort D will be informed by safety and PD data from the 
multiple-dose and single-dose healthy-volunteer cohorts. 
Cohorts (A, B, C and E) 
Based on the judgement of the Principal Investigator and the Sponsor 
Medical Monitor, any cohort may be expanded to enroll additional subjects 
(no more than 2 times the original size) and/or additional single-dose and/or 
multiple-dose cohorts at intermediate dose(s) may be added to better assess 
the safety, tolerability, or pharmacodynamic profile of ION-682884. 
Rationale for Dose and Schedule 
Selection 
A starting dose of 45 mg (approximately 0.6 mg/kg/month body weight in a 
70-kg subject) was selected based on approximately 37-fold safety margin 
and expectation of total body weight-based dose scaling between monkeys 
and humans, where no drug-related toxicologically significant findings were 
observed up to 6 mg/kg/wk (24 mg/kg/month equivalent exposure) after 
13 weeks of treatment in monkeys. The dose of 90 mg will provide an 18-fold 
safety margin. 
Adjustment of Dose and/or 
Treatment Schedule 
Adjustment of dose and/or schedule is not permitted 
Study Visit Schedule and 
Procedures 
Detailed Information regarding the study procedures are outlined in Section 6 
and Appendices A, B, C, and D. 
Blood and urine samples will be collected regularly throughout the study for 
safety, pharmacokinetic, and pharmacodynamics analysis. Appendix B 
shows a list of analytes required for the study. 
The safety of ION-682884 will be monitored in an ongoing fashion during the 
study. 
Single-Dose Cohort C 
The length of each subject’s participation in Cohort C is approximately 
17 weeks from screening to last study visit. There are 2 overnight stays in 
the clinic (Days -1 and 1). On Day 1, subjects will receive a single SC dose 
of Study Drug. 
Multiple-Dose Cohorts A, B and E 
The length of each subject’s participation in Cohorts A, B and E is 
approximately 29 weeks, including a 4-week Screening Period, a 12-week 
Treatment Period, and a 13-week Post-Treatment Evaluation Period. There 
are 3 overnight stays in the clinic (Days -1, 1 and 85). Subjects will receive a 
total of 4, once every 4 weeks, fixed SC doses of Study Drug. 
Multiple-Dose Cohort D 
The length of each subject’s participation in Cohort D is approximately 
29 weeks, including a 4-week Screening Period, a 12-week Treatment 
Period, and a 13-week Post-Treatment Evaluation Period. There is 
1 overnight stay in the clinic (Days -1). Subjects will receive a total of 4, once 
every 4 weeks, fixed SC doses of ION-682884. 
 
 
 
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Study Visit Schedule and 
Procedures Continued 
At the end of the Treatment Period, eligible patients may elect to enroll in an 
OLE study pending study approval by the IRB/IEC and the appropriate 
regulatory authority. Patients not participating in the OLE will enter the 
13-week Post-Treatment Evaluation portion of this study unless consent is 
withdrawn. 
Primary Endpoints 
Analysis of safety labs, AEs, concomitant medications, ECG and physical 
examinations of healthy volunteers and patients with TTR amyloidosis 
following subcutaneously administration of single and/or multiple doses of 
ION-682884. 
Secondary Endpoints 
Analysis of pharmacokinetic data (plasma PK and urinary excretion) and 
pharmacodynamic data (TTR and RBP4 knockdown) in healthy volunteers 
and patients with TTR amyloidosis following subcutaneous administration of 
single and/or multiple doses of ION-682884. 
Additional/Exploratory Endpoints 
Exploratory endpoints for the open-label, hATTR patient cohort are the 
change from Baseline to Week 15 in the: 
• 
Norfolk QOL-DN questionnaire total score 
• 
6MWT 
• 
10MWT 
• 
EQ-5d 
• 
SF-36 questionnaire domain scores 
• 
COMPASS-31 questionnaire 
• 
Amyloidosis-specific QoL questionnaire 
Statistical Considerations 
There is no statistical rationale for the selected sample size of the healthy 
volunteer, single- and multiple-dose treatment cohorts. The sample size was 
based on prior experience to ensure that the safety and tolerability of 
ION-682884 will be adequately assessed while minimizing unnecessary 
subject exposure. 
Unblinded analyses may be conducted after completion of dosing for the 
single-dose and each multiple-dose cohort. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SCREEN 
Day -28 to Day -1 
SCREEN FAIL 
PRE-TREATMENT 
Day -1 to Day 1 
SCREEN FAIL 
POST-TREATMENT 
EVALUATIONS 
Days 2, 3, 4, 8, 15, 29, 50, 71, 92 
 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
Schema for Single-Dose Cohort C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 
TREATMENT PERIOD 
Day 1 
CONSENT 
WITHDRAWAL 
POST-TREATMENT 
Day 1 
EARLY TERM VISIT 
Day 8 


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Schema for Every 4 Week, Multiple-Dose Cohorts (A, B and E) 
 
 
 
 
 
-------, 
SCREEN FAIL 
 
 
 
" 
- ------ 1SCREEN FAIL 
 
 
 
 
 
 
- 
--- 
 
 
 
' ' ' 
·' ------------------ --.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
" 
POST-TREATMENT 
EVALUATIONS 
Days 99,113,127,141,155,176 
1 
EARLY 
TERMINATION VISIT 
Day99 
.. 
SUBJECT WITHDRAWN 
FROM STUDY 
OR 
CONSENT WITHDRAWAL 
TREATMENT 
TERMINATED 
CONSENT NOT 
WITHDRAWN 
SCREEN 
Day -28 to Day -1 
PRE-TREATMENT 
Day-1 to Day 1 
TREATMENT PERIOD 
Day 1, 29, 57 and 85 


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SCREEN 
Day -28 to Day -1 
PRE-TREATMENT 
Day -1 to Day 1 
SCREEN FAIL 
 
 
 
 
 
Schema for Every 4 Week, Multiple-Dose Cohort D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
POST-TREATMENT 
EVALUATIONS 
Days 99, 113, 127, 141, 155, 176 
TREATMENT PERIOD 
Day 1, 29, 57 and 85 
TREATMENT 
TERMINATED 
CONSENT NOT 
WITHDRAWN 
EARLY 
TERMINATION VISIT 
Day 99 
SUBJECT WITHDRAWN 
FROM STUDY 
OR 
CONSENT WITHDRAWAL 
SCREEN FAIL 


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STUDY GLOSSARY 
Abbreviation 
Definition 
+7 
Sum 7 test. Includes measurements of nerve conduction, vibration threshold 
and heart rate to deep breathing 
Alb/C ratio 
albumin/creatinine ratio (performed on urine sample) 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AUC 
area under the curve 
BP 
blood pressure 
BMI 
body mass index 
CKMB 
creatine kinase-muscle/brain 
CM 
cardiomyopathy 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EOT 
end-of-treatment 
ERG 
electroretinogram 
ET 
early termination 
GLS 
global longitudinal strain 
hATTR 
hereditary transthyretin amyloidosis 
hATTR-PN 
hATTR with polyneuropathy 
hATTR-CM 
hATTR with cardiomyopathy 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IXRS 
interactive voice/web-response system 
LLN 
lower limit of normal 
mBMI 
modified body mass index (requires determination of plasma albumin levels; 
mBMI = BMI x serum albumin g/L) 
MGUS 
 monoclonal gammopathy of undetermined significance 
MMRM model 
mixed effect model with repeated measures 
 
 
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mNIS+7 
modified neuropathy impairment score +7. Standard NIS but with 
modifications made to the +7 component 
Modified +7 
+7 test with modifications made to the sensory and nerve conduction testing 
MPV 
mean platelet volume 
NIS 
neuropathy impairment score 
NIS-LL 
neuropathy impairment score-lower limb 
NOAEL 
No Observable Adverse Effect Level 
Norfolk QOL-DN Norfolk quality of life-diabetic neuropathy questionnaire 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OLE 
open label extension 
OLT 
orthotopic liver transplantation 
P/C ratio 
protein/creatinine ratio (performed on urine sample) 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PND 
polyneuropathy disability 
PND Score 
polyneuropathy disability score 
RDA 
recommended daily allowance 
RBP4 
retinol binding protein 4 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous(ly) 
Study Day 1 
defined as the first day Study Drug is administered to the patient 
Study Drug 
ION-682884 or placebo 
SUSARs 
 suspected unexpected serious adverse reactions 
TTR 
transthyretin 
TUCA 
tauroursodeoxycholic acid 
ION-682884 
antisense inhibitor of TTR 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
UTR 
untranslated region 
WOCBP 
woman of child-bearing potential 
 
 
 
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1. 
OBJECTIVES AND ENDPOINTS 
1.1 
Objectives 
1.1.1 
Primary Objectives 
To evaluate the safety and tolerability of single and multiple doses of ION-682884 administered 
subcutaneously to healthy volunteers and patients with hATTR. 
1.1.2 
Secondary Objectives 
To evaluate the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of 
ION-682884 administered subcutaneously to healthy volunteers and patients with hATTR. 
1.1.3 
Exploratory Objectives 
To evaluate the effects in hATTR patients of multiple doses of ION-682884 on the mNIS+7, 
Norfolk QoL, 6MWT, 10MWT, EQ-5d, SF-36, COMPASS, and Amyloidosis-specific QoL. 
1.2 
Study Endpoints 
1.2.1 
Primary Endpoints 
Analysis of safety labs, AEs, concomitant medications, ECG and physical examinations of 
healthy volunteers and patients with TTR amyloidosis following subcutaneously administration 
of single and/or multiple doses of ION-682884. 
1.2.2 
Secondary Endpoints 
Analysis of pharmacokinetic data (plasma PK and urinary excretion) and pharmacodynamic data 
(TTR and RBP4 reduction) in healthy volunteers and patients with TTR amyloidosis following 
subcutaneous administration of single and/or multiple doses of ION-682884. Metabolite 
identification and profiling may be determined in select plasma, urine, and fecal samples. 
Analysis of pharmacodynamic data will determine the change and percent change from Baseline 
in plasma TTR and RBP4 levels following single- and multiple-dose SC administration of Study 
Drug. 
1.2.3 
Additional/Exploratory Endpoints 
Exploratory endpoints for the open-label, hATTR patient cohort are the change from Baseline to 
Week 15 in the: 
• mNIS +7 score 
• Norfolk QOL-DN questionnaire total score 
• 6MWT 
• 10MWT 
• 
EQ-5d 
• SF-36 questionnaire domain scores 
• 
COMPASS-31 questionnaire 
• Amyloidosis-specific QoL questionnaire 
 
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2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
2.1.1 
Disease Background 
Hereditary transthyretin amyloidosis (hATTR) is a progressive, irreversible, and fatal disease. 
Average life expectancy is 3 to 15 years after diagnosis (Gertz 2017; FDA Guidance for Industry 
2005) (pgs 8-9). Patients typically die due to malnutrition and cachexia, renal failure, and 
cardiac disease (Coelho et al. 2008). Hereditary transthyretin amyloidosis is caused by 
mutations in the gene that codes for TTR, a carrier protein for thyroxine and vitamin A. Single- 
point gene mutations destabilize the normal tetrameric structure of the TTR protein, causing its 
dissociation into free monomers. These monomers misfold and subsequently aggregate into 
insoluble, extracellular fibril deposits, causing cell degeneration and death (Quintas et al. 2001; 
Plante-Bordeneuve and Said 2011). 
Aggregation of wild-type transthyretin is also seen to cause lethal disease. Though 
clinically-insignificant amounts of wild-type transthyretin-derived amyloid deposits are routinely 
detected in histological analysis of ventricles in 50% to 80% of patients > 80 years, massive 
accumulation of wild-type transthyretin leads to progressive congestive heart failure referred to 
as wildtype ATTR amyloidosis (wtATTR). Prevalence of wtATTR increases with advancing 
age and is overwhelmingly diagnosed in men aged > 70 years (Ng et al. 2005; Falk 2011). The 
mechanism by which wild-type transthyretin accumulates in the heart with increasing age 
remains unclear. 
In contrast to wtATTR in which amyloid deposits are found primarily in the heart, accumulation 
of amyloid deposits in hATTR occur in multiple organ systems, particularly the nervous system, 
gastrointestinal tract, kidney, and heart. Due to the multiple organ deposition of amyloid, the 
disease has a wide clinical spectrum. The phenotypic presentation of the disease is dependent on 
the pattern of organ involvement. However, historically, hATTR has been divided into 2 major 
phenotypes: Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), when the 
peripheral nerves and gastrointestinal tract are predominantly involved, and hATTR with 
cardiomyopathy (hATTR-CM), when the heart is predominantly involved. 
The worldwide prevalence of hATTR-PN has been estimated at approximately 10,000 patients 
(Coelho et al. 2008). The main clinical manifestations of hATTR-PN are progressive peripheral 
sensorimotor and autonomic neuropathy (Plante-Bordeneuve and Said 2011). Non-specific and 
symmetrical numbness, pain, and temperature sensitivity typically begin in the lower extremities, 
progressing distal to proximal. Motor neuropathy follows within a few years, which affects 
ambulatory status (Coutinho et al. 1980; Sekijima et al. 2009; Plante-Bordeneuve and Said 
2011). Hereditary ATTR-PN is classified into 3 stages based on ambulatory status (Coutinho et 
al. 1980): Stage 1 does not require assistance with ambulation, Stage 2 requires assistance with 
ambulation, and Stage 3 is wheelchair bound. This staging system was used to classify severity 
of disease in patients being considered for enrollment in the pivotal study of ISIS 420915 (CS2). 
Disease severity can also be assessed using the Polyneuropathy Disability (PND) score, which is 
a 5-stage scoring system (Suhr et al. 1996). 
 
 
 
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Life-threatening autonomic dysfunction develops in many patients, affecting the 
cardiocirculatory, gastrointestinal, and genitourinary systems. Symptoms include orthostatic 
hypotension, which can lead to dizziness and frequent falls. Gastrointestinal symptoms include 
diarrhea, severe constipation, alternating diarrhea/constipation, vomiting, and gastroparesis, all 
leading to progressive weight loss. Urinary symptoms, fecal incontinence, and, in men, erectile 
dysfunction may be present (Plante-Bordeneuve and Said 2011). 
Cardiac involvement has been estimated to occur in 80% of transthyretin amyloidosis 
(Plante-Bordeneuve and Said 2011). The age of onset in patients is between 60 and 70 years and 
the mean life expectancy from symptom onset is 5–6 years. In patients with hATTR-CM, 
mutant TTR amyloid fibrils infiltrate the myocardium, with resultant diastolic dysfunction 
progressing to restrictive cardiomyopathy and heart failure (Castano et al. 2015). Conduction 
abnormalities and arrhythmias are also common, and many patients require pacemaker and/or 
defibrillator insertion. Presence of significant cardiomyopathy is associated with poorer 
prognosis. 
Amyloid deposits in the kidney are common and can result in microalbuminuria with progression 
to renal failure in a subset of patients. Symptoms of chronic kidney disease may include lower 
extremity edema, anemia, fatigue and weakness, and decrease in appetite. 
As expected, given the severity of hATTR, there is a significant impact on patients’ and 
caregivers’ QoL (Gertz 2017; Stewart et al. 2013). Caregivers have moderate to high levels of 
fatigue and spend a significant amount of time caring for patients. Hereditary ATTR is 
associated with a substantial disruption in employment rates and work productivity. There is 
also a large mental health burden on both caregivers and patients. 
2.1.2 
Overview of Target – Transthyretin 
The name TTR is derived from transporter of thyroxine and retinol and was formerly known as 
prealbumin. The human TTR gene is over 7 kb in length, has 4 exons, and is found on 
chromosome 18q2.1. It is synthesized primarily in the liver and, to a lesser extent, by the 
choroid plexus and retina. It is secreted as a tetramer by the liver into the plasma as a 55 KD 
protein composed of 4 identical subunits of 14 KD each. A major function of TTR in the plasma 
is to transport retinol (vitamin A) to tissues through the association with retinol binding protein 4 
(RBP4). Retinol is the major circulating form of vitamin A. About 70% of total body retinol is 
stored in the liver and mobilized into the blood stream bound to RBP4 (D'Ambrosio et al. 2011). 
The retinol-RBP4 complex in turn binds to TTR, which prevents the complex from being 
excreted through the kidney. The ratio RBP4:TTR in plasma is around 0.3 in healthy 
individuals, indicating that most of the circulating TTR remains free of RBP4 ligand (Buxbaum 
and Reixach 2009). Besides transporting the retinol-RBP4 complex, TTR also transports 
~15% of plasma thyroxine with the majority of thyroxine transported by either thyroxine binding 
globulin or albumin. Recent evidence has suggested that TTR may also have a neuroprotective 
function in the brain. Brain TTR is produced primarily by the choroid plexus and has been 
proposed to help with nerve regeneration and to play a protective role in the Alzheimer’s disease 
(Buxbaum and Reixach 2009; Fleming et al. 2009) 
 
 
 
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It has been demonstrated that mice treated systemically with a TTR-specific ASO had decreased 
hepatic TTR mRNA levels and serum TTR levels but did not show changes in the expression of 
TTR in the choroid plexus (Benson et al. 2006; Benson et al. 2017). 
 
2.1.3 
Current Therapies 
Current therapeutic strategies to treat hATTR include orthotopic liver transplant (OLT) or 
pharmacotherapy with tafamidis or off-label use of diflunisal, both of which are TTR stabilizers 
that work by preventing dissociation of the tetramer into amyloid-forming monomers (Adams et 
al. 2016). Because most of the amyloidogenic-mutated TTR is secreted by the liver, OLT results 
in rapid disappearance of mutant TTR protein from the serum. However, wild-type TTR protein 
continues to be produced by the donor liver and can deposit in the pre-existing amyloid deposits 
in the tissues after transplantation, leading to continual disease progression and, in some cases, 
accelerating heart disease (Yazaki et al. 2000; Liepnieks and Benson 2007; Yazaki et al. 2007; 
Liepnieks et al. 2010). Younger patients with early disease, Val30Met (V30M) mutation, and 
mild symptoms (typically Stage 1) generally experience better outcomes with OLT. Stage 2 
patients are often not candidates for OLT due to advanced age, cardiac involvement, or other 
health reasons (Herlenius et al. 2004; Stangou and Hawkins 2004). 
In regard to currently-approved therapies, Onpattro (patisiran), a double-stranded small 
interfering RNA (siRNA) product which also works by inhibiting production of TTR protein, is 
approved in the United States for the treatment of the polyneuropathy of hATTR in adults. This 
drug is given IV every 3 weeks after patients are premedicated with high dose dexamethasone. 
Tegsedi (inotersen sodium) is authorized in the European Union, the US and Canada for the 
treatment of Stage 1 or Stage 2 polyneuropathy in adult patients with hATTR. Vyndaqel 
(tafamidis) is indicated for the treatment of ATTR in adult patients with Stage 1 symptomatic 
polyneuropathy to delay peripheral neurological impairment, and is currently approved for use in 
Europe, Japan, and several other countries. In some countries, tafamidis is also indicated for 
patients with more advanced stages of disease (Stage 2 and/or Stage 3). Diflunisal is a NSAID 
that is not currently approved for the treatment of hATTR. Off-label use has been reported in 
patients with Stage 1 and Stage 2 disease (Adams et al. 2016); however, the known 
cardiovascular and renal side effects associated with the NSAID drug class may limit the use of 
this drug in older patients with hATTR-PN or patients with hATTR CM. 
Consequently, there continues to be an unmet medical need for effective, well-tolerated and 
convenient treatments that do not require additional premedication for patients with ATTR (both 
hereditary and wild type) worldwide. 
2.2 
Therapeutic Rationale 
ION-682884 is an antisense drug targeted to human TTR mRNA and its hybridization to the 
cognate TTR mRNA results in the RNase H-mediated degradation of the TTR mRNA, thus 
preventing production of the TTR protein (see Section 2.3). The strategy of treating hATTR 
patients with ION-682884 is to reduce the levels of mutated and wild-type TTR protein secreted 
by the liver, a primary organ for antisense oligonucleotide (ASO) distribution after systemic 
delivery. It should be noted that ASOs are highly charged hydrophilic molecules that do not 
cross the blood brain barrier (Levin et al. 2008) and thus systemic treatment with ION-682884 is 
not predicted to decrease levels of TTR in the brain. It is predicted that decreasing the amount of 
 
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liver-derived TTR protein circulating in the plasma by treatment with ION-682884 will result in 
a decrease in the formation of TTR amyloid fibril deposits, and thus slow or halt disease 
progression. This strategy is a similar strategy to OLT, with the exception that ION-682884 
reduces wild-type protein in addition to the mutated protein. Given that wild-type TTR can 
continue to deposit as amyloid after liver transplant, this distinction may represent a therapeutic 
advantage. 
Clinical trials in patients with hATTR-PN have used the Neuropathy Impairment Score (NIS), or 
derivatives of this score such as the NIS Lower Limb (NIS-LL) or the NIS +7, to assess 
progression of neuropathy. The NIS score was originally developed for assessment of diabetic 
neuropathy and is a quantitative score of motor, sensory, and reflex function as judged by the 
clinician (Dyck et al. 1991). The NIS-LL is a subset of the full NIS and evaluates changes in 
motor, sensory and reflex activity specifically in the lower limbs whereas the full NIS also 
evaluates changes in the upper limbs and cranial nerves. The NIS or NIS-LL scores are 
sometimes combined with the Sum 7 Test (or +7) to give the NIS+7 or NIS-LL+7 composite 
score (Dyck et al. 1997). The +7 Test is an objective score of large fiber function that includes 
measurements of nerve conduction, vibration threshold and heart rate to deep breathing (an 
assessment of autonomic function). Thus, the NIS+7 and NIS-LL+7 scores have the advantage 
of combining a subjective assessment scored by the clinician with objective measurements of 
autonomic and sensory nerve function, which are both affected in patients with hATTR-PN. The 
NIS-LL / NIS-LL+7 score is most appropriate to measure neuropathy progression in early 
Stage 1 hATTR-PN patients. But patients in later Stage 1 and Stage 2 (as is the case for this 
protocol) can reach a ceiling effect on the NIS-LL score, and therefore the full NIS /NIS+7 is a 
more appropriate score for these patients. However, even the NIS+7 may not be optimally 
sensitive for assessment of progression of neuropathy in the target population of this study 
because it is primarily focused on motor function and on large nerve fibers whereas hATTR-PN 
has a significant sensory component and affects both large and small nerve fibers, with a great 
deal of heterogeneity amongst patients in regard to which nerve fiber types are affected (Plante- 
Bordeneuve et al. 2007). Therefore, in this study, progression of neuropathy will be assessed 
using a modified NIS +7 score (mNIS +7), which includes a greater sensory component and 
assesses both large and small nerve fiber function. During the mNIS+7 assessment, the standard 
NIS+7 assessment will also be collected and the NIS+7 will be analyzed as a secondary 
endpoint. The NIS score will be used for selection of the target population (inclusion criteria) 
because there is a greater body of data correlating NIS score with stage of disease. 
The Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire is included 
to assess disease specific changes in the patients’ perceived quality of life. This instrument is a 
nerve fiber-specific, 5-domain tool that has been validated in hATTR-PN patients (Vinik et al. 
2011). In addition, the SF-36 questionnaire is included as a non-disease specific tool to assess 
the patient’s perceived functional health and well-being. 
Many patients with hATTR-PN also have hATTR-CM. There is no widely-accepted method for 
measuring progression of cardiac disease in hATTR-CM. However, recent studies have shown 
that strain imaging with echocardiography or MRI can detect changes within a 1-year time frame 
(Falk 2011; Benson et al. 2017). In addition, the cardiac biomarker N-terminal prohormone of 
brain natriuretic peptide (NT pro-BNP) has been shown to be elevated in patients with cardiac 
amyloidosis due to Primary Amyloidosis and to decline as cardiac function improves following 
 
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removal of the amyloid forming light chain protein with chemotherapy (Palladini et al. 2006). In 
the hATTR patient portion of this study, serum NT-proBNP will be assessed as an endpoint in all 
patients. 
 
2.3 
ION-682884 
2.3.1 
Mechanism of Action 
ION-682884 is a second-generation antisense oligonucleotide (ASO) drug targeted to 
transthyretin, that has been covalently bonded to tri-antennary 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 vs. non-parenchymal cells and has increased ASO potency at least 10-fold in 
mice(Prakash et al. 2014). The ASO portion of ION-682884 is complementary to a region 
within the 3′ untranslated region (3′ UTR) of the transthyretin mRNA and binds to the mRNA by 
Watson-Crick base pairing. The hybridization (binding) of ION-682884 to the cognate mRNA 
results in the RNase H1-mediated degradation of the transthyretin mRNA, thus preventing 
production of the transthyretin protein. Maximal antisense-mediated reduction of target mRNA 
levels is typically greater than 90% of control levels in sensitive tissues (Crooke et al. 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, ION-682884 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphate diester internucleotide linkages, with 
a 5ʹ-Trishexylamino-(THA)-C6GalNAc endcap. The nucleotide sequence of ION-682884 is 
complementary to a 20-nucleotide stretch within the 3′ UTR region of the transthyretin mRNA 
and is the same sequence shown to robustly impact disease progression in hATTR patients (refs). 
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) (MOE)-modified 
ribonucleotides. These MOE-modified nucleotides confer (1) increased affinity to 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 ION-682884 
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 H1 enzyme (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. A fourth region is comprised of a tri-antennary cluster of 
N-acetyl galactosamine (GalNAc) sugars and is linked to the 5ʹ end of ION-682884 via a 
phosphodiester linkage. The GalNAc cluster is a high affinity ligand for the asialoglycoprotein 
 
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receptor (ASGPR), a receptor expressed primarily on the surface of liver hepatocytes (Stockert 
1995). The GalNAc cluster enhances delivery of ION-682884 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). The internucleosidic 
linkages are a mixture of phosphorothioate and phosphodiester. The phosphorothioate linkages 
are introduced into the DNA gap region and at both ends of the oligonucleotide to protect it from 
nuclease mediated metabolism. The mixed backbone design reduces the total number of 
phosphorothioate linkages which reduces non-specific interactions with proteins and further 
enhances potency and therapeutic index of GalNAc conjugated ASOs. 
2.3.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ION-682884 can be 
found in the Investigator’s Brochure. A summary is included below. 
The human TTR ASO, ISIS 420915, was identified from a broad screen of ASOs targeted to 
various regions of the human TTR pre-mRNA. ISIS 420915 was demonstrated to be potent and 
efficacious in reducing human TTR mRNA expression in the human HCC cell line HepG2. 
A 5′-GalNAc-conjugated mixed backbone variant of ISIS 420915, ION-682884, was synthesized 
and evaluated in vitro and in vivo. ION-682884 was found to be significantly more potent than 
the unconjugated parent ASO, ISIS 420915, in inhibiting TTR mRNA expression in human 
hepatocytes in vitro (approximately 51-fold improvement in potency, IC50), with the potential to 
greatly increase the safety margins. 
The activity of human TTR ASO ISIS 420915 has been characterized in both nonhuman 
primates and genetically-modified mice. While the sequence to which ISIS 420915 hybridizes is 
identical for human and cynomolgus monkeys, it is different in rodents. Therefore, human 
TTR transgenic mice were used as a model to test the pharmacologic effects of ISIS 420915. In 
human TTR transgenic mice, the ED50 values for human TTR hepatic mRNA and plasma protein 
reductions were 12.0 and 18.6 mg/kg/wk, respectively, following treatment with ISIS 420915 for 
4 weeks. Treatment of cynomolgus monkeys with 50 mg/kg/wk ISIS 420915 for 12 weeks 
reduced TTR hepatic mRNA and plasma protein levels by approximately 80%. 
ION-682884, which contains the GalNAc conjugate, significantly improved inhibition of human 
TTR hepatic mRNA and plasma protein levels in human TTR transgenic mice (with 28-fold and 
15-fold increase in potency, ED50, respectively), as compared to the unconjugated ASO, which is 
expected for this hepatocyte-expressed target. Treatment of cynomolgus monkeys for 13 weeks 
with 24 mg/kg/wk ION-682884 resulted in 60–70% reduction in TTR hepatic mRNA and plasma 
protein levels. 
These results support the concept that inhibition of TTR through an antisense mechanism may 
serve as an effective strategy to ameliorate TTR-mediated amyloidosis. The results also strongly 
support GalNAc-conjugation to significantly increases ASO potency in inhibiting hepatic mRNA 
and plasma protein with lower doses providing the potential for improved safety. 
2.3.4 
Clinical Experience 
ION-682884 has not been evaluated in any clinical setting. Please refer to the Investigator’s 
Brochure for a detailed description of the preclinical pharmacology, nonclinical toxicology and 
 
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pharmacokinetics, as well as a description of previous clinical experience with other related 
2′-MOE-phosphorothioate oligonucleotides. 
ISIS 420915, also known as inotersen, an unconjugated 2′-O-(2-methoxyethyl) (2′-MOE) ASO 
that has the same base sequence as ION-682884, has been evaluated in clinical studies in more 
than 270 subjects and has shown an acceptable safety profile and clinical efficacy in patient 
populations in terms of clinical pharmacodynamics as well as measurements of primary efficacy 
endpoints mNIS+7 and Norfolk QoL-DN (Benson et al. 2018). 
Significant treatment effect with inotersen on TTR levels was observed throughout the study in 
ISIS 420915-CS2 (Figure 1). In the inotersen group, mean percent changes from Baseline in 
circulating TTR levels decreased steadily through Week 13, which was the time frame when 
drug concentrations in the liver were expected to be approaching steady-state, and then were 
sustained for the (Yu et al. 2016a) duration of the Treatment Period. From Week 13 to Week 65, 
mean decreases in serum TTR ranged from 68.4% to 74.0% (median range: 74.6% to 79.0%) in 
the inotersen group. In the placebo group, mean serum TTR concentration decreased by 8.50% 
at Week 3 and then remained fairly constant throughout the Treatment Period. 
 
Figure 1 
On-Treatment Percent Change from Baseline in TTR over Time 
 
 
Changes from Baseline in mNIS+7 composite score showed a statistically significant difference 
in favor of inotersen compared with placebo at both Week 35 and Week 66. The difference in 
least squares means (LSMs) between treatment groups was -8.69 (95% confidence interval [CI]: 
-13.49, -3.90; p = 0.0005) and -19.73 (95% CI: -26.43, -13.03; p = 0.00000004) at Week 35 and 
Week 66, respectively (Figure 2). Changes from Baseline in Norfolk QoL-DN total score 
showed a statistically significant difference in favor of inotersen compared with placebo at 
both Week 35 and Week 66. The difference in LSMs between treatment groups 
was -6.14 (95% CI: -11.77, -0.52; p = 0.032) and -11.68 (95% CI: -18.29, -5.06; p < 0.0006) 
at Week 5 and Week 66, respectively (Figure 3). 
 
 
 
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Figure 2 
On-Treatment LSM Change from Baseline in mNIS+7 Composite Score 
 
 
Figure 3 
On-Treatment LSM Change from Baseline in Norfolk QoL-DN Total Score 
 
 
Because the GalNAc conjugate approach results in enhanced ASO delivery to hepatocytes vs. 
nonparenchymal cells, thereby resulting in increased ASO potency, it is expected that 
significantly lower doses of ION-682884 will achieve similar target knockdown effects with an 
enhanced safety margin compared to inotersen. 
2.4 
Rationale for Dose and Schedule of Administration 
Estimation of clinical doses for an antisense drug is less difficult than for most drugs in 
preclinical development. The numbers of variables that are normally encountered at this stage of 
development are reduced by the predictability of the pharmacokinetics of ASOs and the 
cumulative experience with other drugs in this class. The pharmacokinetics and disposition of 
many drugs in this class have been characterized and there are remarkable similarities from 
sequence to sequence and across species. In particular, the plasma pharmacokinetics for ASOs 
 
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in monkeys has been highly predictive of those in man. Because distribution to tissues is the 
dominant mechanism for plasma clearance, it can be assumed that plasma pharmacokinetic 
similarities translate into similarities in tissue distribution. This assumption is supported by the 
knowledge that patterns of tissue distribution for oligonucleotides are similar in mice, rats, 
rabbits, dogs and monkeys. Thus, it is possible to predict dose regimens on the basis of 
concentrations at the primary site of activity, the liver. Additionally, ASOs are hydrophilic and 
distribute predominantly to the lean body mass and in our experience, they should be 
administered as a fixed dose, rather than by total body weight. 
Kidney and liver concentrations of ION-682884 collected after 13 weeks of dosing during a 
monkey toxicology study indicate that tissue distribution for this compound is consistent with 
previously administered antisense oligonucleotides. Post-distribution plasma concentrations 
(i.e., terminal elimination phase) of ION-682884 are expected to be in equilibrium with tissue 
concentrations in humans, as was observed in monkeys, mice, and rats for similar 2′-MOE 
gapmers with and without GalNAc-conjugation (Geary et al. 2003; Yu et al. 2016a; Yu et al. 
2016b). The prolonged half-life of ION-682884 in liver of approximately 4 weeks observed in 
monkeys supports the monthly dosing regimens planned in the clinic. Moreover, this dosing 
schedule has been employed safely in previous clinical studies with a number of other 
phosphorothioate ASOs. Plasma pharmacokinetic analysis from this first clinical study will be 
used to characterize any differences from the nonclinical estimates and to adjust the estimates for 
subsequent clinical studies. 
Safety data from the toxicology studies support a weekly or less frequent dose strategy. In the 
toxicology studies with ION-682884 in mice and monkeys, no clinical signs of overt toxicities 
were observed after 13 weeks of treatment (Study Nos. 682884-AS01 and -AS02, refer to the 
ION-682884 Investigator’s Brochure). 
The No Observable Adverse Effect Level (NOAEL) for ION-682884 was determined to be 
6 mg/kg/wk (24 mg/kg/month). Pharmacokinetics observed in monkeys for ASOs predict the 
expected exposures in humans on the basis of mg/kg-equivalent doses (Geary et al. 2003; FDA 
Guidance for Industry 2005) (pgs 8-9); (Yu et al. 2007) and not on the basis of body surface area. 
This pharmacokinetic behavior is class-related and has been shown for all ASOs examined to 
date in the same chemical class as ION-682884. Therefore, the dose range of ION-682884 
chosen for this initial study, 45 to 120 mg monthly (approximately 0.7 to 1.7 mg/kg body weight 
in a 70 kg subject), ranges from ~14- to 37-fold below the NOAEL and is considered a safe dose 
range for this trial. 
In addition to the nonclinical experience of ION-682884, this dose range is supported by the 
nonclinical and clinical safety experience of more than 20 other 2′-MOE-modified ASOs 
including inotersen that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg (Kwoh 2008) and for treatment durations that 
exceed 24 months. 
2.5 
Benefit-Risk Assessment 
2.5.1 
Healthy Volunteer Benefit Assessment 
There are no potential benefits for healthy volunteers. 
 
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2.5.2 
Patient Benefit Assessment 
Administration of ION-682884 to patients may reduce the levels of mutated and wild-type TTR 
protein secreted by the liver, the primary source of TTR production and a primary organ for ASO 
distribution after systemic delivery. By decreasing the amount of liver-derived TTR protein 
circulating in the plasma, ION-682884 treatment may likely result in decreased formation of 
TTR amyloid fibril deposits and thus slows or halts disease progression. 
2.5.3 
Healthy Volunteer and Patient Risk Assessment 
The known potential risks to study participants associated with ION-682884 are detailed in the 
Guidance to Investigator section of the Investigator’s Brochure. Study associated potential 
safety considerations include thrombocytopenia, occurrence of glomerulonephritis, and retinol 
deficiency. 
Thrombocytopenia and occurrence of glomerulonephritis are potential considerations based on 
clinical findings with inotersen, the unconjugated form of ION-682884, administered at a dose of 
300 mg/wk. Frequent platelet, UPCR, and renal function monitoring as well as stopping rules 
will be implemented in this study. 
In the event of confirmed platelet count declines ≤ 100,000/mm3, more frequent monitoring will 
be implemented. The frequency of monitoring and additional laboratory tests will be determined 
by the Investigator in consultation with the Sponsor Medical Monitor or designee. In the event 
of a confirmed platelet count < 75,000/mm3, Study Drug (ION-684882 or placebo) should be 
permanently discontinued and additional laboratory investigations will be conducted. Short-term 
steroid use will be recommended if platelet count drops to < 50,000/mm3. This is based on data 
from other programs at Ionis demonstrating that short-term steroid use can improve recovery 
from thrombocytopenia. If the platelet result is unavailable (e.g., due to hemolysis, clumping, 
etc.) it must be repeated and reviewed prior to dosing during the Treatment Period. 
Because TTR binds the retinol-RBP4 complex and prevents its excretion by the kidney, 
decreased plasma TTR levels result in decreased circulating levels of both RBP4 and retinol. 
This has been shown with the naturally occurring TTR Ile84 mutation that disrupts the 
TTR-RBP4-retinol complex and results in low plasma levels of retinol (Waits et al. 1995). 
Prolonged reduction of circulating retinol could result in impaired delivery of retinol to 
peripheral tissues and consequent signs and symptoms of vitamin A deficiency such as night 
blindness, xerophthalmia or retinopathy. However, chylomicrons are believed to provide an 
alternative route of delivery of retinyl esters to peripheral tissues (Wei et al. 1995) and 
chylomicron-delivered retinyl will not be affected by treatment with ION-682884. Indeed, 
preclinical studies utilizing TTR null mice have shown that although the mice have only 5–7% of 
circulating retinol and RBP4 levels compared to wild-type mice, they are viable and fertile, and 
do not show any observable symptoms of vitamin A deficiency (Episkopou et al. 1993; Wei et al. 
1995). In addition, the levels of retinol within tissues such as the liver, kidney, testis and eye 
were similar in the TTR null mouse compared with wild-type controls (Wei et al. 1995). 
Furthermore, the retinal anatomy and function in these mice has been examined in detail with 
little effect found on the retinal structure or function (Bui et al. 2001). In addition, twins have 
been reported in the literature that have a genetic mutation in RBP4 that causes their RBP4 
protein levels to be below the lower limit of quantification and also results in very low plasma 
retinol levels (Biesalski et al. 1999). In addition, mutations in the RBP4 gene have been 
 
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identified in 2 teenage siblings with no detectable serum RBP and retinol levels less than 
20% normal (Biesalski et al. 1999; Seeliger et al. 1999). Despite the low retinol, they have 
normal retinyl esters levels, normal absorption of fat and vitamin A after a meal challenge, and 
they have mild night blindness and a modest retinal dystrophy but no pronounced effects on 
growth or other physiologic functions that are normally affected during vitamin A deficiency. 
Taken together these findings imply that RBP4 is not essential for maintaining adequate tissue 
retinol levels. To address the potential for impaired retinol delivery to tissues, in this study all 
patients will be required to take oral supplementation of the recommended daily allowance 
(RDA) of vitamin A (approximately 3000 IU vitamin A per day). In addition, an ophthalmic 
examination will be performed at Baseline and after approximately 13 weeks Post-Treatment. 
An electroretinogram (ERG) will also be performed at Baseline and at 13 weeks Post-Treatment 
to exclude subclinical tissue retinol deficiency. 
2.5.4 
Overall Assessment of Benefit:Risk 
The measures taken to minimize risk to subjects participating in the healthy volunteer portion of 
this study, include a short duration of exposure, supplementation with vitamin A and frequent 
safety monitoring thus minimizing any potential risk. Additionally, in healthy volunteer studies, 
reductions in TTR have not been associated with any negative safety effects. The potential risks 
identified in association with ION-682884 in hATTR patients are justified by the anticipated 
benefits that may be afforded to those patients. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This will be a Phase 1/2, double-blind, randomized, placebo-controlled, dose-escalation study 
conducted at a single center for the healthy volunteer cohorts and will consist of 1 single-dose 
cohort and 2 multiple-dose cohorts (n = 12 per cohort, 10 active:2 placebo). 
The open-label, hATTR patient cohort portion of the study will be conducted at multiple centers. 
3.1.1 
Healthy Volunteers (Cohorts A, B, C and E) 
Multiple-Dose Cohorts 
 
Cohort 
Number of Doses 
Total ION-682884 
Cohort A: 45 mg ION-682884 or placebo SC 
4 
180 mg 
Cohort B: 90 mg ION-682884 or placebo SC 
4 
360 mg 
 
Subjects enrolled in the multiple-dose, healthy volunteer cohorts will receive SC doses of Study 
Drug once every 4 weeks for a total of 12 weeks (total of 4 doses). Following the administration 
of the 1st dose of Study Drug in each multiple-dose cohort, individual subjects must have 
completed their Day 15 safety evaluations with an acceptable safety profile, as determined by the 
Safety Committee (comprised of the Investigator, the Sponsor Medical Monitor and an 
Independent Safety Monitor), before receiving additional doses of Study Drug. 
 
 
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Dosing in Cohort B can only proceed when at least 8 subjects in Cohort A have completed 
Day 29 safety evaluations and have demonstrated an acceptable safety profile as determined by 
the Safety Committee. 
Additional Multiple-Dose Cohort 
The additional multiple-dose, healthy volunteer cohort (Cohort E) with 4 every-4-week doses of 
60 mg ION-682884 or placebo, was added to further elucidate safety or PD effects of 
ION-682884. 
Dosing in Cohort E can only proceed when at least 8 subjects in Cohort B have completed 
Day 29 safety evaluations and have demonstrated an acceptable safety profile as determined by 
the Safety Committee. 
 
Cohort 
Number of Doses 
Total ION-682884 
Cohort E: 60 mg ION-682884 or placebo SC 
4 
240 mg 
 
For each dose cohort, the first 2 (sentinel) subjects (randomized 1 active:1 placebo) will be 
dosed on the same day. If no major safety concerns are observed following 48 hours of 
observation, as determined by the Safety Committee, dosing of the remaining 10 subjects 
(randomized 9 active:1 placebo) in that cohort may proceed. 
Single-Dose Cohort 
 
Cohort 
Number of Doses 
Total ION-682884 
Cohort C: 120 mg ION-682884 or placebo SC 
1 
120 mg 
 
Dosing in Cohort C can only proceed when at least 8 subjects in Cohort A have completed 
Day 57 safety evaluations and have demonstrated an acceptable safety profile as determined by 
the Safety Committee. 
Subjects enrolled in the single-dose treatment cohort will receive a single SC dose of the Study 
Drug (ION-682884 or placebo) on Day 1. The first 2 (sentinel) subjects (randomized 
1 active:1 placebo) will be dosed on the same day. If no major safety concerns are observed 
following 48 hours of observation, as determined by the Safety Committee, dosing of the 
remaining 10 subjects (randomized 9 active:1 placebo) in that cohort may proceed. 
 
 
 
 
 
 
 
 
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3.1.2 
hATTR Patients (Cohort D) 
This portion of the study will be multi-center and open-label and consists of 1 multiple-dose 
cohort with the dose level to be selected based upon on the results of the MAD cohorts in healthy 
volunteers. 
 
Cohort 
Number of Doses 
Total ION-682884 
Cohort D: ≤ 120 mg ION-682884 
4 
≤ 480 mg 
 
Patients will receive SC doses of ION-682884 once every 4 weeks for a total of 12 weeks (total 
of 4 doses). Following the administration of the 1st dose of ION-682884, patients must have 
completed their Day 15 safety evaluations with an acceptable safety profile, as determined by the 
Safety Committee, before receiving additional doses of ION-682884. 
3.2 
Number of Study Centers 
The healthy volunteer portion of the study will be conducted at a single center and the hATTR 
patient portion of the study will be conducted at multiple centers in Canada. 
3.3 
Number of Subjects 
Approximately 36 healthy volunteers were planned to be enrolled in this study. Twenty-four 
(24), in the 2 planned multiple-dose cohorts and 12 subjects in the single-dose cohort. An 
additional multiple-dose cohort, Cohort E (n = 12), was added resulting in a total of 
approximately 48 healthy volunteers. If individual cohorts are expanded, a maximum enrollment 
of 60 subjects will be enrolled in the healthy volunteer, Phase 1 portion of the study. 
Approximately 20 hATTR patients will be enrolled in the multi-dose, open-label, Phase 2 
portion of the study. Additional patients may be added to better assess the safety, tolerability, 
pharmacokinetic and pharmacodynamic of ION-682884 to meet study objectives. Maximum 
enrollment will be limited to 30 hATTR patients. 
The dosing cohorts are designed to assess the safety, tolerability, pharmacodynamics and 
pharmacokinetics of Study Drug (ION-682884 or placebo). The sample sizes are selected to 
ensure that the safety and tolerability of ION-682884 will be adequately assessed while 
minimizing unnecessary subject exposure. 
3.4 
Overall Study Duration and Follow-up 
The study will consist of Screening, Treatment, and Post-Treatment Follow-up Periods. Please 
refer to the Schedule of Procedures in Appendix A. 
Single-Dose Cohort (Cohort C) 
The length of each subject’s participation in Cohort C is approximately 17 weeks, including a 
4-week Screening Period, a single-dose on Day 1 and 13 weeks of Post-Treatment Follow-up. 
Subjects will return for outpatient visits as outlined in Appendix A. 
 
 
 
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Multiple-Dose Cohorts (Cohorts A, B, D and E) 
The length of each subject’s participation in Cohorts A, B, D and E is approximately 29 weeks, 
including a 4-week Screening Period, a 12-week Treatment Period, and a 13-week 
Post-Treatment Evaluation Period. Subjects will receive a total of 4, once every 4 weeks, fixed 
SC doses of ION-682884. 
At the end of the Treatment Period, eligible hATTR patients may elect to enroll in an open-label 
extension (OLE) study pending study approval by the IRB/IEC and the appropriate regulatory 
authority. Patients not participating in the OLE will enter the 13-week Post-Treatment 
Evaluation portion of this study unless consent is withdrawn. 
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. 
3.4.1 
Screening and Baseline Assessments 
Healthy Volunteers (Cohorts A, B, C and E) 
Subject eligibility for the healthy volunteer portion of the study will be determined within 
4 weeks prior to study entry. 
hATTR Patients (Cohort D) 
For the hATTR patient portion of the study, a period of 6 weeks is given to complete the 
screening and baseline assessments outlined in the schedule of procedures. The baseline 
assessments should ideally be conducted after patient eligibility has been determined. 
3.4.2 
Treatment 
Healthy Volunteers (Cohorts A, B, C and E) 
Single-Dose 
Eligible participants for Cohort C will report to the Study Center on Day -1 for study treatment 
on Day 1. There are 2 overnight stays in the clinic (Day -1 and Day 1). On Day 1, participants 
will receive a single SC dose of the Study Drug (ION-682884 or placebo). Please refer to the 
Schedule of Procedures in Appendix A for details on Study Day visits during the Treatment 
Period. 
Multiple-Dose 
Eligible participants in the multiple-dose Cohorts A, B and E will report to the Study Center on 
Day -1 for study treatment on Day 1. There are 3 overnight stays in the clinic (Day -1, Day 1, 
and Day 85). Participants will receive a SC dose of the Study Drug (ION-682884 or placebo) 
once every 4 weeks and will report to the Study Center for assessments at regular intervals 
throughout the Treatment Period. Please refer to the Schedule of Procedures in Appendix A for 
details on Study Day visits during the Treatment Period. 
 
 
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hATTR Patients (Cohort D) 
Eligible participants in the multiple-dose Cohort D will report to the Study Center on Day -1 for 
study treatment on Day 1. There is 1 overnight stay in the clinic on Day -1. Participants will 
receive a SC dose of the ION-682884 once every 4 weeks and will report to the Study Center for 
assessments at regular intervals throughout the Treatment Period. Please refer to the Schedule of 
Procedures in Appendix A for details on Study Day visits during the Treatment Period. 
3.4.3 
Post-Treatment 
Healthy Volunteers (Cohorts A, B, C and E) 
Subjects will report to the Study Center for assessments at regular intervals throughout the 
Post-Treatment Period. Please refer to the Schedule of Procedures in Appendix A for details on 
Study Day visits. 
hATTR Patients (Cohort D) 
Patients will report to the Study Center for assessments at regular intervals throughout the 
Post-Treatment Period. Please refer to the Schedule of Procedures in Appendix A for details on 
Study Day visits. Alternatively, at the end of the Treatment Period, eligible patients may elect to 
enroll in an OLE study pending study approval by the IRB/IEC and the appropriate regulatory 
authority. 
3.5 
End-of-Study 
The End-of-Study is defined as the date of the last visit of the last subject remaining in the study. 
3.6 
Safety Committee 
A Safety Committee, comprised of the Investigator, the Sponsor Medical Monitor and an 
Independent Safety Monitor, will assess the safety and tolerability of the Study Drug 
(ION-682884 or placebo) throughout the study. 
In addition, the Safety Committee will formally meet to determine whether: 
• The safety and tolerability profile of the sentinel subjects in a cohort supports the dosing 
of the remaining subjects of that cohort 
• The safety and tolerability profile of subjects after their Day 15 safety evaluations 
supports their receiving the remaining 3 doses of Study Drug 
• The safety and tolerability profile of subjects in a cohort supports dose escalation to a 
higher-dose cohort 
 
 
 
 
 
 
 
 
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Safety Committee Meeting Schedule 
 
Meeting # 
Question for the Safety Committee 
Data to be Reviewed 
Allowed Action 
1 
Does the safety and tolerability profile of 
the sentinel subjects in Cohort A support 
the dosing of the remaining subjects in the 
cohort? 
Observation of sentinel 
subjects for 48 hours post- 
dose to ensure no major safety 
or tolerability issues 
Dosing of remaining 
10 subjects in 
Cohort A 
2 
Have subjects in Cohort A completed their 
Day 15 safety evaluations with an 
acceptable safety profile and tolerability? 
Day 15 safety and lab 
evaluations for subjects in 
Cohort A 
Administration of 
remaining 3 doses of 
Study Drug to 
subjects in Cohort A 
3 
Have at least 8 subjects in Cohort A 
completed Day 29 safety evaluations and 
demonstrated an acceptable safety 
profile? 
Day 29 safety and lab 
evaluations for at least 
8 Cohort A subjects 
Dosing of 2 sentinel 
subjects in Cohort B 
4 
Does the safety and tolerability profile of 
the sentinel subjects in Cohort B support 
the dosing of the remaining subjects in the 
cohort? 
Observation of sentinel 
subjects for 48 hours post- 
dose to ensure no major safety 
or tolerability issues 
Dosing of remaining 
10 subjects in 
Cohort B 
5 
Have subjects in Cohort B completed their 
Day 15 safety evaluations with an 
acceptable safety profile and tolerability? 
Day 15 safety and lab 
evaluations for subjects in 
Cohort B 
Administration of 
remaining 3 doses of 
Study Drug to 
subjects in Cohort B 
6 
Have at least 8 subjects in Cohort A 
completed Day 57 safety evaluations and 
demonstrated an acceptable safety 
profile? 
Day 57 safety and lab 
evaluations for at least 
8 Cohort A subjects 
Dosing of 2 sentinel 
subjects in Cohort C 
7 
Does the safety and tolerability profile of 
the sentinel subjects in Cohort C support 
the dosing of the remaining subjects in the 
cohort? 
Observation of sentinel 
subjects for 48 hours post- 
dose to ensure no major safety 
or tolerability issues 
Dosing of remaining 
10 subjects in 
Cohort C 
8 
Have at least 8 subjects in Cohort B 
completed Day 29 safety evaluations and 
demonstrated an acceptable safety 
profile? 
Day 29 safety and lab 
evaluations for at least 
8 Cohort B subjects 
Dosing of 2 sentinel 
subjects in additional 
Cohort E 
9 
Does the safety and tolerability profile of 
the sentinel subjects in Cohort E support 
the dosing of the remaining subjects in the 
cohort? 
Observation of sentinel 
subjects for 48 hours post- 
dose to ensure no major safety 
or tolerability issues 
Dosing of remaining 
10 subjects in 
Cohort E 
10 
Have subjects in Cohort E completed their 
Day 15 safety evaluations with an 
acceptable safety profile and tolerability? 
Day 15 safety and lab 
evaluations for subjects in 
Cohort E 
Administration of 
remaining 3 doses of 
Study Drug to 
subjects in Cohort E 
11 
Have at least 8 subjects in Cohort B 
completed the Treatment Period (4 x 
90 mg) and demonstrated an acceptable 
safety profile? 
Safety and lab evaluations for 
at least 8 Cohort B subjects 
who completed the Treatment 
Period 
Dosing of patients in 
Cohort D 
12 
Have patients in Cohort D completed their 
Day 15 safety evaluations with an 
acceptable safety profile and tolerability? 
Day 15 safety and lab 
evaluations for patients in 
Cohort D 
Administration of 
remaining 3 doses of 
ION-682884 to 
patients in Cohort D 
 
 
 
 
 
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3.7 
Data and Safety Monitoring Board or Independent Data Monitoring Committee 
An independent Data and Safety Monitoring Board (DSMB) will be assembled for Cohort D, the 
hATTR patient cohort of ION-682884-CS1. The DSMB will review the safety and tolerability 
of ION-682884 during Cohort D of the study at a frequency and duration as outlined in the 
Safety Management Plan and DSMB Charter. 
3.8 
Dose Escalation 
Healthy Volunteers (Cohorts A, B, C and E) 
Dosing of Cohort B (4 x 90 mg ION-682884 or placebo) can only proceed when at least 
8 subjects in Cohort A (4 x 45 mg ION-682884 or placebo) have completed Day 29 safety 
evaluations and have demonstrated an acceptable safety profile as determined by the Safety 
Committee. 
Dosing of Cohort C (1 x 120 mg ION-682884 or placebo) can only proceed when at least 
8 subjects in Cohort A (4 x 45 mg ION-682884 or placebo) have completed Day 57 safety 
evaluations and have demonstrated an acceptable safety profile as determined by the Safety 
Committee 
Dosing of the additional multiple-dose cohort, Cohort E, (4 x 60 mg ION-682884 or placebo) 
can only proceed when at least 8 subjects in Cohort B have completed Day 29 safety evaluations 
and have demonstrated an acceptable safety profile as determined by the Safety Committee. 
hATTR Patients (Cohort D) 
Enrollment in Cohort D (4 x ≤ 120 mg ION-682884) can only proceed when at least 8 subjects in 
Cohort B (4 x 90 mg ION-682884 or placebo) have completed the Treatment Period and have 
demonstrated an acceptable safety profile as determined by the Safety Committee. 
The dose level for Cohort D will be informed by safety and PD data from the multiple-dose, 
healthy volunteer cohorts. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before subjects may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written institutional review board (IRB) approval of the protocol, informed consent form, and all 
other subject information and/or recruitment material. 
Subjects or their legally acceptable representatives must sign the 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 re-used. 
 
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4.2 
Randomization/Registration 
Subjects will be randomized (Cohorts A, B, C and E) or registered (Cohort D) after all Baseline 
and 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 
randomization or registration and assignment of a unique subject identification number. 
Within each single- and multiple-dose cohort, subjects will be randomized 10:2 to receive 
ION-682884 or placebo as outlined in Section 3.1. The Sponsor will prepare the randomization 
list. 
4.3 
Replacement of Subjects 
Subjects withdrawn early from the study before completion of Day 8 assessments (Cohort C) or 
who do not complete all scheduled doses of Study Drug (ION-682884 or placebo) (Cohorts A, B 
and E) may be replaced at the discretion of the Sponsor unless the Safety Committee agree that 
this should not be done for reasons of safety. The additional subjects will be assigned to the 
same Study Drug (ION-682884 or placebo) as the subjects who are being replaced. 
Subjects whose randomization code has been broken will not be replaced. 
Hereditary transthyretin amyloidosis patients who withdraw from the study will not be replaced 
but will be encouraged to complete the 13-week, Post-Treatment Evaluation Period. 
4.4 
Unblinding of Treatment Assignment 
For the healthy volunteer portion of the study, all subjects, monitors, and Study Center personnel 
related to the study, except for the pharmacist (or qualified designee) who dispenses/prepares the 
Study Drug (ION-682884 or placebo) and the pharmacy monitor (and pharmacy monitor report 
reviewer if applicable) who monitors the pharmacy records and procedures, will be blinded 
throughout the study. Sponsor personnel directly involved with the conduct of the study will 
also remain blinded throughout the study. However, if a subject has suffered a Serious Adverse 
Event (as defined in Section 9.3.3), and/or when knowledge of the treatment assignment will 
impact the clinical management of the subject, the Investigator will have the ability to unblind 
the treatment assignment for that subject. The Sponsor will be informed of the unblinding of a 
subject within 24 hours. An unblinded randomization schema will be maintained securely at the 
Study Center and the Sponsor’s designated vendor. In addition, all SUSARs will be unblinded 
by the Sponsor for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendices A and B) prior to unblinding, as knowledge of the treatment arm 
could influence subject assessment. 
For each healthy volunteer cohort, an unblinded interim analysis of may be performed upon 
completion of dosing for that cohort to assess pharmacodynamic effect, and the results 
summarized by treatment group. 
 
 
 
 
 
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5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates for the healthy volunteer portion of the study 
(Cohorts A, B, C and E) must meet the following eligibility criteria at within 28 days of Day 1 or 
at the time point specified in the individual eligibility criterion listed. 
5.1 
Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
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. Healthy males or females of non-childbearing potential, aged 18 to 65 inclusive at the 
time of informed consent 
3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or 
post-menopausal (defined as 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the laboratory 
involved 
Males must be surgically sterile or abstinent*, if engaged in sexual relations with a 
female of child-bearing potential, the subject must be using an acceptable contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent form until 
at least 91 days (single-dose cohorts) or 13 weeks (multiple-dose cohorts) after the last 
dose of Study Drug (ION-682884 or placebo) 
* 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. 
4. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight 
training, intense aerobics classes etc.) for at least 72 hours prior to study visits 
5. Weight ≥ 50 kg and BMI < 32 kg/m2 
6. Willingness to take vitamin A supplements 
5.2 
Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C and E) 
1. Clinically-significant abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of Screening, major surgery within 3 months of Screening) or 
physical examination 
2. Screening laboratory results as follows, or any other clinically-significant abnormalities 
in screening laboratory values that would render a subject unsuitable for inclusion 
• Random spot urine protein/creatinine (P/C) ratio (UPCR) ≥ 200 mg/g. In the event of 
P/C ratio (UPCR) above this threshold ineligibility may be confirmed by a repeat 
random spot UPCR ≥ 200 mg/g or a 24-hr urine ≥ 200 mg/24 hr 
• 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 
 
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• ALT, AST, bilirubin, alkaline phosphatase, serum creatinine, BUN > ULN 
• Fasting blood glucose > ULN 
• Platelet count < LLN 
3. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
4. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
5. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. 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. 
8. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
9. Previous treatment with an oligonucleotide (including siRNA) within 4 months of 
Screening if single dose received, or within 12 months of Screening if multiple doses 
received 
10. History of bleeding diathesis or coagulopathy 
11. Regular use of alcohol within 6 months prior to screening (> 7 drinks/wk for females, 
> 14 drinks/wk for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of 
beer or 1.5 ounces (45 mL) of hard liquor), or use of soft drugs (such as marijuana) 
within 3 months prior to screening, or hard drugs (such as cocaine and phencyclidine) 
within 1 year prior to screening, or positive urine drug screen at Screening 
12. Concomitant medication restrictions including OTC and herbal remedies, other than 
occasional acetaminophen (paracetamol) or ibuprofen unless authorized by the Sponsor 
Medical Monitor 
13. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first 
dose of Study Drug (ION-682884 or placebo) and regular clinical monitoring is 
performed 
14. Smoking limitations: Smoking >10 cigarettes a day 
15. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 
60 days of Screening 
16. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the subject unsuitable for inclusion, or could interfere with the subject participating 
in or completing the Study 
 
 
 
 
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5.3 
Inclusion Criteria for hATTR Patients (Cohort D) 
To be eligible to participate in this study cohort candidates must meet the following eligibility 
criteria within 6 weeks of Study Day 1, or at the time point specified in the individual eligibility 
criterion listed. 
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. Aged 18 to 82 years at the time of informed consent. 
3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or 
post-menopausal (defined as 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the laboratory 
involved 
Males must be surgically sterile or abstinent*, if engaged in sexual relations with a 
female of child-bearing potential, the subject must be using 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 ION-682884. 
* 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. 
4. hATTR-PN as defined by: 
a. Polyneuropathy Disability (PND) Stage I-III 
b. Documented genetic mutation in the TTR gene 
c. Symptoms consistent with polyneuropathy as measured by NIS score > 5 
d. Willingness to take vitamin A supplements 
5. BMI > 16 kg/m2 
 
5.4 
Exclusion Criteria for hATTR Patients (Cohort D) 
1. Clinically-significant abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of Screening, major surgery within 3 months of Screening) or 
physical examination 
2. Screening laboratory results as follows, or any other clinically-significant abnormalities 
in screening laboratory values that would render a subject unsuitable for inclusion 
• ALT/AST > 1.9 x ULN 
• Bilirubin ≥ 1.5 x ULN (patients with bilirubin ≥ 1.5 x ULN may be allowed on study 
following discussion with the Study Medical Monitor if indirect bilirubin only is 
elevated, ALT/AST is not greater than the ULN and genetic testing confirming 
Gilbert’s disease) 
• Platelets < 125 x 109/L 
 
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• Urine protein/creatinine (P/C) ratio (UPCR) ≥ 1000 mg/g. In the event of P/C ratio 
(UPCR) above this threshold ineligibility may be confirmed by a repeat random spot 
UPCR ≥ 1000 mg/g or a 24-hr urine ≥ 1000 mg/24 hr 
• Renal insufficiency as defined by estimated creatinine clearance calculated according 
to the formula of CKD-EPI < 45 mL/min/1.73 m2 at Screen. If the calculated 
creatinine clearance is thought to be artificially low, a 24-hr urine creatinine clearance 
can be completed with prior Sponsor approval 
• TSH values outside normal range (unless approved by the Study Medical Monitor) 
3. Serum retinol level at Screen < LLN 
For patients with a TTR mutation at position 84 (e.g., Ile84Ser or Ile84Asn) and 
retinol < LLN the exclusion criterion is signs or symptoms of vitamin A deficiency (such 
as dry eye, bitots’ spot observed in the ophthalmology exam, that in the opinion of the 
ophthalmologist is consistent with vitamin A deficiency) 
4. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
5. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
6. Known history of or positive test for HIV, hepatitis C or chronic hepatitis B 
7. Uncontrolled hypertension (BP > 160/100 mm Hg) 
8. 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. Patients with a history 
of other malignancies that have been treated with curative intent and which have no 
recurrence within 5 years may also be eligible if approved by the Sponsor Medical 
Monitor 
9. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer. Does not 
apply to tafamidis, diflunisal, doxycycline or TUCA if subject has been on a stable dose 
of drug for ≥ 3 months and continues receiving the same dose for the duration of the 
study 
10. Previous treatment with an oligonucleotide (including siRNA) within 3 months of 
Screening 
11. Karnofsky performance status ≤ 50 
12. Diagnosis of type 1 or type 2 diabetes for equal or more than 5 years; Screening 
HbA1c > 9.5%; or history of severe peripheral neuropathy due to diabetes 
13. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease) 
14. Prior liver transplant or anticipated liver transplant within 1-yr of Screening 
15. New York Heart Association (NYHA) functional classification of ≥ 3 
16. NT-proBNP > 3000 
 
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17. Acute coronary syndrome or major surgery within 3 months of Screening 
18. Known Primary Amyloidosis 
19. Known Leptomeningeal Amyloidosis 
20. Known Multiple Myeloma 
21. Monoclonal gammopathy of undetermined significance (MGUS) unless serum M protein 
level of < 3 g/dL, < 10% clonal plasma cells in the bone marrow, urine monoclonal 
protein < 500 mg/24 hrs and no evidence of end-organ damage 
22. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the subject unsuitable for inclusion, or could interfere with the subject participating 
in or completing the Study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B and C. 
The safety of ION-682884 will be continually monitored throughout the trial by the Safety 
Committee. In addition, a Data and Safety Monitoring Board (DSMB) will be assembled for the 
hATTR patient cohort of this study to review safety, tolerability and efficacy (as needed) data 
collected on ION-682884. Based on its ongoing assessment of the safety and tolerability of 
ION-682884, the DSMB will provide recommendations to the Sponsor for modifying, stopping 
or continuing the hATTR patient cohort as planned. 
6.1.1 
Study Schedule for the Healthy Volunteers (Cohorts A, B, C and E) 
The length of each subject’s participation in Cohort C is up to approximately 17 weeks including 
a 4-week Screening Period and a 13-week Post-Treatment Evaluation Period. 
The length of each subject’s participation in Cohorts A, B and E is up to approximately 
29 weeks, including a 4-week Screening Period, a 12-week (4-dose) Treatment Period, and a 
13-week Post-Treatment Evaluation Period. 
6.1.1.1 
Screening Period 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures. A 28-day 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, height and weight for BMI determination, and have blood and urine 
samples taken for clinical laboratory testing. Subjects will be screened for HIV, hepatitis B 
antigen, and hepatitis C antibody, as well as for drug and alcohol use. 
Blood chemistry samples during screening should be taken after fasting for at least 8 hrs. 
 
 
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6.1.1.2 
Treatment Period 
Single-Dose 
Subjects in Cohort C will be admitted to the Study Center on the evening prior to the single-dose 
administration (Day -1) and remain at the Study Center until discharge on Day 2 (2 overnight 
stays). Study Drug (ION-682884 or placebo) will be given on Day 1. The first 2 (sentinel) 
subjects (randomized 1 active:1 placebo) will be dosed on the same day. If no major safety 
concerns are observed following 48 hours of observation, as determined by the Safety 
Committee, dosing of the remaining 10 subjects (randomized 9 active:1 placebo) in that cohort 
may proceed. 
Dosing of Cohort C (1 x 120 mg ION-682884 or placebo) can only proceed when at least 
8 subjects in Cohort A have completed Day 57 safety evaluations and have demonstrated an 
acceptable safety profile as determined by the Safety Committee. 
Multiple-Dose 
The Treatment Period for all subjects in Cohorts A, B and E consists of 4 doses administered 
once every 4 weeks over the course of 13 weeks. Eligible subjects will be admitted to the Study 
Center on the evening prior to the first Study Drug administration (Day -1) and remain at the 
Study Center until discharge on Day 2 (2 overnight stays). Study Drug will be given on Day 1. 
For the last dose on Day 85, subjects will be admitted to the Study Center and remain until 
discharge on Day 86 (1 overnight stay). 
Dosing of Cohort B (4 x 90 mg ION-682884 or placebo) can only proceed when at least 
8 subjects in Cohort A (4 x 45 mg ION-682884 or placebo) have completed Day 29 safety 
evaluations and have demonstrated an acceptable safety profile as determined by the Safety 
Committee. 
Dosing of the additional multiple-dose cohort, Cohort E, (4 x 60 mg ION-682884 or placebo) 
can only proceed when at least 8 subjects in Cohort B have completed Day 29 safety evaluations 
and have demonstrated an acceptable safety profile as determined by the Safety Committee. 
6.1.1.3 
Post-Treatment Period 
Single-Dose 
Subjects in Cohort C will be followed until Day 92. Subjects in Cohort C will return for 
outpatient visits on Days 3, 4, 8, 15, 29, 50, 71, and 92 for safety and clinical laboratory 
evaluations and for blood sampling for PK analysis. 
Multiple-Dose 
Subjects in Cohorts A, B and E will be followed until Day 176. During the Post-Treatment 
Evaluation Period, subjects will return to the Study Center for outpatient visits on Days 92, 99, 
113, 127, 141, 155, and 176 for safety and clinical laboratory evaluations and for blood sampling 
for PK analysis. 
 
 
 
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6.1.2 
Study Schedule for hATTR Patients (Cohort D) 
The length of each subject’s participation in Cohort D is up to approximately 29 weeks, 
including a 4-week Screening Period, a 12-week (4-dose) Treatment Period, and a 13-week 
Post-Treatment Evaluation Period. 
6.1.2.1 
Screening and Baseline 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form. A 6-week period is given to perform the screening evaluations and 
baselines assessments which must be completed before Study Day 1. The TTR genotyping and 
amyloid biopsy tests may be conducted up to 10 weeks prior to Study Day 1. These tests are 
only conducted if appropriate documentation is not already available. The baseline assessments 
should ideally be performed after patient eligibility has been determined. An abnormal screening 
result may be retested for review by the Study Medical Monitor for eligibility purposes. 
A NIS assessment is performed at Screening to determine patient eligibility only. This 
assessment does not include the +7 components. 
The baseline assessment for mNIS+7 must be performed twice and the 2 assessments must be 
performed on separate days and within 14 days prior to the first dose of ION-682884 (Day 1). In 
addition, every effort should be made to conduct the 2 assessments < 7 days apart. If the ERG or 
ophthalmology examination are to be performed on a mNIS+7 assessment day, they must be 
performed after the mNIS+7 assessment is complete. The mNIS+7 assessment procedure 
includes the NIS, +7, and additional sensory and nerve conduction testing. The NSC score is 
collected during the NIS assessment procedure but is analyzed separately. 
For a visit where the Norfolk QOL-DN questionnaire is to be administered, it must be the first 
assessment performed at the visit. Administration of the baseline Norfolk QOL-DN 
questionnaire should be done on the same day as the first mNIS+7 assessment, but prior to the 
mNIS+7 assessment. 
For an individual patient, every effort should be made to ensure the same NIS evaluator performs 
all of the NIS assessments throughout the study. In addition, the NIS evaluator must be insulated 
from the patient’s general study procedures and knowledge of the patient’s adverse events. 
6.1.2.2 
Treatment Period 
The Treatment Period for patients in Cohort D consists of 4 doses administered once every 
4 weeks over the course of 13 weeks. Eligible subjects will be admitted to the Study Center on 
the evening prior to the first ION-682884 administration (1 overnight stay). ION-682884 will be 
given on Day 1. 
Enrollment in Cohort D (4 x ≤ 120 mg ION-682884) can only proceed when at least 8 subjects in 
Cohort B (4 x 90 mg ION-682884 or placebo) have completed the Treatment Period and have 
demonstrated an acceptable safety profile as determined by the Safety Committee. 
Dose level for Cohort D will be informed by PD data from Cohort A (4 x 45 mg doses), Cohort 
B (4 x 90 mg doses) and the additional healthy volunteer cohort, Cohort E, (4 x 60 mg 
 
 
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ION-682884) in conjunction with an acceptable safety profile in all cohorts as determined by the 
Safety Committee. 
 
6.1.2.3 
End-of-Treatment Efficacy Assessment Period 
The end-of-treatment (EOT) efficacy assessments are conducted on Week 15. 
The EOT efficacy assessments should also be performed on patients that terminate from 
treatment early. In this case, the early termination visit and EOT efficacy assessments should be 
performed at the same time. 
6.1.2.4 
Post-Treatment Period 
Subjects in Cohort D will be followed until Day 176. During the Post-Treatment Evaluation 
Period, subjects will return to the Study Center for outpatient visits on Days 92, 99, 113, 127, 
141, 155, and 176 for safety and clinical laboratory evaluations and for blood sampling for 
PK analysis. 
6.2 
Study Assessments 
6.2.1 
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-hr urine collection) 
should be taken after fasting for at least 8 hours. During this time the patient can drink water and 
they should ensure that they consume sufficient water in order to not become dehydrated. 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to 
clumping, hemolysis or quantity not sufficient) or missing, a repeat blood specimen should be 
re-drawn as soon as possible (ideally within 7 days). 
6.2.2 
Congestive Heart Failure 
Any patient that develops signs, symptoms or test results suggestive of new onset or worsening 
(if pre-existing) congestive heart failure should have the following evaluations performed (in 
addition to any tests deemed to be necessary by the attending physician) as soon as possible and 
the Investigator should consider referral to a cardiologist: 
• Chest x-ray 
• 12 lead ECG 
• Echocardiogram 
6.2.3 
Arrhythmias 
Any patient that develops signs, symptoms or test results suggestive of new cardiac arrhythmia 
should have the following evaluations performed (in addition to any tests deemed to be necessary 
 
 
 
 
 
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by the attending physician) as soon as possible and the Investigator should consider referral to a 
cardiologist: 
• 12 lead ECG 
• Echocardiogram 
6.2.4 
Myocardial Ischemia 
Any patient that develops signs, symptoms or test results suggestive of myocardial ischemia 
should have the following evaluations performed (in addition to any tests deemed to be necessary 
by the attending physician) and the Investigator should consider referral to a cardiologist: 
• Serial 12 lead ECGs 
• Serial cardiac enzyme evaluation (CKMB, cardiac troponin I or cardiac troponin T) 
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
Male subjects must refrain from sperm donation and either be abstinent† or, if engaged in sexual 
relations with a woman of child-bearing potential (WOCBP), the subject or the subject’s 
non-pregnant female partner must use a highly effective contraception method from the time of 
signing the informed consent form until at least 13 weeks after their last dose of Study Drug. 
Highly effective contraception for the male subject comprises a vasectomy with negative semen 
analysis at Follow-up. Highly-effective contraception for WOCBP partners of male subjects 
comprises surgical sterilization (e.g., bilateral tubal occlusion), hormonal contraception 
associated with inhibition of ovulation (combined estrogen and progestogen containing, or 
progestogen-only), intrauterine contraception device or intrauterine hormone-releasing system 
(IUS). Male subjects with partners that are pregnant must use condoms to ensure that the fetus is 
not exposed to the Study Drug. 
† Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of study 
participation) 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 2 can result in either or both products failing. 
6.3.2 
Other Requirements 
Subjects must refrain from taking strenuous exercise/activity (for example heavy lifting, weight 
training, intense aerobics classes etc.) for at least 72 hours prior to study visits. 
All subjects will be required to fast for at least 8 hours before a blood sample is taken for the 
pharmacodynamic and retinol assessments. 
 
 
 
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7. 
STUDY DRUG 
7.1 
Study Drug Description 
7.1.1 
ION-682884 
A solution of ION-682884 (150 mg/mL, 0.8 mL) contained in 2-mL stoppered glass vials and its 
storage and preparation instructions will be provided by the Sponsor. ION-682884 must be 
stored securely at 2–8 °Celsius and be protected from light. 
7.1.2 
Placebo 
The placebo for this study is 0.9% sterile saline and will be provided by the Study Center. 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged ION-682884 labeled in accordance 
with specific country regulatory requirements. Placebo will be provided by the Study Center. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
ION-682884 supplies provided by the Sponsor according to Sponsor instruction and in 
accordance with institutional policy. 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
ION-682884 solution and placebo will be prepared by an unblinded pharmacist (or qualified 
delegate) shortly before use, using aseptic technique. Vials are for single-use only. Study staff 
supporting the healthy volunteer portion of the study will be blinded to the identity of the drug. 
Doses of 45, 60, 90 and 120 mg will be administered as a single SC injection at the Study Center. 
Volumes to be administered are shown in Table 1. Please refer to the Study Drug Manual 
provided by the Sponsor for more detailed instructions for Study Drug (ION-682884 or placebo) 
preparation and administration. 
Table 1 
Study Drug Dosing Information 
 
Cohort 
Volume to 
Administer 
Dose per Injection 
Number of 
Doses 
Total Dose 
Cohort A 
0.3 mL 
45 mg ION-682884 or placebo 
4 
180 mg 
Cohort B 
0.6 mL 
90 mg ION-682884 or placebo 
4 
360 mg 
Cohort C 
0.8 mL 
120 mg ION-682884 or placebo 
1 
120 mg 
Cohort D 
≤ 0.8 mL 
≤ 120 mg ION-682884 
4 
≤ 480 mg 
Cohort E 
0.4 mL 
60 mg ION-682884 or placebo 
4 
240 mg 
 
 
 
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8.2 
Other Protocol-Required Drugs 
All study participants will take daily oral supplemental doses of the RDA of vitamin A 
(approximately 3000 IU vitamin A or the closest approximate dose as available in the region in 
which the patient resides). Commercially available vitamin A as a single supplement, or as part 
of a multivitamin, will be provided by the Study Center or designee, in accordance with local 
regulatory requirements and availability. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures. 
 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
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 tests 
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. 
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. All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection). For stopping rules, if the initial 
laboratory result is observed during the Treatment Period, the results from the retest must be 
available prior to administering the next dose of Study Drug (ION-682884 or placebo). 
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 Safety Committee (or 
appropriately qualified designee) should confer as to whether additional close monitoring of the 
subject is appropriate. If any of the stopping criteria described below (refer to Sections 8.6.1 to 
8.6.3) are met, the subject will be permanently discontinued from further treatment with Study 
Drug (ION-682884 or placebo), evaluated fully as outlined below and in consultation with the 
Sponsor Medical Monitor or appropriately qualified designee, and will be followed up in 
accordance with Section 8.8. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft 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. 
 
 
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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 above. 
Additional, confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements: Subjects with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, ALP, INR and total bilirubin) retested at least once-weekly 
until ALT and AST levels become ≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was 
> ULN. 
Further Investigation into Liver Chemistry Elevations: For subjects with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> 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 (HAV IgM, HBsAg, HCV antibody, 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 
subject’s ALT and/or AST levels reach 5 x ULN. 
For a definition of Baseline, please refer to guidance in Section 8.5. 
8.5.2 
Safety Monitoring Rules for Platelet Count Results 
Please refer also to Table 2. 
Platelet count will be monitored at least every 2 weeks during the Treatment Period and for the 
first 4 weeks after discontinuation of treatment. The Investigator should review all platelet count 
results within 48 hours of receipt. If a patient’s platelet count falls to 100,000/mm3 or less, then 
the patient’s platelet counts should be monitored weekly. In case of platelet reduction to below 
75,000/mm3, the platelet monitoring rule defined in Stopping rules (Section 8.6.3) should be 
followed. 
Treatment should be held if there is no evaluable platelet count within the 2 weeks prior to the 
scheduled dose. Any unreportable platelet count result must be rechecked and determined not to 
have met a stopping rule before dosing can continue. 
 
 
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In the event of a platelet count < 75,000/mm3, additional laboratory investigations should be 
conducted (Table 2). 
Table 2 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 
 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes and mean platelet volume (MPV) 
Serum B12 and folate 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement: total C3, total C4, Bb, C5a 
hsCRP 
Serology for: 
HBV, HCV, HIV (if not done for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
Note: The above labs may change as additional data is assessed, and sites will be updated regarding any changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5.3 
Safety Monitoring for Minor Bleeding Events 
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, gingival bleeding on brushing teeth. If a minor bleeding event 
occurs, additional testing of coagulation parameters (aPTT, PT, INR) 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 laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a subject 
with Study Drug (ION-682884 or placebo) will be stopped permanently; values that are not 
confirmed due failure to retest or missing lab values will be presumed confirmed: 
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, and/or concomitant eosinophilia 
(> ULN) 
 
8.6.2 
Stopping Rules for Renal Function Test Results 
Healthy Volunteers (Cohorts A, B, C and E) 
In the event of laboratory results for either of the following criteria, without an alternative 
explanation, dosing of a subject with Study Drug (ION-682884 or placebo) will be stopped 
permanently: 
1. Confirmed serum creatinine increase that is both ≥ 0.3 mg/dL (26.5 µmol/L) and ≥ 40% 
above Baseline creatinine values (refer to definition of Baseline in Section 8.6) 
2. Proteinuria: Random urine protein/creatinine (P/C) ratio ≥ 750 mg/g (confirmed by a 
repeat random spot UPCR ≥ 750 mg/g or a 24 hr UPCR ≥ 750 mg/24 hr 
The follow-up schedule for any events meeting either of these stopping criteria will be 
determined by the Investigator in consultation with the Sponsor Medical Monitor or designee. 
 
 
 
 
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hATTR Patients (Cohort D) 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for either of the 
2 criteria below, dosing of a patient with ION-682884 may be stopped temporarily: 
1. A decrease in eGFR > 30%/min/1.73 mm2 
2. Proteinuria: Random urine protein/creatinine (P/C) ratio > 5x baseline AND > 150 mg/g; 
or absolute UPCR value > 2000 mg/g (confirmed by a repeat random spot UPCR 
≥ 2000 mg/g or a 24 hr UPCR ≥ 2000 mg/24 hr) 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
 
8.6.3 
Stopping Rule for Platelet Count Results 
8.6.3.1 
Healthy Volunteers (Cohorts A, B, C and E) 
In the event of a confirmed platelet count less than 75,000/mm3, dosing of a subject with Study 
Drug (ION-682884 or placebo) will be stopped permanently. The platelet count should be tested 
weekly until it is above 75,000/mm3 then subsequent monitoring should be per the schedule of 
procedures. 
8.6.3.2 
hATTR Patients (Cohort D) 
Please refer also to Table 2. 
In the event of any platelet count less than 25,000/mm3, dosing of the patient with ION-682884 
will be stopped permanently. Platelet count should be monitored daily until 2 successive values 
above 25,000/mm3. Then monitor twice-weekly until 3 successive values above 75,000/mm3. 
Then weekly monitoring until stable. Administration of steroids is recommended for patients 
whose platelet count is less than 25,000/mm3. Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2–4 weeks for 14 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: Patient may require continuation with oral 
steroids after methylprednisolone). 
In the event of a platelet count ˂ 75,000/mm3 and ≥ 25,000/mm3, and in the absence of major 
bleeding or clinically-relevant non-major bleeding (defined below), dosing with ION-682884 
should be suspended temporarily until the platelet count has recovered to > 100,000/mm3. 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, and 
the speed of recovery of platelet count after interruption of dosing. If dosing is reinitiated, 
platelet count must be measured twice-weekly (consider more frequent monitoring if platelet 
count < 50,000/mm3 and additional risk factors for bleeding are present [see Table 3]) until 
3 successive values above 75,000/mm3 then weekly until the end of study. Treatment should be 
held if there is no evaluable platelet count within the 2 weeks prior to the scheduled dose. Any 
 
 
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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 and Kearon 2005): 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome 
3. Clinically-overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 2.0 mg/dL (1.24 mmol/L) or more within 24 hours 
Definition of Clinically-Relevant Non-Major Bleeding Events 
Clinically-relevant non-major bleeding (CRNMB) is defined as overt bleeding not meeting the 
criteria for major bleeding but that resulted, for example, in medical examination, intervention, 
or had clinical consequences for a subject. 
Definition of Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or 
clinically-relevant, non-major bleeding events (defined above), for example excess bruising, 
petechiae, gingival bleeding on brushing teeth. 
Table 3 
Actions in Patients with Low Platelet Count 
If the subsequent test confirms the initial test result, then monitoring frequency and dosing 
should be adjusted as recommended in the table. 
 
Platelet Count 
(/mm3) 
Monitoring Frequency 
Dosing 
≥ 100K 
Every 2 weeks 
Every 4-week dosing should be continued 
≥ 75K to < 100K 
Every week 
Every 4-week dosing should be continued 
≥ 50K to < 75K 
Twice-weekly until 3 successive values above 
75K then weekly monitoring. 
Dosing should be paused until 3 successive 
values > 100K. On re-initiation of treatment, 
dosing frequency should be reduced from 
once every 4 weeks to once every 8 weeks 
≥ 25K to < 50K‡* 
Twice-weekly until 3 successive values above 
75K then weekly monitoring. 
Consider more frequent monitoring if additional 
risk factors for bleeding are present. 
Dosing should be paused until 3 successive 
values > 100K. On re-initiation of treatment, 
dosing frequency should be reduced from 
once every 4 weeks to once every 8 weeks 
Consider corticosteroids if additional risk 
factors for bleeding are present. 
< 25K* 
Daily until 2 successive values above 25K. 
Then monitor twice-weekly until 3 successive 
values above 75K. Then weekly monitoring 
until stable. 
Treatment should be permanently 
discontinued. 
Corticosteroids strongly recommended. 
‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplatelet medicinal products, and 
/or prior history of major bleeding events 
* In cases of severe thrombocytopenia, please consider based on PI clinical judgment, risk factors for TCP, and potential 
contraindication for corticosteroid, whether the patient would benefit from receiving glucocorticoid therapy to reverse the 
platelet decline as 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 
24 weeks for 1-4 cycles; Prednisolone 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) 
 
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8.7 
Adjustment of Dose and/or Treatment Schedule 
Adjustment of dose and/or schedule is not permitted. 
 
8.8 
Discontinuation of Study Drug 
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 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 subject experiences an AE that necessitates unblinding of the Investigator to the 
subject’s treatment assignment 
• The subject meets any of the following Exclusion Criteria (see Section 5.4): 
- 
For Cohort D: if patient receives a liver transplant 
 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Subjects who discontinue Study Drug will enter the Post-Treatment Period unless consent is 
withdrawn. For subjects withdrawn for reasons other than withdrawal of consent every effort 
should be made to complete the early termination of study procedures and observations at the 
time of withdrawal (see Appendix A) and ideally within 2 weeks from the last dose of Study 
Drug. 
8.9 
Withdrawal of Subjects from the Study Procedures 
Subjects must be withdrawn from study procedures 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 study procedures might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
 
 
 
 
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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 of study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 2 weeks from the last dose of Study Drug. 
8.10 
Cohort and Study Stopping Rules 
Dosing of a cohort and the study, will be terminated, and no further dose escalation will occur, in 
the event that there is 1 SAE or 2 severe AEs in a cohort considered by the Safety Committee to 
be at least possibly-related to Study Drug. An exception to this rule, would be an SAE where the 
only seriousness criterion is hospitalization and the hospitalization was only for observation and 
no specific treatment was administered for the event leading to hospitalization. 
8.11 
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. 
8.11.1 
Concomitant Therapy 
Healthy Volunteers (Cohorts A, B, C and E) 
A concomitant therapy is any non-protocol specified drug or substance (including over-the- 
counter medications, herbal medications and vitamin supplements) administered between signing 
of informed consent and the last study visit. 
Allowed Concomitant Therapy 
Acetaminophen (paracetamol) or ibuprofen may be used for symptomatic relief. Any other 
therapy should be approved by the Sponsor Medical Monitor or designee. 
Disallowed Concomitant Therapy 
The use of prescription and over-the-counter medications including nonsteroidal 
anti-inflammatory drugs and herbal remedies 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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hATTR Patients (Cohort D) 
Allowed Concomitant Therapy 
Treatment with either Vyndaqel®, Diflunisal, doxycycline or TUCA is allowed only if the 
patient has been on a stable regimen for at least 4 weeks prior to screening and is planned to 
remain on a stable regimen through the end of the Post-Treatment Follow-Up period. 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
All study participants are required to take daily RDA supplemental doses of vitamin A during the 
treatment and Post-Treatment evaluation periods. The vitamin A supplements will be provided 
by the Study Center or designee. A patient may choose to substitute the Study Center provided 
vitamin A supplement with their own, only after consultation with the Study Medical Monitor. 
Additional vitamin A supplements (other than those described above) are not allowed at any time 
during the study unless approved by the Study Medical Monitor (this includes multivitamin 
supplements that contain vitamin A). 
The use of the following is allowed only if the patient has been on a stable regimen for at least 
4 weeks prior to screening and is planned to remain on a stable regimen through the end of the 
Post-Treatment Follow-up Period: 
• Due to known potential adverse effects of nonsteroidal anti-inflammatory drugs 
(NSAIDs), e.g., diflunisal, angiotensin-converting enzyme (ACE) inhibitors, and 
angiotensin II receptor blockers (ARBs) on renal function, it is recommended that they 
should be used with caution. Discussion with the Sponsor Medical Monitor prior to 
initiation of drugs that may affect renal function is recommended 
8.11.2 
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 
signing of informed consent and Week 26 visit. 
8.12 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff. 
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 in accordance with 
the applicable Ionis and/or designee SOPs throughout the conduct of the clinical trial. 
 
 
 
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9.2 
Regulatory Requirements 
The Sponsor 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 GCP. 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. The Data and Safety Monitoring Board (DSMB) will 
be notified of any SAE as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor will evaluate the 
available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that the Study Drug (ION-682884 or placebo) is 
causally related to a reported SAE. 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. 
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs to Regulatory Agencies in blinded or unblinded 
fashion according to local law. The Sponsor will submit SUSARs to Investigators in a blinded 
fashion. 
For Study Drug “expected” events, refer to the Investigator Brochure. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population. For Study Drug (ION-682884 or placebo) “expected” AEs, refer to the 
Investigator’s Brochure. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
medicinal (investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at Baseline 
 
 
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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from Study Drug 
Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
9.3.2 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the adverse event has been determined by the Sponsor as at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction 
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
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 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
 
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• 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 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]; OR Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials; the 
event itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
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. Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
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 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 which is defined as final study visit. When the Investigator is reporting by telephone, it is 
important to speak to someone in person vs. leaving a message. SAEs should be reported using 
an electronic SAE submission form whenever possible. In situations where the electronic SAE 
submission is unavailable, an Initial Serious Adverse Event Form should be completed, and a 
copy should be faxed or emailed to the Sponsor. The SAE reporting instruction, including the 
fax number and email address can be found in the investigator site file for the study. 
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. 
 
 
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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, which is defined as the final study 
visit. 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 (ION-682884 or placebo) is characterized by one 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 (ION-682884 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 (ION-682884 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 
Healthy Volunteers 
The severity of AEs and SAEs relating to laboratory tests and adverse events at the injection site 
will be graded based on criteria from the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept 2007 (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 
 
 
 
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hATTR Patients 
The severity of AEs and SAEs relating to laboratory tests and adverse events at the injection site 
will be graded based on criteria from the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0, November 2017 (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 (ION-682884 or placebo) due to the event is characterized by one 
of the following: 
• None: No changes were made to Study Drug (ION-682884 or placebo) administration 
and dose 
• Not Applicable: SAE/AE was reported during Screening Period prior to Study Drug 
administration 
• Permanently Discontinued: Study Drug was discontinued and not restarted 
• Temporarily Interrupted, Re-started – Same Dose: Dosing and/or dosing frequency 
was temporarily interrupted/changed or delayed due to the AE and restarted at the same 
dose 
• Reduced Dose: Dosing was reduced, temporarily interrupted or delayed due to the AE 
and restarted at the next lower dose or reduced dosing frequency 
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 one of the 
following: 
• AE Persists: Patient terminates from the trial and the AE continues 
• Recovered: Patient recovered completely from the AE 
 
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• 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 one 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 AE 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) 
• Recovered with Sequelae: The signs/symptoms of the reported SAE have improved but 
not completely resolved, and a new baseline for the subject is established since full 
recovery is not expected 
• Fatal: Patient died (the date of death should be entered as the SAE resolution date) 
• Unknown: The outcome of the reported SAE is not available, e.g., patient is lost to 
follow-up 
9.4.3.6 
Follow-up of Adverse Event 
Investigator Follow-Up 
During the study period, the Investigator should follow each AE until the event has resolved to 
baseline grade or better, the event is assessed as stable, the patient is lost to follow-up, or the 
patient withdraws consent. Every effort should be made to follow all SAEs considered to be 
related to Study Drug or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification. 
Investigator should follow-up or support the Sponsor’s effort to follow up with all pregnancies 
reported during the study from either the study subject or the female partner of male study 
subject until pregnancy outcome is available. 
Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in subjects who has completed or terminated study, the 
Sponsor or a designee should follow-up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
 
 
 
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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 Safety Committee. 
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. 
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 (ION-682884 or placebo) errors (including overdose, underdose, and administration 
error) 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 Case Report Form. If the subject takes a dose 
of Study Drug (ION-682884 or placebo) 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. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study treatment is not itself an adverse 
event, but it may result in an adverse event. All adverse events associated with an overdose or 
 
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incorrect administration of Study Drug should be recorded on the Adverse Event eCRF. If the 
associated adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event). 
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 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 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 to obtain additional 
information relevant to the pregnancy progress and outcome. A longer follow-up may be 
required if a newborn child experiences a medical condition. Follow-up will be performed to the 
extent permitted by the applicable regulations and privacy considerations; e.g., pregnancy ICF 
may be required. 
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 
follow-up with the mother and may request access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome. A 
longer follow-up may be required if a newborn child experiences a medical condition. 
Follow-up will be performed to the extent permitted by the applicable regulations and privacy 
considerations; e.g., partner ICF may be required. 
 
 
 
 
 
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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
Analysis of safety labs, AEs, concomitant medications, ECG and physical examinations of 
healthy volunteers and patients with TTR amyloidosis following subcutaneously administration 
of single and/or multiple doses of ION-682884. 
10.1.2 
Secondary Endpoints 
10.1.2.1 
Pharmacokinetic Endpoints 
The plasma pharmacokinetics of ION-682884 (as total full-length oligonucleotide, including 
fully conjugated, partially conjugated, and unconjugated ION-682884) will be assessed 
following single and multiple SC administration. The amount of ION-682884 excreted in urine 
over selected 24-hour collection intervals will be determined. Metabolite identification and 
profiling may be determined in some of the collected plasma, urine, and fecal samples at a later 
time. 
10.1.2.2 
Pharmacodynamic Endpoints 
Analysis of pharmacodynamic data will determine the change and percent change from Baseline 
in plasma TTR and RBP4 levels following single- and multiple-dose SC administration of Study 
Drug. 
10.1.3 
Additional/Exploratory Endpoints 
Exploratory endpoints for the open-label, hATTR patient cohort are the change from Baseline to 
Week 15 in the: 
• mNIS +7 score 
• Norfolk QOL-DN questionnaire total score 
• 6MWT 
• 10MWT 
• 
EQ-5d 
• SF-36 questionnaire domain scores 
• 
COMPASS-31 questionnaire 
• Amyloidosis-specific QoL questionnaire 
10.2 
Sample Size Considerations 
There is no statistical rationale for the selected sample size of the single-dose and multiple-dose 
treatment cohorts. The sample size was based on prior experience with second generation ASOs 
in healthy volunteers to ensure that the safety, tolerability, PK, and preliminary PD of 
ION-682884 will be adequately assessed while minimizing the unnecessary subject exposure. 
 
 
 
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10.3 
Populations 
Full Analysis Set: All randomized subjects who received at least 1 injection of Study Drug 
(ION-682844 or placebo). 
Per Protocol Set: Subset of the Full Analysis Set that have received at least a certain percentage 
of the prescribed doses of Study Drug and that have no significant protocol deviations that would 
be expected to affect efficacy assessments. 
Safety Set: All randomized subjects who receive at least 1 injection of Study Drug. 
Pharmacokinetic Set: All subjects who are randomized and receive at least 1 dose of active 
Study Drug (ION-682844) and have at least 1 evaluable PK sample. 
 
10.4 
Definition of Baseline 
Baseline will be defined as the average of the pre-dose measurement closest to Day 1 and Day 1 
Pre-dose. Day 1 Pre-dose is the Day 1 measurement taken prior to the time of the first dose. 
For other assessments, baseline will be defined as the last non-missing measurement prior to the 
date and time of the first dose of Study Drug (ION-682884 or placebo). 
The 2 mNIS+7 assessments must be performed on separate days and within 14 days prior to the 
first dose of Study Drug (Day 1). In addition, every effort should be made to conduct the 
2 assessments < 7 days apart. 
 
10.5 
Interim Analysis 
Unblinded analyses will be conducted after completion of dosing in each healthy volunteer 
cohort. 
10.6 
Planned Methods of Analysis 
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. Where appropriate, p-values will be reported. All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rate unless otherwise stated. 
The placebo subjects will be pooled and analyzed for multiple-dose placebo groups in Cohort A, 
B and E. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group. Patient randomization will be summarized by cohort and treatment group. The 
subject disposition will be summarized. All subjects enrolled will be included in a summary of 
subject disposition. 
10.6.2 
Safety Analysis 
The safety analysis will be conducted on the Safety Set. 
 
 
 
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Treatment duration and amount of Study Drug (ION-682884 or placebo) received will be 
summarized by treatment group. Subject incidence rates of all adverse events will be tabulated 
by Medical Dictionary for Regulatory Activities (MedDRA) system organ class, and by 
MedDRA term. 
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 (ION-682884 or placebo) will be summarized. 
Laboratory tests to ensure subject safety including chemistry panel, complete blood count with 
differential, coagulation panel, complement etc., will be summarized by study visits for each 
treatment group. These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ION-682884 or placebo) administration, as 
appropriate. 
Vital sign and ECG measures will be tabulated by treatment group. In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
10.6.3 
Pharmacokinetic Analysis 
The plasma PK of ION-682884 (as total full-length ASO) will be assessed following single and 
multiple SC administration. The amount of ION-682884 (as total full-length ASO) excreted in 
urine over 24-hr intervals will be determined following single and multiple doses. Metabolite 
identification and profiling may be determined in some of the collected plasma, urine, and fecal 
samples at a later time. 
Noncompartmental PK analysis of ION-682884 will be carried out on each individual subject 
data set. The Cmax and the Tmax will be obtained directly from the concentration-time data. The 
plasma half-life (t1/2 λz) associated with the apparent terminal elimination phase will be 
calculated, if appropriate using available data, from the equation, t1/2λz = 0.693/λz, where λz is the 
rate constant associated with the apparent terminal elimination phase. Partial areas under the 
plasma concentration-time curve from zero time (pre-dose) to selected times (t) after the 
SC administration (AUC0-t) will be calculated. 
The amount of ION-682884 excreted in the urine will be determined from the following 
expression: 
 
𝐴𝐴𝐴𝐴𝑡𝑡 = 𝐶𝐶𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝐴𝐴 𝑥𝑥 𝑉𝑉𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝐴𝐴 
Where, Aet is the amount excreted up to some fixed time (t) (i.e., 24 hours), Curine is the urine 
concentration of the analyte, and Vurine is the total urine volume. The percentage of the 
administered dose excreted in urine will then calculated from the following expression: 
𝐴𝐴𝐴𝐴𝑡𝑡 
% 𝐷𝐷𝐷𝐷𝐷𝐷𝐴𝐴 𝐸𝐸𝑥𝑥𝐸𝐸𝑢𝑢𝐴𝐴𝑡𝑡𝐴𝐴𝐸𝐸 = (  
 
𝐴𝐴𝐸𝐸𝐴𝐴𝑢𝑢𝑢𝑢𝑢𝑢𝐷𝐷𝑡𝑡𝐴𝐴𝑢𝑢𝐴𝐴𝐸𝐸 
𝐷𝐷𝐷𝐷𝐷𝐷𝐴𝐴 
) 𝑥𝑥 100% 
Other plasma and urine PK parameters, as appropriate, may be determined or calculated at the 
discretion of the PK scientist. 
 
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Plasma and urine PK parameters will be summarized using descriptive statistics. Additional 
details regarding the PK analysis will be described in the Statistical Analysis Plan. 
Potential relationships between selected PD (e.g., TTR level), safety (e.g., ECG parameters) and 
PK measures may also be explored, where deemed appropriate. 
10.6.4 
Pharmacodynamic Analysis 
The PD analysis will be conducted in the Full Analysis Set and Per Protocol Set. The change 
and percent change from baseline in TTR and RBP4 will be summarized. 
10.6.5 
Additional Analyses 
Exploratory endpoints for the hATTR patient cohort will be summarized. Details will be 
described in the SAP. 
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. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject 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 (ION-682884 or placebo) are administered. The subject 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 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. 
11.2 
Ethical Conduct of the Study 
All 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 
must be followed. 
11.3 
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 IRB for written approval. A copy of 
the written approval of the protocol and informed consent form must be received by the Sponsor 
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 IRB must 
 
 
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also be received by the Sponsor before recruitment of subjects into the study and shipment of 
Study Drug. The Investigator’s Brochure must be submitted to the IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document. The 
Investigator should notify the IRB of deviations from the protocol in accordance with ICH GCP. 
The Investigator should also notify the IRB of SAEs occurring at the Study Center and other AE 
reports received from the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB approval/renewal throughout the 
duration of the study. Copies of the Investigator’s reports, all IRB submissions and the IRB 
continuance of approval must be sent to the Sponsor. 
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, 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 (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 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. Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document. The regulatory authority and 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 IRB to 
the Sponsor. 
12.2 
Study Termination 
The Sponsor 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 should notify the IRB in writing of the trial’s completion or early termination and 
send a copy of the notification to the Sponsor. 
 
 
 
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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. In this study, 
eCRF may not be used as source documents. 
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 
ICH GCP, suitable for inspection at any time by representatives from the Sponsor 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 IRB and the Sponsor 
• 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 
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. 
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 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. 
 
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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. 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. 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. 
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. Generic names and trade names are acceptable 
for concomitant medications. Combination medications should be recorded using their trade 
name. 
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. 
REFERENCES 
Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of 
transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016; 29 Suppl 1: S14-26. 
Altmann KH, Fabbro D, Dean NM, et al. Second-generation antisense oligonucleotides: structure-activity 
relationships and the design of improved signal-transduction inhibitors. Biochem Soc Trans 1996; 24: 630-637. 
Benson MD, Dasgupta NR, Rissing SM, et al. Safety and efficacy of a TTR specific antisense oligonucleotide in 
patients with transthyretin amyloid cardiomyopathy. Amyloid 2017; 24: 217-223. 
Benson MD, Kluve-Beckerman B, Zeldenrust SR, et al. Targeted suppression of an amyloidogenic transthyretin 
with antisense oligonucleotides. Muscle Nerve 2006; 33: 609-618. 
Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen Treatment for Patients with Hereditary Transthyretin 
Amyloidosis. N Engl J Med 2018; 379: 22-31. 
Biesalski HK, Frank J, Beck SC, et al. Biochemical but not clinical vitamin A deficiency results from mutations in 
the gene for retinol binding protein. Am J Clin Nutr 1999; 69: 931-936. 
Bui BV, Armitage JA, Fletcher EL, et al. Retinal anatomy and function of the transthyretin null mouse. Exp Eye Res 
2001; 73: 651-659. 
Buxbaum JN, and Reixach N. Transthyretin: the servant of many masters. Cell Mol Life Sci 2009; 66: 3095-3101. 
Castano A, Drachman BM, Judge D, et al. Natural history and therapy of TTR-cardiac amyloidosis: emerging 
disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 2015; 20: 
163-178. 
Coelho T, Ericzon BG, Falk R, et al. A Physician’s Guide to Transthyretin Amyloidosis. 2008. 
Coutinho P, Martins da Silva A, Lopes Lima J, et al. Forty years of experience with Type 1 amyloid neuropathy. 
Review of 483 cases. Amyloid and Amyloidosis 1980: 88-98. 
Crooke ST, Graham MJ, Zuckerman JE, et al. Pharmacokinetic properties of several novel oligonucleotide analogs 
in mice. J Pharmacol Exp Ther 1996; 277: 923-937. 
D'Ambrosio DN, Clugston RD, and Blaner WS. Vitamin A metabolism: an update. Nutrients 2011; 3: 63-103. 
Dyck PJ, Davies JL, Litchy WJ, et al. Longitudinal assessment of diabetic polyneuropathy using a composite score 
in the Rochester Diabetic Neuropathy Study cohort. Neurology 1997; 49: 229-239. 
Dyck PJ, Kratz KM, Lehman KA, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of 
neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 1991; 41: 799-807. 
Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene results in mice with depressed 
levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A 1993; 90: 2375-2379. 
Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 2011; 124: 1079-1085. 
FDA Guidance for Industry Jp-. Guidance for industry: estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers. 
https://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078932.pdf. . 
2005. 
Fleming CE, Nunes AF, and Sousa MM. Transthyretin: more than meets the eye. Prog Neurobiol 2009; 89: 266-276. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2'-O-(2- 
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 1419- 
1428. 
Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care 2017; 23: 
S107-s112. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Herlenius G, Wilczek HE, Larsson M, et al. Ten years of international experience with liver transplantation for 
familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant 
Registry. Transplantation 2004; 77: 64-71. 
Inoue H, Hayase Y, Iwai S, et al. Sequence-dependent hydrolysis of RNA using modified oligonucleotide splints 
and RNase H. FEBS Lett 1987; 215: 327-330. 
 
76 


ION-682884-CS1 
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Amendment 2 
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78 of 103 
 
 
 
Kwoh J. Chapter 13: An Overview of the Clinical Safety Experience of First- and Second-Generation Antisense 
Oligonucleotides. in S. T. Crooke (ed.), Antisense Drug Technology: Principles, Strategies, and Applications. 2008. 
(Boca Raton). 
Levin AA, Yu RZ, and Geary RS. Chapter 7: Basic Principles of the Pharmacokinetics of Antisense Oligonucleotide 
Drugs. in S. T. Crooke (ed.), Antisense Drug Technology: Principles, Strategies, and Applications. 2008. (CRC 
Press: Boca Raton). 
Liepnieks JJ, and Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis 
patients after liver transplantation. Amyloid 2007; 14: 277-282. 
Liepnieks JJ, Zhang LQ, and Benson MD. Progression of transthyretin amyloid neuropathy after liver 
transplantation. Neurology 2010; 75: 324-327. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure: a comparison with 
light chain-associated amyloidosis. Arch Intern Med 2005; 165: 1425-1429. 
Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic 
peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 2006; 107: 3854- 
3858. 
Plante-Bordeneuve V, Ferreira A, Lalu T, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid 
polyneuropathy (TTR-FAP). Neurology 2007; 69: 693-698. 
Plante-Bordeneuve V, and Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011; 10: 1086-1097. 
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using 
triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 2014; 42: 8796-8807. 
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Quintas A, Vaz DC, Cardoso I, et al. Tetramer dissociation and monomer partial unfolding precedes protofibril 
formation in amyloidogenic transthyretin variants. J Biol Chem 2001; 276: 27207-27213. 
Schulman S, and Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Seeliger MW, Biesalski HK, Wissinger B, et al. Phenotype in retinol deficiency due to a hereditary defect in retinol 
binding protein synthesis. Invest Ophthalmol Vis Sci 1999; 40: 3-11. 
Sekijima Y, Yoshida K, Tokuda T, et al. Familial Transthyretin Amyloidosis. 2009. 
Stangou AJ, and Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr 
Opin Neurol 2004; 17: 615-620. 
Stewart M, W. L, and Loftus J. Evaluating the quality of life and burden of illness in an ultra-rare disease in the 
U.S.: transthyretin familial amyloid polyneuropathy (TTR-FAP) patients & caregivers. Abstract presented at: the 
IXth International Syposium on Familial Amyloidotic Polyneuropathy (ISFAP); November 10-13, 2013; Rio de 
Janeiro, Brazil. Abstract E16. 2013. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Suhr O, Danielsson A, Rydh A, et al. Impact of gastrointestinal dysfunction on survival after liver transplantation for 
familial amyloidotic polyneuropathy. Dig Dis Sci 1996; 41: 1909-1914. 
Vinik EJ, Vinik AI, and J.F. P. Validation of Norfolk QOL-DN as a measure of QOL in patients with transthyretin 
familial amyloid polyneuropathy. Poster at the Biennial meeting of the Peripheral Nerve Society. Potomac, MD. 
June 25-29. 2011. 
Waits RP, Yamada T, Uemichi T, et al. Low plasma concentrations of retinol-binding protein in individuals with 
mutations affecting position 84 of the transthyretin molecule. Clin Chem 1995; 41: 1288-1291. 
Wei S, Episkopou V, Piantedosi R, et al. Studies on the metabolism of retinol and retinol-binding protein in 
transthyretin-deficient mice produced by homologous recombination. J Biol Chem 1995; 270: 866-870. 
 
77 


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Yazaki M, Mitsuhashi S, Tokuda T, et al. Progressive wild-type transthyretin deposition after liver transplantation 
preferentially occurs onto myocardium in FAP patients. Am J Transplant 2007; 7: 235-242. 
Yazaki M, Tokuda T, Nakamura A, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy consists 
of abundant wild-type transthyretin. Biochem Biophys Res Commun 2000; 274: 702-706. 
Yu RZ, Graham MJ, Post N, et al. Disposition and Pharmacology of a GalNAc3-conjugated ASO Targeting Human 
Lipoprotein (a) in Mice. Mol Ther Nucleic Acids 2016a; 5: e317. 
———. Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human 
Lipoprotein (a) in Monkeys. Mol Ther Nucleic Acids 2016b; 5: e317. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second- 
generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab Dispos 
2007; 35: 460-468. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A 
Schedule of Procedures 
 
Single-Dose Cohort C 
Multiple-Dose Cohorts A, B and E 
Multiple-Dose Cohort D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A  Schedule of Procedures - Single-Dose Cohort C 
 
Study Day 
Screen 
Pre- 
Treatment
Single-Dose and Post-Treatment Evaluation 
-28 to -2 
-1 
1 
2 
3 
4 
8 or 
Early 
Term 
15 
29 
50 
71 
92 
Visit Window 
0 
0 
0 
0 
0 
1 
1 
2 
2 
2 
2 
2 
Overnight Stay 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Body Weight and BMI 
X 
Physical Exam1 
X 
X 
X 
X 
X 
Vital Signs2 
X 
X 
x• 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B & C 
X 
FSH3 
X 
Pregnancy Test4 
X 
X 
X 
X 
X 
Chemistry Panel (Fasting)5, 6 
X 
x• 
Xb 
X 
X 
X 
X 
X 
X 
X 
Hematology6 
X 
x• 
Xb 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
x• 
Xb 
X 
X 
X 
X 
X 
X 
X 
PD Panel5 
X 
x• 
Xb 
X 
X 
X 
X 
X 
X 
X 
Inflammatory Panel 
x• 
xc 
X 
X 
Complement (C5a, Bb) 
Xd 
Xb 
X 
PT, INR, aPTT 
X 
Xd 
Xb 
X 
ECG (12-Lead, triplicate) 
X 
x• 
Xb 
X 
X 
X 
Thyroid Panel 
X 
Drug/Alcohol Screen7 
X 
X 
Study Drug Administration 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Appendix A 
Schedule of Procedures – Single-Dose Cohort C Continued 
 
Study Day 
Screen 
Pre- 
Treatment 
Single-Dose and Post-Treatment Evaluation 
-28 to - 
2 
-1 
1 
2 
3 
4 
8 or 
Early 
Term 
15 
29 
50 
71 
92 
Visit Window 
0 
0 
0 
0 
0 
1 
1 
2 
2 
2 
2 
2 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling8 
Xf 
Xb 
X 
X 
X 
X 
X 
X 
PK 24-hr Urine Sampling8, 9 
X 
PK 24-hr Fecal Collection8, 9 
X 
Immunogenicity Testing10 
Xa 
X 
X 
X 
Archived Serum/Plasma Samples11 
Xa 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
Note: 
If not specifically labeled, “X” means anytime 
Subjects that terminate early during the Post-Treatment Period should complete all procedures for Study Day 8 
1 
Full physical exam to be given at Screening and abbreviated physical exam to be given thereafter 
2 
Blood Pressure (BP), Heart Rate (HR), Respiration Rate (RR), temperature 
3 
Women who are not surgically sterile as confirmation of menopause 
4 
Women who are not surgically sterile as confirmation of menopause. Dipstick acceptable at Day-1 only. Serum test at all other timepoints 
5 
Fasted samples should be taken after fasting for at least 8 hours and preferably not more than 12 hours. During this time the patient can drink water and they 
should ensure that they consume sufficient water in order to not become dehydrated 
6 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing a repeat 
blood specimen should be re-drawn as soon as possible (ideally within 7 days) 
7 
Urine-test at Screening will be sent to the Central Laboratory for analysis. Day -1 will be done at the site using e.g., a breathalyzer or a urine test 
8 
Refer to Appendix C for PK sampling schedule 
9 
Start 24-hr urine and fecal PK collection post SC injection of ION-682884. Pool and record total urine volume. Ensure subjects have voided bladder prior to 
start of dosing 
10 If time is not specified, Immunogenicity testing can be done at any time 
11 Stored at -70 °C for follow-up exploration of pharmacodynamics, laboratory findings and/or adverse events (e.g., measurement of cytokine and/or chemokine 
levels, measurement of additional markers of kidney function, etc.) in this or subsequent clinical studies of ION-682884 
Time (time is in reference to Study Drug administration): 
a 
Pre-dose 
d 
Pre-dose, 3 hours 
b 
24 hours 
e 
Pre-dose, 1, 2, 3, 4, 8 hours 
c 
48 hours 
f 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours 


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Appendix A  Schedule of Procedures - Multiple-Dose Cohorts A, B and E 
 
Study Week 
Screen
Pre- 
Treatment 
Treatment Period1 
(13 Weeks) 
Post-Treatment Evaluation Period1 
(13 Weeks) 
-4 to -1
-1 
1 
2 
3 
5 
7 
9 
11 
13 
14 
15 
or ET
17 
19 
21 
23 
26 or ET
FU 
Study Day 
-28 to -2
-1 
1 
2 
3 
8 
15 
29 
43 
57 
71 
85 
86 
87 
92 
99 
113 
127
141
155
176 
Visit Window 
(days) (+/-) 
0 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
Overnight Stay 
X 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Body Weight and BMI 
X 
X 
X 
Physical Exam2 
X 
X 
X 
X 
X 
Vital Signs3 
X 
X 
x• Xb xc X 
X 
x• X 
x• X 
x• Xb 
xc X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B & C 
X 
FSH4 
X 
Pregnancy Test5 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel7 
(Fasting6) 
X 
x• Xb 
X 
X 
x• X 
x• X 
x• Xb 
X 
X 
X 
X 
X 
X 
X 
Hematology7 
X 
x• Xb 
X 
X 
x• X 
x• X 
x• Xb 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
x• Xb 
X 
X 
x• X 
x• X 
x• Xb 
X 
X 
X 
X 
X 
X 
X 
PD Panel (Fasting6) 
X 
x• 
X 
X 
x• X 
x• X 
x• 
X 
X 
X 
X 
X 
X 
Inflammatory Panel 
x• Xb xc 
X 
x• 
x• Xb 
xc X 
X 
X 


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Appendix A Schedule of Procedures -Multiple-Dose Cohorts A, B and E Continued 
 
Study Week 
Screen
Pre- 
Treatment 
Treatment Period1 
(13 Weeks) 
Post-Treatment Evaluation Period1 
(13 Weeks) 
-4 to -1
-1 
1 
2 
3 
5 
7 
9 
11 
13 
14 
15 
or ET 
17 
19 
21 
23 
26 or 
ET-FU 
Study Day 
-28 to 
2 
-1 
1 
2 
3 
8 
15 
29 
43 
57 
71 
85 
86 
87 
92 
99 
113 
127 
141 
155 
176 
Visit Window (days) 
(+/-) 
0 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
Complement (C5a, Bb) 
Xd Xb 
x• 
x• 
X 
X 
X 
PT, INR, aPTT 
X 
Xd Xb 
x• 
x• 
X 
X 
X 
ECG (12-Lead) 
X 
xe 
Xb 
xe Xb 
X 
X 
X 
Thyroid Panel 
X 
Drug/Alcohol Screen8 
X 
X 
Study Drug 
Administration 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling9 
X! 
Xb xc X 
X 
x• X 
x•
X 
Xt 
Xb xc X 
X 
X 
X 
X 
X 
X 
PK 24-Hr Urine 
Sampling9• 10 
X 
X 
PK 24-hr Fecal 
Collection9• 10, 11 
X 
X 
lmmunogenicity Testing12 
x• 
X 
x• 
X 
X 
X 
Archived Serum/Plasma 
Samples13 
x• Xb xc X 
X 
x• X 
x•
X 
x• Xb xc X 
X 
X 
X 
X 
Note: If not specifically labeled, "X" means any time 
A 10-minute time window applies to all procedures to allow for flexibility where multiple procedures are scheduled at the same time 


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Amendment 2 
12 June 2019 
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Appendix A 
Schedule of Procedures –Multiple-Dose Cohorts A, B and E Continued 
Legend Continued 
1 
Subjects who terminate early from the Treatment Period of the study should be encouraged to participate in the Post-Treatment Period. If the subject agrees, 
the subject should complete the Early Termination (ET) visit approximately 2 weeks after the last dose of Study Drug, followed by subsequent Post-Treatment 
visits. Subjects who terminate early from the Post-Treatment Period (and subjects who terminate early from the Treatment Period of the study and do not 
agree to participate in the Post-Treatment Period) should be encouraged to complete an ET visit 
2 
Full physical exam to be given at Screening and abbreviated physical exam to be given during Treatment and Post-Treatment Period as indicated to assess 
changes from Screening 
3 
Blood Pressure (BP), heart rate (HR), respiratory rate (RR), temp 
4 
Women who are not surgically sterile as confirmation of menopause 
5 
Conducted only in women who are not surgically sterile. Dipstick acceptable at Day -1 only; all other pregnancy tests should be conducted on serum or 
plasma samples 
6 
Fasted samples should be taken after fasting for at least 8 hours and preferably not more than 12 hours. During this time the patient can drink water and they 
should ensure that they consume sufficient water in order to not become dehydrated 
7 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing a repeat 
blood specimen should be re-drawn as soon as possible (ideally within 7 days) 
8 
Urine-test at Screening will be sent to the Central Laboratory for analysis. Day -1 will be done at the site using e.g., a breathalyzer or a urine test 
9 
See Appendix C for specific PK schedules 
10 Start 24-hr urine and fecal PK collection post SC injection of ION-682884. Pool and record total urine volume. Ensure subjects have voided bladder prior to 
start of dosing 
11 Fecal PK only to be collected for Cohort B 
12 If time is not specified, Immunogenicity testing can be done at any time 
13 Stored at -70 °C for follow-up exploration of pharmacodynamics, laboratory findings and/or adverse events (e.g., measurement of cytokine and/or chemokine 
levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of ION-682884 
 
Time (time is in reference to Study Drug administration): 
a 
Pre-dose 
b 
24 hours 
c 
48 hours 
d 
Pre-dose, 3 hours 
e 
Pre-dose, 1, 2, 3, 4, 8 hours 
f 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours 


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12 June 2019 
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Appendix A  Schedule of Procedures - Multiple-Dose Cohort D 
 
Study Week 
Screen
Baseline 
Assess- 
ments 
Treatment Period1 
(13 Weeks) 
Post-Treatment Evaluation Period1 
(13 Weeks) 
-6 to -1 
-6 to -1 
1 
2 
3 
5 
7 
9 
11 
13 
14 
15 
or ET 
17 
19 
21 
23 
26 or 
ET-FU 
Study Day 
-42 to -2
-42 to -1 
1 
8 
15 
29 
43 
57 
71 
85 
92 
99 
113 
127 
141 
155 
176 
Wisit Window (days) (+/-) 
0 
0 
0 
2 
2 
2 
2 
2 
2 
1 
2 
2 
2 
2 
2 
2 
2 
K)vemight Stay 
X 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
l:)ody Weight and BMI 
X 
X 
X 
myloid disease history 
X 
ITTR Genotyping2 
X 
Physical Exam3 
X 
X 
X 
X 
r..;ital Signs4 
X 
X 
x• 
X 
X 
x• 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B & C 
X 
FSH5 
X 
Pregnancy Test6 
X 
X 
X 
X 
X 
X 
themistry Panel7 
KFasting8) 
X 
x• 
X 
X 
x• 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
Hematology7 
X 
x• 
X 
X 
x• 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
x• 
X 
X 
x• 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 
K)phthalmology Exam 
X 
X 
ERG Exam 
X 
X 
Retinol (Fasting8) 
X 
x• 
x• 
x• 
x• 
X 
X 
X 
PD Panel (Fasting8) 
X 
x• 
X 
X 
x• 
X 
x• 
X 
x• 
X 
X 
X 
X 
X 
X 
X 


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CO:NFIDENTIAL 
Amendment2 
12 June 2019 
Appendix A Schedule of Procedures - Multiple-Dose Cohort D Continued 
87 
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Study Week 
Screen 
Baseline 
Assess- 
ments 
Treatment Period1 
(13 Weeks) 
Post-Treatment Evaluation Period1 
(13 Weeks) 
-6 to -1 
-6 to -1 
1 
2 
3 
5 
7 
9 
11 
13 
14 
15 
or ET 
17 
19 
21 
23 
26 or 
ET-FU 
Study Day 
-42 to -2
-42 to -1 
1 
8 
15 
29 
43 
57 
71 
85 
92 
99 
113 
127 
141 
155 
176 
Visit Window (days) (+/-)
0 
0 
0 
2 
2 
2 
2 
2 
2 
1 
2 
2 
2 
2 
2 
2 
2 
6-Minute Walk Test 
X 
X 
X 
NYHA Classification/Score 
X 
X 
Transthoracic ECHO 
X 
Cardiac MRI 
X 
NT-proBNP 
X 
x• 
X 
Troponin I 
X 
x• 
X 
NIS 
X 
mNIS+713 
2X 
X 
Kansas City 
Cardiomyopathy 
Questionnaire 
X 
X 
EuroQoL-5 Dimension - 
5 Level 
X 
X 
Nortolk QOL-DN9 
X 
X 
SF-36 Questionnaire 
x• 
X 
PND Score 
X 
X 
Compass-31 Autonomic 
Neuropathy Score 
X 
X 
Amyloidosis-Specific 
Qol questionnaire 
X 
X 


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CO:NFIDENTIAL 
Amendment2 
12 June 2019 
Appendix A Schedule of Procedures - Multiple-Dose Cohort D Continued 
88 
88 of 103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d 
o 
 
r 
a 
Note: If not specifically labeled, "X" means any time 
A 10-minute time window applies to all procedures to allow for flex bility where multiple procedures are scheduled at the same time 
Study Week 
Screen 
Baseline 
Assess- 
ments 
Treatment Period1 
(13 Weeks) 
Post-Treatment Evaluation Period1 
(13 Weeks) 
-6 to -1 
-6 to -1 
1 
2 
3 
5 
7 
9 
11 
13 
14 
15 
or ET 
17 
19 
21 
23 
26 or 
ET-FU 
Study Day 
-42 to -2
-42 to -1 
1 
8 
15 
29 
43 
57 
71 
85 
92 
99 
113
127 
141 
155 
176 
Wisit Window (days) (+/-)
0 
0 
0 
2 
2 
2 
2 
2 
2 
1 
2 
2 
2 
2 
2 
2 
2 
Inflammatory Panel 
x• 
X 
x• 
x• 
X 
X 
tomplement (C5a, Sb) 
Xb 
X 
x• 
X 
X 
PT, INR, aPTT 
X 
Xb 
X 
x• 
X 
X 
ECG (12-Lead, triplicate) 
X 
xc 
xc 
X 
X 
hyroid Panel 
X 
ION-682884 
ministration 
X 
X 
X 
X 
dverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ncomitant  Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling10, 11 
xc X 
X 
x• X 
x• X 
xc 
X 
X 
X 
X 
X 
X 
X 
lmmunogenicity Testing11 
x• 
X 
x• 
X 
X 
chived Serum/Plasma 
mples12 
x• X 
X 
x• 
x• X 
x• 
X 
X 
X 
X 
X 


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Amendment 2 
12 June 2019 
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Appendix A 
Schedule of Procedures – Multiple-Dose Cohort D Continued 
Legend Continued 
1 
Subjects who terminate early from the Treatment Period of the study should be encouraged to participate in the Post-Treatment Period. If the subject agrees, 
the subject should complete the Early Termination (ET) visit approximately 1-week after the last dose of ION-682884, followed by subsequent Post-Treatment 
visits. Subjects who terminate early from the Post-Treatment Period (and subjects who terminate early from the Treatment Period of the study and do not 
agree to participate in the Post-Treatment Period) should be encouraged to complete an ET visit 
2 
For determination of patient elig bility only if appropriate documentation is not available. In this case the tests may be conducted up to 10 weeks prior to Day 1. 
For biopsy, location per local practice. 
3 
Full physical exam to be given at Screening and abbreviated physical exam to be given during Treatment and Post-Treatment Period as indicated to assess 
changes from Screening 
4 
Blood Pressure (BP), heart rate (HR), respiratory rate (RR), temp 
5 
Women who are not surgically sterile as confirmation of menopause 
6 
Conducted only in women who are not surgically sterile. Dipstick acceptable at Day -1 only; all other pregnancy tests should be conducted on serum or 
plasma samples 
7 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing a repeat 
blood specimen should be re-drawn as soon as possible (ideally within 7 days) 
8 
Fasted samples should be taken after fasting for at least 8 hours and preferably not more than 12 hours. During th s time the patient can drink water and they 
should ensure that they consume sufficient water in order to not become dehydrated 
9 
The Norfolk QOL-DN questionnaire must be administered prior to any other study procedures. During the baseline and EOT efficacy assessment periods, the 
Norfolk QOL-DN questionnaire should be administered on the same day as the first mNIS+7 assessment. The mNIS+7 assessment procedure includes the 
NIS, +7, NSC, and additional sensory and nerve conduction testing. If an ERG or ophthalmology examination are to be conducted on a mNIS+7 assessment 
day, the mNIS+7 assessment must be conducted first 
• 
Two (2) independent mNIS+7 assessments will be performed at Baseline on separate days. Both assessments should be performed within 14 days prior 
to the first dose of ION-682884 (Day 1). In addition, every effort should be made to conduct the 2 assessments < 7 days apart 
For an individual patient, every effort should be made to use the same mNIS+7 evaluator throughout the study and the evaluator must be insulated from the 
patient’s general study procedures and knowledge of the patient’s adverse events 
10 See Appendix C for specific PK schedules 
11 If time is not specified, Immunogenicity testing can be done at any time 
12 Stored at -70 °C for follow-up exploration of pharmacodynamics, laboratory findings and/or adverse events (e.g., measurement of cytokine and/or chemokine 
levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of ION-682884 
Time (time is in reference to ION-682884 administration): 
a 
Pre-dose 
b 
Pre-dose, 3 hours 
c 
Pre-dose, 1, 2, 3, 4, 6 hours 


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12 June 2019 
CONFIDENTIAL 
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Appendix B 
List of Laboratory Analytes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90 


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Clinical Chemistry Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect (unconjugated) 
bilirubin 
• ALT 
• AST 
• Alkaline phosphatase 
• Creatinine kinase 
• Total IgG 
• Total IgM 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• FSH (women only) 
• Serum βhCG 
• Drug/Alcohol screen 
Complement 
• C5a 
• Bb 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC, RDW, 
MPV 
• Platelets 
• White blood cells 
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Inflammatory 
• hs-CRP 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
PD Panel 
• Tranthyretin 
• Retinol binding protein 4 
Thyroid Panel 
• TSH 
• Free T44 
• Total T34 
Urinalysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C Ratio and A/C ratio 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte esterase 
• Nitrate 
• Microscopic 
examination3 
Other 
• Retinol 
• Retinyl palmitate 
• NT-proBNP 
• Troponin I 
Pharmacokinetics1 
• ION-682884 in plasma 
• ION-682884 in urine 
Immunogenicity2 
• Anti-ION-682884 antibodies 
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 ION-682884 or other similar 
oligonucleotides. 
 
1 
Plasma, urine, and feces PK samples may also be used for profiling of drug binding proteins, bioanalytical 
method validation purposes, stability assessments, metabolite assessments, immunogenicity testing (or possibly 
for purposes of immunogenicity assay development and/or validation) or to assess other actions of ION-682884 
with plasma constituents 
2 
May be evaluated 
3 
Will be performed on abnormal findings unless otherwise specified 
4 
To be measured if TSH is outside of normal range 
 
 
 
 
 
 
 
 
 
 
91 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix C 
PK Sampling Schedule for Single- and 
Multiple-Dose Cohorts 
 
PK Sampling Schedule for Multiple-Dose Cohorts A, B and E 
PK Sampling Schedule for Single-Dose Cohort C 
PK Sampling Schedule for Multiple-Dose Cohort D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
92 


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12 June 2019 
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Appendix C 
PK Sampling Schedule for Single- and Multiple-Dose Cohorts 
 
 
PK Sampling Schedule for Multiple-Dose Cohorts A, B and E 
 
D1 
D2 
D3 
D8 
D15 
D29 
D43 
D57 
D71 
Blood: 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, and 12 hours post-SC 
injection 
Blood: 
24 hours post-SC 
injection 
Blood: 
48 hours post-SC 
injection 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Anytime 
Urine: 24-hour collection 
Feces: 24-hour collection1 
 
 
D85 
D86 
D87 
D92 
D99 
D113 
D127 
D141 
D155 
D176 
Blood: 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, and 12 hours post-SC 
injection 
Blood: 
24 hours post-SC 
injection 
Blood: 
48 hours post-SC 
injection 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Urine: 24-hour collection 
Feces: 24-hour collection1 
1 
Fecal PK only to be collected for Cohort B 
Note: SC = subcutaneous, D = Day 
 
 
PK Sampling Schedule for Single-Dose Cohort C 
 
D1 
D2 
D8 
D15 
D29 
D50 
D71 
D92 
Blood: 
Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, and 12 hours post-SC 
injection 
Blood: 
24 hours post-SC 
injection 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Urine: 24-hour collection 
Feces: 24-hour collection 
Note: SC = subcutaneous, D = Day 


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Protocol 
Amendment 2 
12 June 2019 
CONFIDENTIAL 
94 
95 of 103 
 
 
 
Appendix C 
PK Sampling Schedule for Single- and Multiple-Dose Cohorts Continued 
 
 
PK Sampling Schedule for Multiple-Dose Cohort D 
 
D1 
D8 
D15 
D29 
D43 
D57 
D71 
Blood: 
Pre-dose, 1, 2, 3, 4, and 6 hours 
post-SC injection 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Anytime 
SC = subcutaneous, D = Day 
 
 
D85 
D92 
D99 
D113 
D127 
D141 
D155 
D176 
Blood: 
Pre-dose, 1, 2, 3, 4, and 6 hours 
post-SC injection 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
SC = subcutaneous, D = Day 


ION-682884-CS1 
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Amendment 2 
12 June 2019 
CONFIDENTIAL 
96 of 103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
Healthy Volunteers (Cohorts A, B, C and E) 
hATTR Patients (Cohort D) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
95 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Healthy Volunteers (Cohorts A, B, C and E) 
The following grading recommendations for adverse events relating to lab test abnormalities and 
adverse events at the injection site are based upon the Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept. 2007. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
96 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
Healthy Volunteers (Cohorts A, B, C and E) Continued 
 
 
 
 
 
 
 
 
 
 
97 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
Healthy Volunteers (Cohorts A, B, C and E) Continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
98 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
hATTR Patients (Cohort D) 
The following grading recommendations for adverse events relating to lab test abnormalities and 
adverse events at the injection site are based upon the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0, November 2017. 
 
 
 
 
 
99 


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Amendment 2 
12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
hATTR Patients (Cohort D) Continued 
 
 
100 


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12 June 2019 
CONFIDENTIAL 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
hATTR Patients (Cohort D) Continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
101 


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Protocol 
 
 
 
Version: 2 
Version Date: 13 Jun 2019 
Title: A Phase 1/2 Stidu tp Evaluate the Safety, Tolerabilikty, Pharmacokinetics, and 
Pharmacodynamics of ION-682884, an Antisense Inhibitor of Transthreytin 
Production, in Healthy Volunteers and Patients with Transthyretin-Mediated 
 
 
 
 
 
 
 
 
APPROVALS: 
 
, 13-Jun-2019 21:45:48 GMT+0000 


 
 
Official Title: 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy Volunteers 
and Patients with Hereditary Transthyretin-Mediated Amyloidosis 
NCT Number: 
NCT03728634 
Document Date: 
SAP Version 2: 07-April-2020 


1 of 26 
 
 
Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc. 
Study Number: ION-682884-CS1 
 
 
11 November 2021 
 16. Appendices 
 
 
 
1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan, Version 2.0 (06 April 2020), is provided. 
Note to File – Revised Tables, Figures, and Listings 


2 of 26 
 
 
682884-CS01 Statistical Analysis Plan 
06 Apr 2020 | 2.0 
 
Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
 
April 6, 2020 
Statistical Analysis Plan 
 
ION-682884-CS1 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
ION-682884-CS1 
 
A Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ION-682884, an 
Antisense Inhibitor of Transthyretin Production, in Healthy 
Volunteers and Patients with Hereditary Transthyretin-Mediated 
Amyloidosis 
 
 
 
Date: April 6, 2020 
 
Version: 2.0 
 
 
 
 
CONFIDENTIAL 
 
Confidential/Trade Secret information subject to 18-USC-1905 and to which all claims of privilege and 
confidentiality are asserted in both statutory and common law. Further dissemination may be made 
only with the express written permission of Ionis Pharmaceuticals, Inc. 


682884-CS01 
Statistical Analysis Plan 
06 Apr 2020 I 2.0 
Ionis Phannaceuticals, Inc. 
Statistical Analysis Plan 
April 6, 2020 
ION-682884-CS1 
CONFIDENTIAL 
3 of26 
 
 
 
 
Statistical Analysis iPlan.Signature Page 
 
Ionis Phannaceuticals, Inc. 
2855 Gazelle Court Carlsba 
CA 92010 
Compound Name: [ON-'682884 
Protocol: 
CSl 
 
Study Title: 
 
 
 
 
 
Issue Date: 
A Phase 112Stndy to Evaluate the Safe1y, 'Dolerability, 
IPharmacokmetics. and Pharmaoodynamics ofION-682884, an 
Antisense Jnluoitor of Tr:anstbyretin Production. in Healthy 
Volunteers and Patients with Hereditary Transthyretin-Mediated 
Amyloidosis 
 
12 June 2019 (P:rotocolAmemlmenl2) 
 
 
 
 
 
 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
SignaLure: 
 
 
 
 
 
lonis Pharmactuticnls, Inc. 
2-855 Gazelle Courit 
Carlsbad CA 92010 
 
 
 
 
 
 
 
 
11 


682884-CS01 
Statistical Analysis Plan 
06 Apr 2020 I 2.0 
Ionis Phannaceuticals, Inc. 
Statistical Analysis Plan 
April 6, 2020 
ION-682884-CS1 
CONFIDENTIAL 
4 of26 
 
 
 
 
 
 
 
 
Signature:  
 
 
 
 
lonis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 
 
 
Signature: _ 
 
 
 
 
 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1ll 
---- 
Date: 
oms 
armaceut1ca s, 


682884-CS01 
Statistical Analysis Plan 
06 Apr 2020 | 2.0 
Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
April 6, 2020 
ION-682884-CS1 
CONFIDENTIAL 
4 
5 of 26 
 
 
 
Table of Contents 
PRIMARY RATIONALE FOR AMENDMENT ............................................................ 6 
1. 
INTRODUCTION .................................................................................................. 7 
1.1 
Study Overview .................................................................................................. 7 
1.2 
Objectives ........................................................................................................... 9 
1.2.1 
Primary Objectives ......................................................................................... 9 
1.2.2 
Secondary Objectives ..................................................................................... 9 
1.2.3 
Exploratory Objectives ................................................................................... 9 
1.3 
Endpoints ............................................................................................................ 9 
1.3.1 
Primary Endpoints .......................................................................................... 9 
1.3.2 
Secondary Endpoints ...................................................................................... 9 
1.3.2.1 
Pharmacokinetic Endpoints .................................................................................................... 9 
1.3.2.2 
Pharmacodynamic Endpoints ................................................................................................. 9 
1.3.3 
Additional/Exploratory Endpoints.................................................................. 9 
2. 
PROCEDURES .................................................................................................... 10 
2.1 
General Overview of Procedures...................................................................... 10 
2.2 
Randomization & Treatment Allocation .......................................................... 10 
2.3 
Conduct ............................................................................................................ 10 
2.4 
Data Monitoring ................................................................................................ 11 
2.4.1 
Safety Data Monitoring ................................................................................ 11 
2.5 
Data Management .............................................................................................. 11 
2.5.1 
Case Report Form Data ................................................................................ 11 
2.5.2 
Laboratory Data ............................................................................................ 11 
2.5.3 
Pharmacokinetic Data................................................................................... 11 
3. 
ANALYTICAL PLAN ......................................................................................... 12 
3.1 
General Overview of Analyses ......................................................................... 12 
3.1.1 
Statistical Methods ....................................................................................... 12 
3.1.2 
Subject Population Analyzed ....................................................................... 13 
3.1.3 
Sample Size Consideration ........................................................................... 13 
3.1.4 
Planned Interim Analysis ............................................................................. 13 
3.1.5 
Incomplete or Missing Data ......................................................................... 14 
3.2 
Demographic and Baseline Characteristics ...................................................... 14 
3.3 
Safety Analyses ................................................................................................ 14 


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3.3.1 
Adverse Events ............................................................................................. 14 
3.3.2 
Laboratory Measurements ............................................................................. 16 
3.3.3 
Vital Signs, Weight, and BMI ...................................................................... 17 
3.3.4 
Physical Examinations ................................................................................... 18 
3.3.5 
12-Lead Electrocardiograms (ECG) ............................................................. 18 
3.3.6 
Concomitant Medications ............................................................................ 18 
3.4 
Pharmacokinetic Analysis ................................................................................ 18 
3.4.1 
Plasma Pharmacokinetics ............................................................................. 19 
3.4.1.1 
Plasma Concentration Data of Total Full-Length Oligonucleotides ..................................... 19 
3.4.1.2 
Plasma Pharmacokinetic Parameters .................................................................................... 19 
3.4.2 Urinary Excretion ............................................................................................... 21 
3.4.3 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis ............. 21 
3.4.4 
Metabolism .................................................................................................. 21 
3.4.5 
Immunogenicity (IM) Data Analysis ........................................................... 22 
3.4.5.1 
Sample Level ADA Data ..................................................................................................... 22 
3.4.5.2 
Subject Level ADA Data ..................................................................................................... 23 
3.4.5.3 
Evaluation of IM Impact on PK, PD, and Safety.................................................................. 25 
3.5 
Pharmacodynamic Analysis ............................................................................. 25 


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PRIMARY RATIONALE FOR AMENDMENT 
The following major modifications have been made to ISIS 682884 CSl SAP, version 1.0, 
dated 18 April 2019. 
List of Major Modifications 
 
Section 
Title 
Change/Rationale 
1.1 
Study Overview 
Added Coho1t EI To reflect the changes in the Protocol 
Amendment 2. 
Removed the descriptions for Cohort D / It has been 
decided that the coho1t will not be conducted 
3.4.3 
Pha1macokinetic/Pha1macodynamic 
Exposure-Response Analysis 
Update analysis method for exposure-response analysis 
3.4.4 
Metabolism 
Add metabolism assessment and analysis plan 
3.4.5 
Immunogenicity (IM) Data 
Analysis 
Add immunogenicity data analysis plan 
3.6 
Additional Analysis 
Removed/ It has been decided the coho1t D will not be 
conducted 


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1. 
INTRODUCTION 
This document provides a description of the study organization, study procedures, and the plan 
for the statistical analysis of the study data. Section 1 discusses study design, objectives, and 
endpoints; Section 2 provides the study procedures; Section 3 provides the detailed plan for 
the statistical analyses. 
As with any statistical analysis plan (SAP), the proposed methods and approaches to the data 
analysis should be viewed as flexible. The statistical analysis to some degree is iterative since 
so much of the planning is based on statistical and other assumptions, which require 
verification. 
 
1.1 
Study Overview 
 
This will be a Phase 1/2 study, consists of 2 portions. The healthy volunteer, Phase 1 portion 
will be a double-blind, randomized, placebo-controlled, dose-escalation study. It will be 
conducted at a single center and consist of 1 single-dose cohort and 2 planned multiple-dose 
cohorts (n = 12 per cohort, 10 active : 2 placebo). Approximately 36 healthy volunteers are 
planned to be enrolled. Twenty-four (24) subjects will be enrolled in the 2 planned multiple- 
dose cohorts and 12 subjects will be enrolled in the single-dose cohort. An additional multiple- 
dose cohort, Cohort E (n = 12), was added resulting in a total of approximately 48 healthy 
volunteers. The individual cohorts may be expanded to better assess the safety, tolerability, 
pharmacokinetic and pharmacodynamic of ION-682884 to meet study objectives. Maximum 
enrollment will be limited to 60 subjects in this portion. 
 
The second portion of the study will be an open-label, multi-dose study in hATTR patients. It 
has been decided that this portion of the study, Cohort D (hATTR patient cohort), will not be 
conducted as planned. Therefore, the data analysis for Cohort D will not be performed. 
 
Multiple-Dose Healthy Volunteer Cohorts 
Cohort 
Number of Doses 
Total ION-682884 
Cohort A: 45 mg ION-682884 or placebo SC 
4 
180 mg 
Cohort B: 90 mg ION-682884 or placebo SC 
4 
360 mg 
 
Subjects enrolled in the multiple-dose, healthy volunteer cohorts will receive SC doses of 
Study Drug once every 4 weeks for a total of 12 weeks (total of 4 doses). Following the 
administration of the 1st dose of Study Drug in each multiple-dose cohort, individual subjects 
must have completed their Day 15 safety evaluations with an acceptable safety profile, as 
determined by the Safety Committee, before receiving additional doses of Study Drug. Dosing 
in Cohort B can only proceed when at least 8 subjects in Cohort A have completed Day 29 


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safety evaluations and have demonstrated an acceptable safety profile as determined by the 
Safety Committee. 
 
An additional multiple-dose, healthy volunteer cohort (Cohort E) with 4 every-4-week doses 
of 60 mg ION-682884 or placebo, was added to further elucidate safety and PD effects of 
ION-682884. Dosing in Cohort E can only proceed when at least 8 subjects in Cohort B have 
completed Day 29 safety evaluations and have demonstrated an acceptable safety profile as 
determined by the Safety Committee. 
Cohort 
Number of Doses 
Total ION-682884 
Cohort E: 60 mg ION-682884 or placebo SC 
4 
240 mg 
The length of each subject’s participation in the multiple dose cohorts (Cohorts A, B, and E) 
is approximately 29 weeks, including a 4-week Screening Period, a 12-week Treatment Period, 
and a 13-week Post-Treatment Evaluation Period. Subjects will receive a total of 4, once every 
4 weeks, fixed SC doses of ION-682884. 
 
Single-Dose Healthy Volunteer Cohort 
Cohort 
Number of Doses 
Total ION-682884 
Cohort C: 120 mg ION-682884 or placebo SC 
1 
120 mg 
 
Dosing in Cohort C can only proceed when at least 8 subjects in Cohort A have completed 
Day 57 safety evaluations and have demonstrated an acceptable safety profile as determined 
by the Safety Committee. Subjects enrolled in the single-dose treatment cohort will receive a 
single SC dose of the Study Drug (ION-682884 or placebo) on Day 1. 
 
For each multiple-dose or single-dose healthy volunteer cohort, the first 2 (sentinel) subjects 
(randomized 1 active:1 placebo) will be dosed on the same day. If no major safety concerns 
are observed following 48 hours of observation, as determined by the Safety Committee, 
dosing of the remaining 10 subjects (randomized 9 active:1 placebo) in that cohort may 
proceed. 
 
The length of each subject’s participation in the single dose cohort (Cohort C) is approximately 
17 weeks, including a 4-week Screening Period, a single-dose on Day 1 and 13 weeks of Post- 
Treatment Follow-up. Subjects will return for outpatient visits as outlined in protocol 
Appendix A. 
 
 
hATTR Patient Cohort 
It has been decided that Cohort D (hATTR patient cohort) will not be conducted. 


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1.2 
Objectives 
 
1.2.1 
Primary Objectives 
To evaluate the safety and tolerability of single and multiple doses of ION-682884 
administered subcutaneously to healthy volunteers and patients with hATTR. 
 
1.2.2 
Secondary Objectives 
To evaluate the pharmacokinetic and pharmacodynamic profiles of single and multiple doses 
of ION-682884 administered subcutaneously to healthy volunteers and patients with hATTR. 
 
1.2.3 
Exploratory Objectives 
To evaluate the effects in hATTR patients of multiple doses of ION-682884 on the mNIS+7, 
Norfolk QoL, 6MWT, 10MWT, EQ-5d, SF-36, COMPASS, and Amyloidosis-specific QoL. 
 
Since Cohort D (hATTR patient cohort) will not be conducted, the corresponding objectives 
and endpoints for the cohort will not be evaluated. 
 
1.3 
Endpoints 
 
1.3.1 
Primary Endpoints 
Analysis of safety labs, AEs, concomitant medications, ECG and physical examinations of 
healthy volunteers and patients with TTR amyloidosis following subcutaneously 
administration of single and multiple doses of ION-682884. 
 
1.3.2 Secondary Endpoints 
 
1.3.2.1 Pharmacokinetic Endpoints 
The plasma pharmacokinetics of ION-682884 will be assessed following single and multiple 
SC administration(s). The amount of ION-682884 excreted in urine over selected 24-hour 
collection intervals will be determined, and metabolite identification and profiling may also be 
determined in some of the collected plasma, urine, and fecal samples, at a later time. 
 
1.3.2.2 Pharmacodynamic Endpoints 
Analysis of pharmacodynamic data will determine the change and percent change from 
Baseline in plasma TTR and RBP4 levels following single- and multiple-dose SC 
administration of Study Drug. 
 
1.3.3 
Additional/Exploratory Endpoints 
Exploratory endpoints for the open-label, hATTR patient cohort are the change from Baseline 
to Week 14 or Week 15 in the following: 


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• Modified neuropathy impairment score +7 (mNIS +7) score 
• Norfolk quality of life-diabetic neuropathy (Norfolk QOL-DN) questionnaire total 
score 
• 6 Minute walk test (6MWT) 
• 10 Meter Walk Test (10-MWT) 
• EuroQoL-5 Dimensions (EQ-5d) 
• SF-36 physical functioning domain and physical component score 
• COMPASS-31 autonomic neuropathy questionnaire 
• Amyloidosis-specific QoL questionnaire 
 
Since Cohort D (hATTR patient cohort) will not be conducted, the exploratory endpoints 
described in this section will not be evaluated. 
 
2. 
PROCEDURES 
2.1 
General Overview of Procedures 
Ionis Pharmaceuticals, Inc. will review all study data including source documents, CRFs, and 
laboratory reports. The study site will enter subject source data into the case report form. 
Central laboratory data will be transferred electronically to Ionis Pharmaceuticals, Inc. 
 
2.2 
Randomization & Treatment Allocation 
Subjects will be randomized (Cohorts A, B, E and C) after all Baseline and Screening 
assessments have been completed and after the Investigator has verified that they are eligible 
per criteria in protocol Sections 5.1 and 5.2 (Cohorts A, B, E and C). No subject may begin 
treatment prior to randomization or registration and assignment of a unique subject 
identification number. 
 
For Cohorts A, B, E and C, within each cohort, subjects will be randomized 10:2 to receive 
ION-682884 or placebo as outlined in protocol Section 3.1. The randomization list will be 
prepared by an independent external vendor. 
 
2.3 
Conduct 
The study will be conducted in accordance with current Good Clinical Practice (GCP) and 
International Conference on Harmonization (ICH) guidelines, the World Medical Association 
Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of Federal 
Regulations, and all other local regulatory requirements. 


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2.4 
Data Monitoring 
 
2.4.1 Safety Data Monitoring 
Ionis Pharmaceuticals, Inc. (or designee) is responsible for processing all reported adverse 
events (AEs). All serious adverse events (SAEs), reported to Ionis Pharmaceuticals, Inc. (or 
designee), are reviewed according to standard operating procedures. The medical monitor will 
review all AEs and SAEs on an ongoing basis throughout the study. Ionis Pharmaceuticals, 
Inc. (or designee) will prepare and submit safety reports to the health authorities worldwide in 
accordance with local requirements. If it becomes necessary to communicate new safety 
information, Ionis Pharmaceuticals, Inc. (or designee) will also prepare a safety notification 
letter and transmit it to study site. 
 
2.5 Data Management 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this Study. 
 
2.5.1 
Case Report Form Data 
BioClinica (or designee) is responsible for creating the Electronic Data Capture (EDC) data 
entry screens, database and edit checks using definitions developed by Ionis Pharmaceuticals, 
Inc. Ionis Pharmaceuticals, Inc. is responsible for the review, data management querying and 
locking of the database. 
Data are single-entered into the EDC system by the site staff. Programmed edit checks 
(computer logic that checks the validity of the data entered and also prompts for missing data 
that is expected to be entered) are run and automatic queries are generated. Ionis 
Pharmaceuticals, Inc. reviews all data for accuracy and validity and generates additional 
queries in the EDC system when necessary. The data is corrected or an explanation concerning 
the query is provided in the EDC system. After all data are entered, reviewed (by Data 
Management and Clinical Development) and queried, and all queries resolved, the database is 
locked. 
 
2.5.2 
Laboratory Data 
Ionis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data 
transfers, transfer schedule and review of the clinical laboratory data. This lab data will be 
stored as SAS data sets or Excel files. 
 
2.5.3 
Pharmacokinetic Data 
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the plasma and 
urine drug concentration data. Final data, which has been approved by Quality Assurance, 
will be stored in controlled repository. 


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3. 
ANALYTICAL PLAN 
3.1 
General Overview of Analyses 
 
3.1.1 
Statistical Methods 
Descriptive summary statistics including number of subjects, 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. All statistical tests will be conducted using 2- 
sided tests with 5% Type I error rate unless otherwise stated. In view of the exploratory nature 
of this study, adjustments for multiplicity of testing will generally not be used. 
 
Both central and local lab data will be used in platelet analyses, including by visit 
summaries/figures and abnormality summary. For other lab tests, only central laboratory data 
will be used. 
PK parameters will be summarized using number of subjects, mean, standard deviation, 
coefficient of variation (CV), geometric mean, geometric %CV, median, minimum, and 
maximum. 
The placebo subjects in the multiple-dose healthy volunteer cohorts (Cohorts A, B, and E) 
will be pooled. 
The summaries will be presented separately for: 
• Single-dose healthy volunteer cohort (Cohort C) 
• Multiple-dose healthy volunteer cohorts (Cohorts A, B, and E) 
Baseline definition 
For ECG, baseline for numeric results will be defined as the average of the triplicates taken on 
Day 1 Pre-dose, if more than one time point is taken on Day 1 pre-dose, all non-missing 
assessments (time points and replicates) will be averaged as the baseline value. Baseline for 
character results will be defined as the worst of Day 1 Pre-dose assessments. 
 
For platelet count, baseline will be defined as the average of all non-missing pre-dose 
assessments, including unscheduled visits. 
 
For other assessments, when 2 or more measurements are obtained prior to the subject or 
patient receiving their first dose of Study Drug, baseline will be defined as the average of the 
pre-dose measurement closest to Day 1 and Day 1 pre-dose. Day 1 pre-dose is the Day 1 
measurement taken prior to the time of the first dose. Otherwise baseline will be defined as the 


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last non-missing measurement prior to the date and time of the first dose of Study Drug (ION- 
682884 or placebo). 
 
Analytical visits: 
Data will be summarized using the visit labels provided in the data. Multiple results with the 
same visit label will be averaged. Results with visit labels as “Unscheduled” or “Early 
Termination Follow-up” will not be included in the by-visit summary tables and figures 
except for determining baseline and laboratory abnormality summaries, but will be presented 
in data listings. 
 
3.1.2 
Subject Population Analyzed 
The following analysis populations will be used for the analysis of data as described within 
each analysis population. 
Full Analysis Set: All randomized subjects (Cohorts A-C, E) who receive at least 1 injection 
of Study Drug (ION-682884 or placebo). 
Per Protocol Set: Subset of the Full Analysis Set that have received at least 3 doses of Study 
Drug (1 for the single-dose healthy volunteer cohort) and that have no significant protocol 
deviations that would be expected to affect efficacy assessments. 
Safety Set: All randomized subjects (Cohorts A-C, E) who receive at least 1 injection of Study 
Drug. 
Pharmacokinetic Set: All subjects who are randomized and receive at least 1 dose of active 
Study Drug (ION-682884) and have at least 1 evaluable PK sample. 
In addition to the above analysis populations, it is recognized that some data displays will be 
provided for “All Screened”, “Screening Failures” and “All Randomized” subjects but no 
data analysis will be executed in these populations except for the disposition table that 
includes all screened subjects. 
 
3.1.3 
Sample Size Consideration 
There is no statistical rationale for the selected sample size of the single-dose and multiple- 
dose treatment cohorts. The sample size was based on prior experience with second generation 
ASOs in healthy volunteers to ensure that the safety, tolerability, PK, and preliminary PD of 
ION-682884 will be adequately assessed while minimizing the unnecessary subject exposure. 
 
3.1.4 
Planned Interim Analysis 
Unblinded analyses may be conducted after completion of dosing in each healthy volunteer 
cohort. 


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3.1.5 
Incomplete or Missing Data 
Missing values will not be imputed unless otherwise specified 
 
3.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g., age, gender, race, height, weight, BMI, TTR 
type) will be summarized using descriptive statistics by treatment group. 
For race summary, if multiple races were recorded in database, ‘Multiple Race’ will be used 
in the summary table, details will be provided in the listing. 
Medical history will be provided in the data listings. 
Subject enrollment and disposition will be summarized for each treatment group and for all 
subjects. The summaries will include: the total number of screened subjects, the number of 
randomized or registered subjects, the number of subjects in each analysis set (with the 
exception of the PK Set), the number of subjects completing treatment, the primary reason 
for terminating treatment, the number of subjects completing post-treatment follow-up, and 
the primary reason for terminating post-treatment follow-up. 
 
3.3 
Safety Analyses 
The safety analysis will be conducted on the Safety Set. 
 
3.3.1 
Adverse Events 
An adverse event will be regarded as treatment emergent if it is present prior to receiving the 
first dose of Study Drug and subsequently worsens, or is not present prior to receiving the 
first dose of Study Drug but subsequently appears. 
If there is no “Formlink” link, and the AE (start date/time) occurs after the subject’s first dosing 
date/time, then the AE is treatment-emergent. Otherwise, if the AE (start date/time) occurs 
prior to the subject’s first dosing date/time, then the AE is not treatment-emergent. 
 
If there is a “Formlink” link between two AE records, the records will be compared as a pair, 
and consider two cases, where the AE severity (mild/moderate/severe) will be compared 
between the two records in the pair. The 2 records will be chronologically ordered by AE start 
date and referred to as the “first” and “second” AEs. 
 
Case 1: The first AE record in the pair occurs before first dosing, and the second record occurs 
after dosing. 
 
If the AE severity on the second record is worse than the severity on the first record, then only 
count the second AE as treatment-emergent. But, if the severity improves (second record 


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severity is less severe than the first record severity), then neither record is counted as treatment- 
emergent. 
 
Case 2: Both AE records in the pair occur after first dosing. 
 
If the AE severity on the second record is worse than the severity on the first record, then count 
both records as treatment-emergent. But, if the severity improves, then only count the first 
record as treatment-emergent. 
 
When counting the total number of treatment-emergent events, events linked together through 
change in severity will still be counted as separate events. 
 
The most conservative approach will be used to determine if the event occurs after treatment. 
For example, if the onset date or resolution date of an AE is prior to the first study treatment 
date, it will be considered to have occurred prior to the study period. If the onset or 
resolution date of an AE is a partial date with only month or year available or completely 
missing, then the event is assumed to be within the study period unless the year is prior to the 
year of the first study treatment date, or if in the same year, the month is prior to the month of 
the first study treatment date. 
The incidence of AEs will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) (version 21.1) preferred term and system organ class for: 
• Any treatment emergent adverse events 
• Related treatment emergent adverse events. Related is defined as “Related”, 
“Possible”, or missing relationship to study drug 
• Any treatment emergent adverse events by severity. At each level of patient 
summarization, a patient is classified according to the highest severity if the 
patient reported one or more events. Adverse events with missing severity will 
categorized as “Missing” for this summary 
• Related treatment emergent adverse events by severity 
• Serious treatment emergent adverse events 
• Serious and related treatment emergent adverse events 
AEs that lead to study discontinuation or investigational drug discontinuation will be listed. 
Non-treatment emergent adverse event will be flagged in the data listing. 
 
Local Cutaneous Reactions at the Injection Site 


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Local cutaneous reaction at injection site (LCRIS) is defined as adverse events with the 
preferred terms (PTs) Injection site erythema, Injection site swelling, Injection site pruritus, or 
Injection site pain that started on the day of injection, persisted for at least two days or ongoing. 
Events with onset date on the day of injection and missing resolution date will also be included. 
The number and percent of patients in each treatment group experiencing LCRIS will be 
tabulated. 
Percentage of injections leading to LCRIS will also be summarized. Percentage of injections 
leading to LCRIS will be calculated for each patient as (A/B)*100, where A is the number of 
injections with LCRIS, and B is the total number of injections. 
LCRIS will be listed. 
 
Flu-like Reactions 
 
Flu-like reaction (FLR) is defined as adverse events with PTs including either (A) Influenza 
like illness or (B) Pyrexia or Feeling hot or Body temperature increased, plus at least two of 
the following symptoms with the PTs: Chills, Myalgia, or Arthralgia, starting on day of 
injection or the next day. 
FLRs will be summarized using the MedDRA coding system, by preferred term. 
Percentage of injections leading to FLRs will be summarized by treatment group using the 
descriptive statistics. 
Percentage of the injections leading to FLRs will be calculated as follows for each patient: 
(A/B)*100, where A=number of injections leading to FLRs, and B=total number of 
injections. 
FLRs will be listed. 
 
3.3.2 
Laboratory Measurements 
The following is the list of lab analytes that will be collected throughout the study: 
• Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, 
calcium, magnesium, phosphorus, BUN, creatinine, uric acid, total bilirubin, 
direct (conjugated) bilirubin, indirect (unconjugated) bilirubin, ALT, AST, 
alkaline phosphatase, creatinine kinase, total IgG, and total IgM 
• Hematology: red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, 
RDW, MPV, platelets, white blood cells, and wBC differential (percentage and 
absolute count) (basophils, eosinophils, lymphocytes, monocytes and neutrophils) 
• Coagulation: aPTT, PT, INR 


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• Complement: Bb, C5a 
• Thyroid Panel: TSH, free T4, total T3. The data will only be displayed in subject 
listings. 
• Screening Tests: hepatitis B surface antigen, hepatitis C antibody, HIV antibody, 
FSH (women only, if applicable), serum βhCG (women only) and Drug/alcohol 
screen. The data will only be displayed in subject listings. 
• Inflammatory: hs-CRP. 
• Urinalysis: color, appearance, specific gravity, PH, P/C ratio, A/C ratio, protein, 
blood, ketones, urobilinogen, glucose, bilirubin, leukocyte esterase, nitrate, 
microscopic examination. The numeric results will be summarized. 
All lab data will be displayed in subject listings. 
Chemistry, hematology, coagulation, complement, inflammatory, and urinalysis (result, 
change and percent change from baseline) will be summarized using descriptive statistics (n, 
mean, median, standard error, standard deviation, Q1, Q3, minimum, and maximum) by 
treatment group and study visit. 
For ALT and AST, the number and percent of subjects falling in each of the following 
categories based on the confirmed results will be tabulated by treatment group: 
• ALT/AST > 3 x ULN, which is confirmed 
• ALT/AST > 5 x ULN, which is confirmed 
For platelet count, the number and percentage of subjects falling in each of the following 
categories based on the confirmed results will be tabulated by treatment group: 100,000/mm3 
to <140,000/mm3, 75,000 to <100,000/mm3, 50,000 to <75,000/mm3, 25,000 to <50,000/mm3, 
0 to <25,000/mm3, which is confirmed. 
 
A confirmed value is based on a consecutive lab value within 7 days. If that value is in the 
same or worse category the initial value is confirmed. If the consecutive value is in a better 
category, then the initial value is confirmed using the consecutive value category. If there is 
no retest within 7 days, then the initial value is presumed confirmed. If there are multiple results 
on the same day, no matter from the same lab vendor or different lab vendors, then the worst 
value will be utilized in the analysis. 
 
3.3.3 
Vital Signs, Weight, and BMI 
Vital signs will include heart rate, respiratory rate, body temperature, systolic and diastolic 
blood pressure. Summary tables will be created to present the descriptive statistics (n, mean, 
standard error, standard deviation, median, Q1, Q3, minimum, and maximum) for vital sign 


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values, weight, BMI as well as the change and percent change from baseline at each study 
visits. 
 
3.3.4 
Physical Examinations 
Adverse changes in physical examinations that are deemed clinically significant by the 
Investigator will be classified as adverse events. All physical examination data will be 
provided in a data listing. 
 
3.3.5 
12-Lead Electrocardiograms (ECG) 
The ECG data will include ventricular rate, PR interval, QRS duration, QT, QTcF (QT 
corrected using the Fridericia’s formula), QTcB (QT corrected using the Bazett’s formula), 
and Overall interpretation. QTcF and QTcB will be calculated based on the subject’s 
reportable ECG data at each time point using the formula described below: 
QTcF = QT / (RR) 1/3, where RR= 60/VR 
QTcB = QT / (RR) 1/2, where RR= 60/VR 
QTcF and QTcB will be calculated from each ECG triplicate measurement. The machine- 
specific QTcB values (recorded from ECG machine on the CRF) will not be summarized. 
Summary tables will be created to present the descriptive statistics for ECG parameters as well 
as the change and percent change from baseline at each study visits. For triplicates or multiple 
results at same visit, the average will be used in the summary. 
 
For the categorical data, counts and percentages will be provided. For triplicates or multiple 
results at the same visit, the worst case result will be used in the summary. 
 
3.3.6 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug dictionary (version Global B3 
September 2018) and summarized by ATC class, generic name and treatment group. 
 
3.4 
Pharmacokinetic Analysis 
The plasma pharmacokinetics of ION-682884 (measured as total full-length oligonucleotides 
or ION-682884-equivalent, i.e., ION-682884-eq, including fully conjugated, partially 
conjugated, and unconjugated ION-682884), will be assessed following SC administration. 
The amount of ION-682884-eq excreted in urine over selected 24-hr collection intervals will 
be determined following single and multiple SC administrations. 
 
Data from metabolite identification and profiling in some of the collected plasma, urine, and 
fecal samples will be reported either in the CSR or separately, if the samples are analyzed at 
a later time. 


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3.4.1 
Plasma Pharmacokinetics 
 
3.4.1.1 Plasma Concentration Data of Total Full-Length Oligonucleotides 
Plasma concentrations of ION-682884-eq., along with the scheduled (nominal) and actual 
samples times (i.e., time from SC dosing) will be listed for each subject, by treatment group, 
dose cohort, nominal dose, and day. In addition, percent differences between scheduled and 
actual sampling times will also be listed for all subjects. 
 
Plasma concentrations below the lower limit of quantification (LLOQ) will be indicated by 
“BLQ”. For the purpose of calculating typical descriptive statistics (n, mean, SD, %CV, 
geometric mean, geometric %CV, median, minimum, and maximum) for plasma 
concentrations, all BLQ values will be set to zero. Mean plasma concentrations that are BLQ 
will be presented as BLQ, and the SD, %CV, geometric mean, and geometric %CV, will be 
reported as not applicable. Summary statistics of the ION-682884 plasma concentrations will 
be tabulated by treatment group, dose cohort, nominal dose, day, and scheduled time point. At 
the discretion of the pharmacokineticist and/or biostatistician, samples may be excluded from 
descriptive statistics if there are large deviations between scheduled and actual sampling times, 
or large deviations between actual dose and nominal dose. 
 
ION-682884-eq. plasma concentration versus time (actual) profiles for each subject that 
received ION-682884 active treatment, as well as the median plasma concentrations versus 
time (scheduled) profiles in both single- and multiple-dose cohorts, will be presented 
graphically on linear and/or semilogarithmic scales. At the discretion of the 
pharmacokineticist and/or biostatistician, samples may be excluded from the median plots if 
there are large deviations between scheduled and actual sampling times. 
 
3.4.1.2 Plasma Pharmacokinetic Parameters 
Non-compartmental pharmacokinetic analysis of ION-682884-eq. will be carried out on each 
individual subject data set using Phoenix WinNonlin Version 8 or higher (Certara L.P., 
Mountain View, CA). Plasma pharmacokinetic parameters in each subject (when applicable) 
will be determined. For calculation of PK parameters, all BLQ values will be set to zero. The 
following plasma PK parameters for ION-682884-eq. will be calculated (when applicable and 
not necessarily limited to) and based on actual sampling times: 
• Cmax: the maximum observed ION-682884-eq. concentration in plasma. 
• Tmax: the time at which Cmax occurs. 
• AUC0-24h: partial areas under the plasma concentration-time curve from zero time (pre- 
dose) to 24 hours will be calculated using the linear up-log down trapezoidal rule 
• AUClast: partial areas under the plasma concentration-time curve from zero time 
(predose) to the last quantifiable concentration (Tlast) using Cobserved will be calculated 


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using the linear up-log down trapezoidal rule for the single-dose cohort (i.e., Cohort C) 
only. 
• AUC0-∞: area under the plasma concentration-time curve (AUC) from time zero to the 
last quantifiable concentration (AUClast) with extrapolation to infinity observed will be 
calculated using the linear up-log down trapezoidal rule. This parameter will be 
calculated for the single-dose cohort (i.e., Cohort C). 
• %AUCextr: percentage of extrapolated area under the curve from Tlast to infinity, 
expressed as percentage of AUC0-∞. This parameter will be calculated for Cohort C 
only. 
• AUC0-672h (i.e., AUC): partial area under the plasma concentration-time curve (AUC) 
over a dosing interval (i.e., from time zero to 672 hours), will be calculated using the 
linear up-log down trapezoidal rule, as appropriate. 
• CL/F: Apparent plasma clearance after SC administration. This parameter will be 
calculated as CL/F = Actual Dose/AUC0-∞ for Cohort C only. 
• CL0-24h/F: Apparent plasma clearance from time zero to 24 hours after SC 
administration. This parameter will be calculated as CL0-24h/F = Actual Dose/AUC0-24h. 
• CLss/F: Apparent plasma clearance at steady-state after SC administration. This 
parameter will be calculated as CLss/F = Actual Dose/AUC following the last dose in 
the MD cohorts only. 
• t1/2λz: apparent terminal elimination half-life will be calculated from the equation, t1/2λz 
= 0.693/λz, where λz is the rate constant associated with the apparent terminal 
elimination phase. This parameter will be calculated for Cohort C (if data permitted) 
and following the last dose in the MD cohorts, as appropriate. 
• Vz/F: Apparent volume of distribution in the terminal phase will be calculated from 
Vz/F = CLss/F/ λz. This parameter will be calculated for Cohort C and following the 
last dose in the MD cohorts, as appropriate. 
 
z shall be determined over a time interval equal to at least 1.5 x t1/2λz. A minimum of three 
data points in the elimination phase will be used to calculate z using log-linear regression 
analysis and the adjusted correlation of determination values (r2_adj) shall be at or greater than 
0.8 for the estimate to be accepted. If at least one of these three conditions are not fulfilled, 
the PK parameters depending on z (i.e., AUC0-∞, %AUCextr, t1/2λz, and Vz/F) shall be flagged 
as not reliable if calculated and listed. They will generally be excluded from descriptive 
statistics and statistical testing procedures, or at the discretion of the pharmacokineticists, who 
are in charge of the PK analysis. 


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Plasma pharmacokinetic parameters will be summarized using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric %CV, median, minimum, and maximum) by treatment 
group, dose cohort, nominal dose, and day. Additionally, the relationship between dose and 
plasma exposure parameters (Cmax and AUC) of total full-length ASOs (ION-682884-eq.) will 
be evaluated using linear-regression analysis of the log-transformed mean data. 
 
3.4.2 Urinary Excretion 
The amount and percentage of the administered dose excreted in urine as total full-length 
oligonucleotides (ION-682884-eq.) following 0 to 24-hour collection will be calculated using 
the following equation on Day 1 in single-dose cohorts, and following the first and last dose in 
multiple-dose cohorts: 
Ae0-24h = Curine x Vurine 
Where, Ae0-24h is the amount excreted up to 24 hours, Curine is the urine concentration of 
ION-682884-eq., and Vurine is the total urine volume. The percentage of the administered dose 
excreted in urine (as ION-682884) will then be calculated from the following expression: 
 
% Dose Excreted = (Ae0-24h Administered Dose) x 100% 
 
Renal clearance (CLr) will also be determined from the following expression: 
𝐴𝐴𝐴𝐴0-24h 
𝐶𝐶𝐶𝐶𝑟𝑟 = 𝐴𝐴𝐴𝐴𝐶𝐶 
Urinary excretion PK parameters will be summarized using descriptive statistics (n, mean, SD, 
%CV, geometric mean, geometric CV%, median, minimum, and maximum) by treatment 
group, cohort, nominal dose and day. At the discretion of the pharmacokineticist and/or 
biostatistician, urinary excretion PK parameters may be excluded from the statistical summary 
if the collection interval is less than 16.8 hours (i.e., <30% of planned collection interval) 
and/or missing collection interval. 
 
3.4.3 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis 
Exposure-response relationship may be explored graphically between plasma trough and 
post-treatment concentrations, and selected PD measures (e.g., TTR level and/or %baseline), 
if the data deemed appropriate. 
 
Population PK and PKPD analysis may be performed using the PK and PD data from this 
study, and/or combined with other clinical study data and reported separately in the future. 
 
3.4.4 
Metabolism 
A subset of plasma, urine, and fecal samples collected from the study will be further analyzed 
using a non-validated HPLC-MS/MS method to characterize and profile the relative abundance 
0-24h 


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of each full-length oligonucleotide species, including parent compound ION-682884, ION- 
682884 with 1, 2, and/or 3GalNAc sugar deletions, and unconjugated ION-682884. Evaluation 
of oligonucleotide metabolites of ION-682884 (shortmer metabolites) will be conducted using 
a non-validated HPLC-UV-MS method. Lastly, the presence of ION-682884 linker-related 
metabolites will be characterized in a subset of the collected plasma, urine, fecal samples using 
a non-validated HPLC-MS/MS method. 
 
For metabolism data associated with identification and characterization of the concentrations 
and relative abundance of each full-length oligonucleotide species, including fully conjugated 
ION-682884, ION-682884 with 1, 2, and/or 3 GalNAc sugar deletions, and unconjugated ION- 
682884, concentrations of total full-length oligonucleotides will be calculated by the sum of 
molar concentrations of each full-length oligonucleotide species (including fully conjugated, 
partially conjugated, and unconjugated ION-682884) for each sample collected for metabolite 
identification and profiling. Relative abundance of each full-length oligonucleotide species in 
the sample will be calculated as the molar concentration each full-length oligonucleotide 
species divided by the molar concentrations of the total full-length oligonucleotides and 
expressed as percentage. Concentrations and relative abundance of each full-length 
oligonucleotide species will be summarized by limited descriptive statistics (n, mean, and SD). 
All BLQ values will be set to zero when calculating descriptive statistics. Percent abundance 
of each full-length oligonucleotide species will not be calculated if all the full-length 
oligonucleotide species in the sample are BLQ. 
 
Data from profiling of length-based oligonucleotide metabolites associated with nuclease- 
mediated metabolism (shortmer oligonucleotide metabolites), i.e., percent peak areas, as well 
as characterization of linker-related metabolites, will reside in their respective bioanalytical 
reports, and may be summarized using limited descriptive statistics if deemed necessary. 
 
3.4.5 Immunogenicity (IM) Data Analysis 
 
Samples collected Days 1, 15, 29, 92/99, and 176, including early termination samples from 
both single and multiple dose cohorts, will be analyzed for anti-ION-682884 antibodies 
(ADA) to evaluate ION-682884 immunogenicity. Samples for IM assessment were 
collected prior to dosing if the subject received a study drug administration on the day of IM 
sample collection. 
 
3.4.5.1 
Sample Level ADA Data 
An evaluable sample will be designated ‘Positive’ based on both positive screening and 
confirmation assay results (i.e., confirmed positive result), and otherwise will be deemed 
‘Negative’. Sample ADA results (screen positive/negative, confirmed positive/negative, or 
unevaluable (“Unknown”), and when applicable, titer of anti-ION-682884 antibodies) before, 


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during, and after treatment with study drug (ION-682884 or placebo) (sample ADA status) 
will be listed by treatment, dose, and day of collection. 
 
The sample ADA incidence (number) and incidence rate (percent) at each evaluated study 
day will be determined and appropriately summarized by treatment and dose as the total 
number of and percentage of evaluated subjects with sample ADA negative, positive, and 
unknown status. 
 
3.4.5.2 
Subject Level ADA Data 
Subject ADA status overall (ADASTAT) will be defined as “Positive” status if they have at 
least one confirmed positive sample result at any time during the treatment or post-treatment 
evaluation periods; “Negative” status if all evaluated ADA sample results during the 
treatment and post-treatment evaluation periods are ADA negative and they have at least one 
evaluable ADA result collected post study drug treatment. Otherwise, a study subject will be 
assigned “Unknown” subject ADA status. 
 
Furthermore, subjects with positive overall ADA status will be further classified into 
different ADA types (ADATYPE) based on their baseline ADA status and the change in 
ADA titer between pre- and post-treatment as described below (Shankar et al.,2014): 
• Treatment-Induced ADA: ADA developed de novo (seroconversion) following 
biologic drug administration (i.e., formation of ADA any time after the initial drug 
administration in a subject without pre-existing ADA, i.e., baseline negative ADA) 
• Treatment-Boosted ADA: Pre-existing ADA that were boosted to a higher level 
following biologic drug administration (i.e., any time after the initial drug 
administration the ADA titer is greater than the baseline titer by a factor of 4-fold or 
more) 
• Treatment-Unboosted ADA: Pre-existing ADA that are not boosted following 
biologic drug administration (i.e., any time after the initial drug administration the 
ADA titer is less than 4-fold of the baseline titer) 
• ADATYPE would be not applicable (NA) if the subject overall ADA status is 
negative. 
 
Other subject level IM parameters to be calculated/defined will include but may not limited 
to: 
• Subject ADA Status at Baseline (ADASTATB): "Positive" if the subject has Week 1 
Day 1 pre-dose sample (baseline) is confirmed positive; "Negative" if the subject has 
Week 1 Day 1 pre-dose sample (baseline) is confirmed negative; "Unknown" if the 
subject has Week 1 Day 1 pre-dose sample (baseline) unevaluable. 


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• Onset of ADA (TFSTADA): i.e., the first day ADA positive sample observed, will be 
calculated by: the date of first sample has “positive” sample IM status - first dose date 
+1 
• Last Positive ADA Study Day (TLSTADA): defined as the last positive ADA sample 
observed from the start of study drug treatment and will be calculated by: the date of 
last sample has “positive” sample IM status - first dose date +1 
• Last IM Sampling Study Day (TLSTSAMP): defined as the last ADA sample 
collected from the start of study drug treatment and will be calculated by: the date of 
last sample collected - first dose date +1 
• Peak titer (PEAKTIT): the highest titer observed for the subject 
• Time to peak titer (TPEAKTIT): the time to reach peak titer will be calculated by: 
the date of first peak titer observed- first dose date +1 
• Total number of ADA Positive Samples (NOPOSAMP): the total number of ADA 
samples being confirmed positive for the subject 
• Total number of ADA Samples evaluated (NOADASAMT): the total number of 
ADA samples being collected and analyzed successfully with reportable results for 
the subject 
• Percentage of Positive Samples (PCPOSAMP): the percentage of ADA samples 
being confirmed positive for the subject and will be calculated by: 
NOPOSAMP 
PCPOSAMP (%) = 100 × 
 
 
NOADASAMT 
 
Lastly, subjects with positive ADA status may further be classified as being transient or 
persistent ADA response, if there are sufficient number of subjects with transient ADA 
status. Transient and persistent ADA definitions are defined below and based on Shankar et 
al. (2014): 
Transient ADA response: 
• Treatment-induced ADA detected only at one sampling time point during the 
treatment or follow-up observation period (excluding the last sampling time point, 
which will be considered persistent unless shown to be undetectable at a later time) or 
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the ﬁrst and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the subject’s last sampling time point is ADA-negative. 
Persistent ADA response: 
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the ﬁrst and last ADA-positive 


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samples (irrespective of any negative samples in between) are separated by a period 
of 16 weeks or longer or 
• Treatment-induced ADA detected only at the last sampling time point of the study 
treatment period or at a sampling time point with less than 16 weeks before an ADA- 
negative last sample. 
 
 
The subject level ADA prevalence, incidence, and positive ADA response being transient or 
persistent (if applicable) will be calculated as the number and the proportion (percent) of the 
study population during the study period by treatment and dose. Subject level IM parameters 
(as described above) will be listed by treatment and dose for all evaluable subjects, and also 
appropriately summarized (using descriptive statistics) as median, quartiles (25% and 75%), 
and range and/or presented graphically, if deemed appropriate, by treatment and dose at the 
discretion of the designated study pharmacokineticist and/or statistician. 
 
3.4.5.3 
Evaluation of IM Impact on PK, PD, and Safety 
If deemed necessary, the impact of IM on PK, PD, and safety may be evaluated by stratifying 
PK, PD, and selected safety measures by subject IM status and summarized using typical 
descriptive statistics. Other stratifications (e.g., based on antibody titer, onset of ADA, etc.) 
of selected PK, efficacy and safety assessments may also be performed if deemed warranted 
at the discretion of the pharmacokineticist, medical monitor, and/or biostatistician. 
 
3.5 
Pharmacodynamic Analysis 
The PD analysis will be conducted in the Full Analysis Set and Per Protocol Set. The change 
and percent change from baseline in TTR and RBP4 will be summarized. 
For healthy volunteer cohorts, the data will also be compared between the ION-682884 
treatment groups and placebo using one-way ANOVA (if data departs substantially from 
normality, the Wilcoxon Rank Sum test will be used). 


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Study Number: ION-682884-CS1 
11 November 2021 
 
 
Note to File 
Date: 7 March 2022 
 
To: 
ION-682884-CS1 Clinical Study Report 
From: 
 
Re: 
ION-682884-CS1 Tables, Figures, and Listings 
 
 
 
Upon further review of the draft CSR, it was discovered that the parameter ATPTLDN (Nominal 
Timepoint from Previous Dose) was incorrectly computed in the ADPC file used to generate 
tables, figures, and listings (TFLs) received from Parexel with time stamp of 07Oct2021. The 
ADPC file was corrected and all TFLs listed below were subsequently updated with a time stamp 
of 07Feb2022. 
• 
Tables: 14.2.2.1 to 14.2.2.4, 14.3.5.3-1 to 14.3.5.3-7, 14.3.5.4-1, 14.3.5.4-2, 14.3.5.5-1, 
14.3.5.5-2, 14.3.5.6-1 to 14.3.5.6-4, 14.3.5.7-1 to 14.3.5.7-4, 14.3.5.8-1, 14.3.5.8-2, 
14.3.5.9-1, and 14.3.5.9-2 
• 
Figures: 14.2.2.1-1 to 14.2.2.1-5, 14.2.2.2, 14.2.2.3-1, 14.2.2.3-2, and 14.2.2.4 
• 
Listings: 16.2.5.2.1 to 16.2.5.2.4, 16.2.8.7.1, and 16.2.8.7.2 
 
 
ATPTLDN only applies to the TFLs detailed below, while the content of all other TFLs listed 
above were unaffected by the ATPTLDN correction. Thus, only the TFLs listed below were 
included in the CSR with time stamp of 07Feb2022, while all other TFLs listed above were kept 
in the CSR with time stamp of 07Oct2021. 
• 
Tables: 14.2.2.1, 14.3.5.4-1 and 14.3.5.4-2 
• 
Figures: 14.2.2.1-1 to 14.2.2.1-5, and 14.2.2.2 
• 
Listing: 16.2.5.2.1 
 
 
 
 
 See electronic signature and date attached at end of document 
 
 


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Study Number: ION-682884-CS1 
11 November 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 1 
Version Date: 06 Mar 2022 
Title: 
 
 
 
 
 
 
 
APPROVALS: 
 
, 06-Mar-2022 16:49:29 GMT+0000