A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients With Hereditary Angioedema
Phase: PHASE2
Conditions: Hereditary Angioedema
Sponsor: Ionis Pharmaceuticals, Inc.

 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy 
of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in 
Patients With Hereditary Angioedema.  
 
NCT04030598  
 
5 May 2020 

 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 721744-CS2 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study 
to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
 
Protocol Amendment 3 – 5 May 2020 
 
EudraCT No:  2019-001044-22 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number:  760-603-4665 
Fax Number:  760-603-2625 
Key Sponsor Contact: 
 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
2 
ISIS 721744-CS2 
Protocol Amendment 3 
EudraCT No:  2019-001044-22 
 
Clinical Phase:  2a 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study 
to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
 
Protocol History: 
Original Protocol: 
 
3 May 2019 
Amendment 1: 
 
21 October 2019 
Amendment 2: 
 
29 January 2020 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA  92010 
 
 
 
 
  
 
 
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. 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
3 
Protocol Signature Page 
 
Protocol Number: 
ISIS 721744-CS2 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to 
Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients with 
Hereditary Angioedema 
Amendment:  
Amendment 3 
Date:  
 
5 May 2020 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy 
of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in 
Patients with Hereditary Angioedema,” dated 5 May 2020, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonisation 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) 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
4 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT .........................................................................................................8 
PROTOCOL SYNOPSIS ..............................................................................................................12 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................21 
STUDY GLOSSARY ....................................................................................................................22 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
1.1. 
Objectives ...................................................................................................................24 
1.1.1. 
Primary Objective .......................................................................................................24 
1.1.2. 
Secondary Objectives .................................................................................................24 
1.1.3. 
Exploratory Objectives ...............................................................................................24 
1.2. 
Study Endpoints ..........................................................................................................24 
1.2.1. 
Primary Endpoints ......................................................................................................24 
1.2.2. 
Secondary Endpoints ..................................................................................................24 
1.2.3. 
Safety Endpoints .........................................................................................................25 
1.2.4. 
Exploratory Endpoints ................................................................................................25 
2. 
BACKGROUND AND RATIONALE .......................................................................25 
2.1. 
Overview of Disease ...................................................................................................25 
2.2. 
Therapeutic Rationale .................................................................................................26 
2.3. 
ISIS 721744 ................................................................................................................26 
 
 
 
 
2.3.3. 
Preclinical Experience ................................................................................................28 
2.3.4. 
Clinical Experience .....................................................................................................28 
2.4. 
Rationale for Dose and Schedule of Administration ..................................................29 
2.5. 
Benefit-Risk Assessment ............................................................................................29 
2.5.1. 
Benefit Assessment .....................................................................................................29 
2.5.2. 
Risk Assessment .........................................................................................................29 
2.5.3. 
Overall Assessment of Benefit:Risk ...........................................................................30 
3. 
EXPERIMENTAL PLAN ..........................................................................................30 
3.1. 
Study Design ...............................................................................................................30 
3.2. 
Number of Study Centers ...........................................................................................31 
3.3. 
Number of Patients .....................................................................................................31 
3.4. 
Overall Study Duration and Follow-up ......................................................................31 
3.4.1. 
Screening ....................................................................................................................31 
3.4.2. 
Treatment Period ........................................................................................................31 
3.4.3. 
Post-Treatment Period ................................................................................................32 
3.5. 
End-of-Study ...............................................................................................................32 
3.6. 
Data and Safety Monitoring Board .............................................................................32 
4. 
PATIENT ENROLLMENT ........................................................................................32 
4.1. 
Screening ....................................................................................................................32 

ISIS 721744-CS2 
CONFIDENTIAL 
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Protocol 
5 May 2020 
 
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4.2. 
Randomization ............................................................................................................33 
4.3. 
Replacement of Patients .............................................................................................33 
4.4. 
Unblinding of Treatment Assignment ........................................................................33 
5. 
PATIENT ELIGIBILITY ...........................................................................................34 
5.1. 
Inclusion Criteria ........................................................................................................34 
5.2. 
Exclusion Criteria .......................................................................................................35 
6. 
STUDY PROCEDURES ............................................................................................36 
6.1. 
Study Schedule ...........................................................................................................36 
6.1.1. 
Screening ....................................................................................................................37 
6.1.2. 
Treatment Period ........................................................................................................37 
6.1.3. 
Post-Treatment Period ................................................................................................38 
6.2. 
Study Assessments......................................................................................................39 
6.2.1. 
Collection of Hereditary Angioedema Attack Details ................................................39 
6.2.2. 
Patient-Reported Outcomes ........................................................................................40 
6.2.2.1. 
Angioedema Quality of Life Questionnaire ...............................................................40 
6.2.2.2. 
Angioedema Activity Score ........................................................................................40 
6.2.3. 
Laboratory Assessments .............................................................................................41 
6.3. 
Restriction on the Lifestyle of Patients .......................................................................41 
6.3.1. 
Contraception Requirements ......................................................................................41 
7. 
STUDY DRUG ...........................................................................................................42 
7.1. 
Study Drug Description ..............................................................................................42 
7.2. 
Packaging and Labeling ..............................................................................................42 
7.3. 
Study Drug Accountability .........................................................................................42 
8. 
TREATMENT OF PATIENTS ..................................................................................43 
8.1. 
Study Drug Administration.........................................................................................43 
8.2. 
Other Protocol-Required Drugs ..................................................................................43 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................43 
8.4. 
Treatment Precautions ................................................................................................43 
8.5. 
Safety Monitoring Rules .............................................................................................43 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................44 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results...................................................44 
8.5.3. 
Safety Monitoring Rules for Renal Function Test Results .........................................45 
8.5.4. 
Safety Monitoring for Minor Bleeding Events ...........................................................45 
8.6. 
Stopping Rules ............................................................................................................45 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................45 
8.6.2. 
Stopping Rules for Platelet Count Results ..................................................................46 
8.6.3. 
Temporary Stopping Rules for Renal Function Test Results .....................................48 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................48 
8.8. 
Discontinuation of Study Drug ...................................................................................48 
8.9. 
Withdrawal of Patients from the Study Procedures ....................................................49 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
6 
8.10. 
Concomitant Therapy and Procedures ........................................................................49 
8.10.1. 
Concomitant Therapy .................................................................................................49 
8.10.2. 
Concomitant Procedures .............................................................................................50 
8.11. 
Treatment Compliance ................................................................................................50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................50 
9.1. 
Sponsor Review of Safety Information ......................................................................50 
9.2. 
Regulatory Requirements ...........................................................................................50 
9.3. 
Definitions ..................................................................................................................51 
9.3.1. 
Adverse Event .............................................................................................................51 
9.3.2. 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ............51 
9.3.3. 
Serious Adverse Event ................................................................................................52 
9.3.4. 
Adverse Events of Special Interest .............................................................................52 
9.4. 
Monitoring and Recording Adverse Events ...............................................................52 
9.4.1. 
Serious Adverse Events ..............................................................................................53 
9.4.2. 
Non-Serious Adverse Events ......................................................................................53 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................53 
9.4.3.1. 
Relationship to the Study Drug...................................................................................53 
9.4.3.2. 
Severity .......................................................................................................................54 
9.4.3.3. 
Action Taken with Study Drug ...................................................................................54 
9.4.3.4. 
Treatment Given for Adverse Event ...........................................................................54 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................54 
9.4.3.6. 
Follow-up of Adverse Event .......................................................................................55 
9.5. 
Procedures for Handling Special Situations ...............................................................56 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................56 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................56 
9.5.3. 
Dosing Errors ..............................................................................................................56 
9.5.4. 
Contraception and Pregnancy .....................................................................................57 
10. 
STATISTICAL CONSIDERATIONS .......................................................................57 
10.1. 
Sample Size Considerations .......................................................................................58 
10.2. 
Populations .................................................................................................................58 
10.3. 
Definition of Baseline .................................................................................................58 
10.4. 
Data and Safety Monitoring Board .............................................................................58 
10.5. 
Interim Analysis ..........................................................................................................59 
10.6. 
Planned Methods of Analysis .....................................................................................59 
10.6.1. 
Demographic and Baseline Characteristics ................................................................59 
10.6.2. 
Safety Analysis ...........................................................................................................59 
10.6.3. 
Efficacy Analysis ........................................................................................................59 
10.6.3.1. 
Primary Efficacy Analysis ..........................................................................................60 
10.6.3.2. 
Secondary Efficacy Analysis ......................................................................................60 
10.6.3.3. 
Exploratory Efficacy Analysis ....................................................................................60 

ISIS 721744-CS2 
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10.6.4. 
Pharmacokinetic Analysis ..........................................................................................60 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................61 
11.1. 
Informed Consent .......................................................................................................61 
11.2. 
Ethical Conduct of the Study ......................................................................................61 
11.3. 
Independent Ethics Committee/Institutional Review Board ......................................61 
11.4. 
Patient Confidentiality ................................................................................................62 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................62 
12.1. 
Protocol Amendments ................................................................................................62 
12.2. 
Study Termination ......................................................................................................63 
12.3. 
Study Documentation and Storage .............................................................................63 
12.4. 
Study Monitoring ........................................................................................................63 
12.5. 
Language .....................................................................................................................64 
12.6. 
Compensation for Injury .............................................................................................64 
13. 
REFERENCES ...........................................................................................................65 
14. 
APPENDICES ............................................................................................................66 
APPENDIX A. SCHEDULE OF PROCEDURES .....................................................................67 
APPENDIX B. LIST OF LABORATORY ANALYTES ..........................................................72 
APPENDIX C. PHARMACOKINETIC SAMPLING SCHEDULE .........................................74 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ..............................................................76 
 
 
LIST OF TABLES 
Table 1: 
Study Drug Characteristics .........................................................................................42 
Table 2: 
Actions in Patients with Low Platelet Count ..............................................................47 
 
 
LIST OF FIGURES 
Figure 1: 
Design of GalNAc3-Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer) ..............................................................................27 
 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
8 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 721744-CS2 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to 
Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
Amendment Number: 3 
Amendment Date: 
5 May 2020 
 
The following modifications to Protocol ISIS 721744-CS2 Amendment 2, dated 29 January 
2020, have been made.  
1) To adjust the length of time patients must not have received lanadelumab, prior to 
screening for ISIS 721744-CS2, from 6 months to 10 weeks (i.e., 5 times the ~14-day 
half life for lanadelumab).  
2) To decrease the burden of site visits where feasible for patients, Study Drug 
administration, assessements and procedures may be conducted by either a Home 
Healthcare professional (if available) or the Study Center, as arranged by the Study 
Center personnel, for visits as noted in Appendix A. 
3) To decrease the burden of PK sampling for patients, only a subgroup of approximately 
6 patients (rather than all patients) will have blood draws of pre-dose, 1, 2, 4, and 6 hours 
post-dose on Day 1 and Day 85.  This, along with a pre-dose and a 2 hour post-dose 
blood collection on Day 1 and Day 85 in all patients, will provide enough information to 
determine PK parameters. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
9 
The following table provides a summary list of major changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
PROTOCOL 
SYNOPSIS 
Study Population 
Exclusion Criteria 
 
Section 5.2.11.b 
Exclusion Criteria 
Deletions in strikeout and additions in bold: 
11.b  Chronic prophylaxis with Llanadelumab within 
10 weeks 6 months prior to Screening 
To adjust the length of time 
patients must not have received 
lanadelumab, prior to screening 
for ISIS 721744-CS2, to 
5 times the ~14 day half life for 
lanadelumab. 
PROTOCOL 
SYNOPSIS 
Study Visit Schedule 
and Procedures 
 
Section 6.1.2  
Treatment Period 
Deletions in strikeout and additions in bold: 
The first dose of Study Drug will be administered at the 
Study Center on Day 1.  ISIS 721744 Study Drug will be 
administered as a SC injection in the abdomen, thigh, or 
outer area of the upper arm by qualified personnel at the 
Study Center or Home Healthcare professional (if 
available and after dosing instructions and training are 
provided by qualified site personnel).  The first dose of 
Study Drug will be administered at the Study Center on 
Day 1.  Study visits Center personnel (or Home 
Healthcare if available), will complete procedures  per 
the Schedule of Procedures in Appendix A. will be 
performed during the Treatment Period at Week 1 
(Administration 1), Week 3 (safety monitoring), Week 5 
(Administration 2), Week 9 (Administration 3), and Week 
13 (Administration 4); 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 
Section 6.1.3 
Post-Treatment 
Period 
Additions in bold: 
Each patient will be followed for safety assessments for up 
to 13 weeks after the last dose of Study Drug.  During the 
Post-Treatment Period, patients will return to the Study 
Center (or have Home Healthcare (if available), as 
arranged by the Study Center personnel, per the 
Schedule of Procedures in Appendix A) for visits at 
Weeks 17, 21, and 26/ET for safety and clinical laboratory 
evaluations and for blood sampling for PK/PD analyses.   
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 
Section 8.1 
Study Drug 
Administration 
Additions in bold: 
Study Drug (ISIS 721744 or placebo) will be administered 
as a single-SC injection once every 4 weeks by blinded 
study staff during on-site visits at the Study Centers or by 
Home Healthcare professional (if available and after 
dosing instructions and training are provided by 
qualified site personnel).   
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
10 
Protocol Section 
Description of Change 
Rationale 
Section 10.6.4 
Pharmacokinetics 
Analysis 
Deletions in strikeout and additions in bold: 
The plasma PK of ISIS 721744 will be assessed following 
SC administration.  For all patients, pre-dose (trough) and 
post-treatment plasma ISIS 721744 concentrations will 
be determined and summarized using descriptive 
statistics.  Plasma terminal elimination half-life will also 
be calculated using the Post-Treatment follow up 
ISIS 721744 plasma concentrations, if data permits. For 
patients in the PK sub group, nNon-compartmental PK 
analysis of ISIS 721744 will be carried out on each 
individual patient dataset.   
Added paragraph to define how 
PK data will be analyzed and 
described 
STUDY 
GLOSSARY 
 
Section 10.6.4 
Pharmacokinetics 
Analysis 
Additions in bold: 
Additional details regarding the PK analysis along with 
immunogenicity (IM) analysis will be described in the 
SAP. 
Added “along with IM 
analysis” to clarify that 
immunogenicity analysis will 
be performed 
Appendix A 
Footnote  
Added: 
17 Assessments and procedures may be conducted by either 
a Home Healthcare professional (if available), or the 
Study Center as arranged by the Study Center personnel.  
Physical Exam will be labeled Body Assessment if 
conducted by Home Healthcare professional.  Study drug 
administration by Home Healthcare professional may be 
done only after study drug for home use is available 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients 
Appendix A 
Footnote  
Additions in bold: 
b 
Pre-dose, 1, 2, 4, and 6 hours post-dose (PK Subgroup) 
or Pre-dose and 2-hours post-dose 
Added to note changes in PK 
schedule 
Appendix A  
Removed: 
Week 3 pregnancy test 
Pregnancy test only needed 
every 4 weeks 
Appendix B  
Removed 
Thyroid Panel 
TSH 
Free T4 
Free T3 
Thyroid panel is not a per 
protocol assessment 
Appendix C  
Added: 
PK samples on Day 1 and Day 85 will be collected pre-dose, 
and 1, 2, 4, and 6 hours post-dose in PK subgroup only 
(approximately 6 patients) while pre-dose and 2 hours post-
dose samples on Day 1 and Day 85  will be collected for all 
other patients. The rest of the sampling schedule will be the 
same for both sets of pateints (see table below): 
Added to describe PK sampling 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
11 
Protocol 
Section 
Description of Change 
Rationale 
Appendix C 
Addions in bold: 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 176 
All 
Patients 
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime 
Blood 
Anytime 
Blood 
Anytime 
PK 
Subgroup 
Blood:  
Pre-dose, 
1, 2, 4, 
and 
6 hours 
post-dose 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood:  
Pre-dose, 
1, 2, 4, 
and 
6 hours 
post-dose 
Blood:  
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
To decrease the 
burden of PK 
sampling for 
patients, only a 
subgroup of 
approximately 
6 patients (rather 
than all patients) 
will have blood 
draws of pre-
dose, 1, 2, 4, and 
6 hours post-
dose on Day 1 
and Day 85. 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
12 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense 
Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema 
Study Phase 
2a 
Indication 
Hereditary angioedema (HAE) 
Primary 
Objective 
The primary objective of the study is to evaluate the clinical efficacy of antisense 
inhibitor of prekallikrein (ISIS 721744) in patients with HAE type 1 (HAE-1), HAE 
type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH). 
Secondary 
Objectives 
The secondary objectives of the study are to evaluate safety and tolerability of 
ISIS 721744 in patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1-
INH) and to evaluate the effect of ISIS 721744 on plasma prekallikrein (PKK) and 
other relevant biomarkers.   
Exploratory 
Objectives 
The exploratory objectives of the study are to evaluate pharmacokinetics (PK) of 
ISIS 721744 (as a total full-length antisense oligonucleotide (ASO), including fully 
conjugated, partially conjugated, and unconjugated ISIS 721744) over time and to 
assess potential PK/pharmacodynamic (PD) correlations on relevant biomarkers and 
clinical outcomes, as appropriate.   
Study Design 
The study will be randomized, double-blind, and placebo-controlled in Part A and will 
be open-label in Part B. 
Number of 
Patients 
Approximately 24 patients with HAE are planned to be enrolled in the study:  
approximately 18 patients with HAE-1/HAE-2 are planned to be enrolled in Part A of 
the study, and, in parallel, approximately 6 patients with HAE-nC1-INH are planned to 
be enrolled in Part B of the study.  Due to the rarity of HAE-nC1-INH, enrollment in 
Part B may be ended early if Study Centers are unable to enroll sufficient patients with 
HAE-nC1-INH; this will not impact completion of Part A. 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
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PROTOCOL SYNOPSIS CONTINUED 
Study 
Population 
Inclusion Criteria 
1. Patients must provide written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements for the duration of the study. 
2. Patients must be aged ≥ 18 years at the time of informed consent. 
3. Patients must have a documented diagnosis of HAE-1/HAE-2 (for inclusion in 
Part A) or HAE-nC1-INH (for inclusion in Part B) as defined below: 
a. Documented diagnosis of HAE-1/HAE-2 based upon ALL of the following: 
i. Documented clinical history consistent with HAE (subcutaneous [SC] or 
mucosal, non-pruritic swelling episodes without accompanying urticaria) 
(Maurer et al. 2018). 
ii. Diagnostic testing results that confirm HAE-1/HAE-2:  C1-INH functional 
level < 40% normal level.  Patients with a functional level of 40% to 50% 
of normal can be enrolled if their complement factor C4 (C4) level is 
below the lower limit of normal (LLN) or if a known pathogenic mutation 
in the SERPING1 gene has been demonstrated. 
iii. At least 1 of the following:  age at reported HAE onset ≤ 30 years; a 
family history consistent with HAE-1/HAE-2; or complement component 
1q within the normal range. 
b. Documented diagnosis of HAE-nC1-INH based upon documented clinical 
history consistent with HAE (SC or mucosal, non-pruritic swelling episodes 
without accompanying urticaria) (Maurer et al. 2018) AND any 1 of the 
following:  
i. A clinical diagnosis of bradykinin (BK)-mediated angioedema as 
confirmed with threshold-stimulated kallikrein activity and 
Investigator-confirmed response to acute use of a BK targeted treatment 
(icatibant or ecallantide-). 
ii. One (1) of the established mutations (c.1032C>A, Thr309Lys; 
c.1032C>G, Thr309Arg; c.971_1018+24del72*; or c.892_909dup) in the 
factor XII gene. 
iii. The established mutation in the plasminogen gene (c.988A>G, 
p.Lys330Glu). 
iv. The established mutation in the angiopoietin-1 gene (c.355G>T, 
p.A119S). 
 
 

ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
14 
PROTOCOL SYNOPSIS CONTINUED 
Study 
Population 
Continued 
Inclusion Criteria Continued 
4. Patients must: 
a. Experience a minimum of 2 HAE attacks (assessed by the Angioedema 
Activity Score [AAS] and confirmed by the Investigator) during the 
Screening Period. 
b. Complete the AAS questionnaire on a daily basis (minimum of 4 daily 
assessments per week) for the duration of the Screening Period. 
5. Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., 
plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) 
to treat angioedema attacks. 
6. Female patients must be non-pregnant (and not planning a pregnancy during the 
study) and non-lactating, and be either: 
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years of age, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating 
hormone [FSH] levels in the post-menopausal range for the laboratory 
involved). 
c. Abstinent (only acceptable as true abstinence, i.e., when in line with the 
preferred and usual lifestyle of the patient; periodic abstinence [e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods], declaration of 
abstinence for the duration of the study, or withdrawal are not acceptable 
methods of contraception). 
d. If engaged in sexual relations of childbearing potential, agree to use highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of 
signing the informed consent form (ICF) until at least 24 weeks after the last 
dose of Study Drug (ISIS 721744 or placebo). 
7. Male patients must be surgically sterile or, if engaged in sexual relations with a 
female of childbearing potential, the patient must agree to use a highly effective 
contraceptive method (refer to Section 6.3.1) from the time of signing the ICF until 
at least 24 weeks after the last dose of Study Drug (ISIS 721744 or placebo). 
Exclusion Criteria 
1. Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening or Study Periods. 
2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired 
or idiopathic angioedema. 
3. Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks. 
 
 

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PROTOCOL SYNOPSIS CONTINUED 
Study 
Population 
Continued 
Exclusion Criteria Continued 
4. Any clinically significant abnormalities in screening laboratory values that would 
render a patient unsuitable for inclusion in the study.  The following values are 
exclusionary: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 2.5 × upper limit of normal (ULN). 
b. Bilirubin > 1.5 × ULN unless due to Gilbert’s syndrome. 
c. Platelet count < LLN 
d. Estimated glomerular filtration rate (eGFR) < 60 mL/min (as determined by 
the Cockcroft Gault- Equation for creatinine clearance) 
e. aPTT > 1.5 × ULN 
5. Patients with a history of acquired coagulopathies or bleeding diathesis (e.g., 
thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver 
disease, drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting 
factor inhibitors) and inherited bleeding disorders (e.g., hemophilia A, hemophilia 
B, other clotting factor deficiencies, qualitative platelet disorders, inherited 
thrombocytopenia, vascular abnormalities). 
6. Any clinically significant renal or hepatic diseases. 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed prior to dosing. 
8. Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial 
serological testing and confirmed with RNA testing, or prior treatment for hepatitis 
C.  Patients at Screening who test positive by serology, but negative by RNA may 
be allowed in consultation with the Sponsor Medical Monitor.  
9. 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. 
10. Treatment with another investigational drug or biological agent within 1 month or 
5 half-lives, whichever is longer, of Screening. 
11. Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening. 
b. Chronic prophylaxis with lanadelumab within 10 weeks prior to Screening. 
c. Oligonucleotides (including small interfering RNA) within 4 months of 
Screening if single dose received, or within 12 months of Screening if 
multiple doses received. 
12. Any condition that, in the opinion of the Investigator, may compromise the 
patient’s safety or compliance, preclude successful conduct of the study, or 
interfere with the interpretation of results 
 
 

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PROTOCOL SYNOPSIS CONTINUED 
Prohibited 
Concomitant 
Medications 
The following medications/procedures will not be permitted during the study: 
• 
Chronic prophylaxis for angioedema attacks, except for a stable dose of 
androgens.  Any use of lanadelumab will not be permitted. 
NOTE:  The use of acute medications (plasma-derived or recombinant C1-INH 
concentrate or BK2-receptor antagonist) to treat angioedema attacks is allowed as 
medically indicated. 
• 
ACE inhibitors or any estrogen-containing medications with systemic absorption 
(such as oral contraceptive or hormonal replacement therapy). 
• 
Any oligonucleotides (including small interfering RNA) other than ISIS 721744. 
• 
Plasmapheresis. 
• 
Any other investigational drug or device. 
Treatment 
Groups 
A total of approximately 24 patients in Parts A and B combined will be administered 
SC injections of ISIS 721744 80 mg or placebo every 4 weeks.  Patients will be 
allocated into Part A or Part B according to type of HAE, (i.e., either HAE-1/HAE-2 in 
Part A or HAE-nC1-INH in Part B) as follows:  
• 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized to 
SC injections of ISIS 721744 80 mg or placebo in a 2:1 ratio 
(ISIS 721744:placebo).   
• 
In Part B, approximately 6 patients with HAE-nC1-INH will be administered 
open-label SC injections of ISIS 721744 80 mg.  Due to the rarity of 
HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are 
unable to enroll sufficient patients; this will not impact the completion of Part A. 
Study Drug 
Dosage and 
Administration 
The Study Drug (ISIS 721744 or placebo) is contained in 2-mL stoppered glass vials.  
The Study Drug (ISIS 721744 or placebo) and its storage and preparation instructions 
will be provided by the Sponsor or designee.  The Study Drug (ISIS 721744 or 
placebo) must be stored securely at 2 °C to 8 °C and be protected from light. 
During the Treatment Period, Study Drug (ISIS 721744 or placebo) will be 
administered as a single SC injection every 4 weeks.  
 
 

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PROTOCOL SYNOPSIS CONTINUED 
Rationale for 
Dose and 
Schedule 
Selection 
The dose level of 80 mg every 28 days was selected based on the safety, tolerability, 
PK, and PD data from the ISIS 721744-CS1 study in healthy volunteers.  The Phase 1 
study evaluated doses of 20, 40, 60, and 80 mg ISIS 721744 administered once every 
4 weeks for a total of 12 weeks.  All dose levels were generally well-tolerated and 
induced a dose and exposure-dependent reduction in plasma PKK, a biomarker for BK 
and vascular permeability.  The highest dose level of 80 mg produced near-complete 
reduction of plasma PKK levels (a mean reduction of 93.6% from Baseline on Day 99 
[2 weeks after the last dose]).  The estimated half-life (t½) from the Phase 1 PK data 
was approximately 4 to 5 weeks, supporting the once-every-28-day dosing regimen.  
Pharmacokinetic/PD analysis of the Phase 1 data suggested very minor differences in 
plasma PKK reductions at doses higher than 80 mg. 
Adjustment of 
Dose and/or 
Treatment 
Schedule 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the 
study. 
Action taken with Study Drug (ISIS 721744 or placebo) due to an adverse event (AE) 
is characterized by 1 of the following: 
• 
None:  No changes made to Study Drug (ISIS 721744 or placebo) administration 
and dose. 
• 
Not Applicable:  AE reported during the Screening Period prior to Study Drug 
(ISIS 721744 or placebo) administration. 
• 
Permanently Discontinued:  Study Drug (ISIS 721744 or placebo) discontinued 
and not restarted. 
• 
Temporarily Interrupted, Restarted – Same Dose:  Dosing and/or dosing 
frequency temporarily interrupted/changed or delayed due to the AE and restarted 
at the same dose. 
Study Visit 
Schedule and 
Procedures 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will 
be allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 
in Part A or HAE-nC1-INH in Part B).  Part A is randomized, double-blind, and 
placebo-controlled; and Part B is open-label.  The study visit schedule and procedures 
are nearly identical in Part A and Part B, and thus are presented together; any 
differences are indicated where applicable. 
Patients will be screened for eligibility criteria following written informed consent.   
During the Screening Period, the following assessments will be performed:  
demographics; medical history, including a detailed HAE history; prior and 
concomitant medications, including type of prophylaxis (if used) and type of acute 
treatment; HIV, hepatitis B, and hepatitis C screening; pregnancy testing for women of 
childbearing potential and FSH testing for confirmation of menopause per inclusion 
criteria; quality of life as assessed by the angioedema quality of life (AE QoL) 
questionnaire; attack frequency, as assessed by the AAS daily during up to 
8 consecutive weeks, and confirmed by the Investigator; HAE attack assessment; 
physical examinations, including vital signs, body height, and weight; 
electrocardiograms (ECGs); AEs; PD blood sampling; inflammatory panel; and clinical 
laboratory assessments (chemistry, hematology, coagulation, and urinalysis).   

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PROTOCOL SYNOPSIS CONTINUED 
Study Visit 
Schedule and 
Procedures 
Continued 
Threshold stimulated kallikrein activity will be assessed only in patients who have 
HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 
mutation.  Genetic testing will be performed only for patients who do not have HAE 
genetic diagnostic testing results prior to Screening.   
During the Screening Period, patients must experience a minimum of 2 HAE attacks 
(assessed by the AAS and confirmed by the Investigator) to be eligible for the study; 
patients will be instructed to report details of any HAE attack to the study site within 
72 hours of the onset of the attack.  Throughout the Screening Period, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with 
the patient) in order to inquire about any attack that may have occurred.  If a patient 
experiences a third attack, the patient should be randomized as soon as possible, 
assuming all other screening activities have been completed and the patient meets all 
other eligibility requirements; in such cases, the Screening Period may be shorter than 
8 weeks. 
During the course of the study, the use of acute medications (plasma derived or 
recombinant C1 INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to 
treat angioedema attacks is allowed as medically indicated.  Patients can be treated 
with on demand therapy as determined by their treating physician. 
After a Screening Period of up to 8 weeks, those patients who had at least 
2 documented attacks (assessed by the AAS and confirmed by the Investigator) during 
the Screening Period will be enrolled and/or randomized to receive ISIS 721744 80 mg 
or placebo (Part A) or open label ISIS 721744 80 mg (Part B) every 4 weeks for a total 
Treatment Period of 12 weeks. 
Study Drug will be administered as a SC injection in the abdomen, thigh, or outer area 
of the upper arm by qualified personnel at the Study Center or Home Healthcare 
professional (if available and after dosing instructions and training are provided by 
qualified site personnel).  The first dose of Study Drug will be administered at the 
Study Center on Day 1.  Study Center personnel (or Home Healthcare if available), 
will complete procedures per the Schedule of Procedures in Appendix A.  After 
completion of the Week 13 visit, eligible patients may elect to enroll in the Open-Label 
Extension (OLE) Study (ISIS 721744-CS3), pending study approval by the IRB/IEC 
and the appropriate regulatory authority, and will need to sign the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approved informed consent.  Patients 
who complete Study Visit Week 17, and meet eligibility requirements, may start the 
treatment period in the CS3 study anytime after the Week 17 visit and discontinue 
participation in the CS2 Post-Treatment Evaluation Period. 
 
 

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PROTOCOL SYNOPSIS CONTINUED 
Study Visit 
Schedule and 
Procedures 
Continued 
During the study, patients will be instructed to report details of any HAE attack to the 
study site within 72 hours of the onset of the attack.  During the Treatment and 
Post-Treatment Periods, the following data will be collected:  daily AAS and number 
of HAE attacks (assessed by the AAS and confirmed by the Investigator); number of 
HAE attacks that required on-demand treatment; HAE attack details, including 
localization, severity, course, and details of any required treatment (i.e., frequency and 
dose); and vital signs.  Throughout the Treatment and Post-Treatment Periods, site 
personnel will contact the patient once a week (at approximately 7 days after the last 
contact with the patient) in order to inquire about any attack that may have occurred.  
In addition, at study visit time points, site personnel will inquire about any new HAE 
attack information that was not provided through patient contact with the site.  See 
Section 6.2.1 for further information on the collection of data surrounding HAE 
attacks. 
Additionally, blood will be collected at every visit during the Treatment and 
Post-Treatment Periods to assess PD and coagulation parameters, including, but not 
limited to:  plasma PKK, plasma proenzyme activation, cleaved high molecular weight 
kininogen (cHK) levels, D-dimer levels, activated partial thromboplastin time (aPTT), 
plasmin-antiplasmin complexes, C4 split products, and platelet counts.  Blood samples 
will also be collected regularly throughout the study for safety and PK/PD analyses.  
Additional assessments will be performed throughout the study as indicated in the 
Schedule of Procedures table in Appendix A. 
Patients who discontinue treatment will remain in the study and attend the Early 
Termination (ET) Visit unless consent is withdrawn. 
Detailed information regarding the CS2 procedures is presented in Section 6 and 
Appendix A.  Appendix B includes a list of laboratory analytes required for the study. 
Primary 
Endpoint 
The primary endpoint is the time-normalized number of HAE attacks (per month) from 
Week 1 to Week 17. 
Secondary 
Endpoints 
Secondary endpoints include the following: 
• 
The time-normalized number of HAE attacks (per month) from Week 5 to 
Week 17 
• 
The time-normalized number of moderate or severe HAE attacks (per month) 
from Week 5 to Week 17 
• 
The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or 
≥ 90% reduction from Baseline in HAE attack rate) by Week 17 
• 
The number of HAE attacks requiring acute therapy from Week 5 to Week 17 
• 
cHK levels at Weeks 9 and 17 
• 
PKK activity at Weeks 9 and 17 
• 
Consumption of on-demand medication at Weeks 9 and 17 
• 
AE-QoL questionnaire score at Weeks 9 and 17 
 
 

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PROTOCOL SYNOPSIS CONTINUED 
Exploratory 
Endpoints 
Exploratory endpoints include the following: 
• 
The number of HAE attack-free patients by Week 17 
• 
PK parameters, including, but not limited to:  maximum observed plasma 
concentration (Cmax), time to Cmax, area under the plasma concentration-time 
curve, and t½  
• 
Potential exposure-response analysis using relevant exposure parameters and 
biomarkers 
Safety 
Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the 
number, type, severity, and dose-relationship of AEs; vital signs; ECGs; and clinical 
laboratory parameters.  Safety results in patients dosed with ISIS 721744 will be 
compared to safety results in patients dosed with placebo. 
Statistical 
Considerations 
The sample size of 18 patients with HAE-1/HAE-2 (12 patients administered 
SC injections of ISIS 721744 80 mg and 6 patients administered placebo) is from 
clinical considerations for sufficient safety and tolerability evaluation.  The primary 
endpoint is the time-normalized number of HAE attacks (per month) from Week 1 to 
Week 17.  From historical data, the placebo group is estimated to have 6.8 HAE 
attacks per 4-month period.  If the ISIS 721744 80 mg group is assumed to have 
2.8 HAE attacks per 4-month period, then with a 0.05 significance level and Poisson 
model, the sample size of 18 patients will provide at least 90% power for the primary 
endpoint, considering a 10% missing data or dropout rate for both active treatment 
and placebo.  There is no statistical rationale for the sample size of 6 patients with 
HAE-nC1-INH.   
An independent Data and Safety Monitoring Board (DSMB) will be established prior 
to the initiation of the study.  The DSMB will be responsible for monitoring the 
overall safe conduct of the study.  Based on its ongoing assessment of the safety and 
tolerability of ISIS 721744, the DSMB will provide recommendations to the Sponsor 
for modifying, stopping, or continuing the study as planned.  Details on the safety 
assessments, frequency of review, meeting schedules and controlled access to 
unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan. 
Sponsor 
Ionis Pharmaceuticals, Inc.   

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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AAS 
Angioedema Activity Score 
ACE 
angiotensin-converting enzyme 
ADR 
adverse drug reaction 
AE(s) 
adverse event(s) 
AE-QoL 
angioedema quality of life 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BK 
bradykinin 
BUN 
blood urea nitrogen 
C 
centigrade 
C1-INH 
C1-inhibitor 
C4 
complement factor C4 
C5a 
complement factor C5a (activated complement split product) 
cHK 
cleaved high molecular weight kininogen 
Cmax 
maximum observed plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events  
dL 
deciliter 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
ET 
Early Termination 
FSH 
follicle-stimulating hormone 
GalNAc3 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAE 
hereditary angioedema 
HAE-1 
hereditary angioedema type 1 
HAE-2 
hereditary angioedema type 2 
HAE-nC1-INH 
hereditary angioedema with normal C1-inhibitor 
HIV 
human immunodeficiency virus 
HK 
high molecular weight kininogen 
hs-CRP 
C-reactive protein measured by high sensitivity assay 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 

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IgM 
immunoglobulin M 
IM 
imunogenicity 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISIS 721744 
antisense inhibitor of prekallikrein 
ITT 
Intent-to-Treat 
LCRIS 
local cutaneous reaction at injection site 
LLN 
lower limit of normal 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA™ 
Medical Dictionary for Regulatory Activities  
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PKa 
plasma kallikrein 
PKK 
prekallikrein 
PP 
Per-Protocol 
PT 
prothrombin time 
RNA 
ribonucleic acid 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
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 
ISIS 721744 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life  
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed plasma concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 

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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of antisense inhibitor of 
prekallikrein (ISIS 721744) in patients with hereditary angioedema (HAE) type 1 (HAE-1), HAE 
type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH). 
1.1.2. 
Secondary Objectives 
The secondary objectives of the study are to evaluate safety and tolerability of ISIS 721744 in 
patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1-INH) and to evaluate the 
effect of ISIS 721744 on plasma prekallikrein (PKK) and other relevant biomarkers. 
1.1.3. 
Exploratory Objectives 
The exploratory objectives of the study are to evaluate pharmacokinetics (PK) of ISIS 721744 
(as a total full-length antisense oligonucleotide [ASO], including fully conjugated, partially 
conjugated, and unconjugated ISIS 721744) over time and to assess potential 
PK/pharmacodynamic (PD) correlations on relevant biomarkers and clinical outcomes, as 
appropriate. 
1.2. 
Study Endpoints 
The definition of an HAE attack, including discrete attacks, is provided in Section 6.2.1. 
1.2.1. 
Primary Endpoints 
The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 1 
to Week 17. 
1.2.2. 
Secondary Endpoints 
Secondary endpoints include the following: 
• The time-normalized number of HAE attacks (per month) from Week 5 to Week 17 
• The time-normalized number of moderate or severe HAE attacks (per month) from 
Week 5 to Week 17 
• The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or 
≥ 90% reduction from Baseline in HAE attack rate) by Week 17 
• The number of HAE attacks requiring acute therapy from Week 5 to Week 17 
• Cleaved high molecular weight kininogen (cHK) levels at Weeks 9 and 17 
• PKK activity at Weeks 9 and 17 
• Consumption of on-demand medication at Weeks 9 and 17 
• Angioedema quality of life (AE-QoL) questionnaire score at Weeks 9 and 17 

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1.2.3. 
Safety Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of adverse events (AEs); vital signs; electrocardiograms (ECGs); 
and clinical laboratory parameters.  Safety results in patients dosed with ISIS 721744 will be 
compared to safety results in patients dosed with placebo. 
1.2.4. 
Exploratory Endpoints 
Exploratory endpoints include the following: 
• The number of HAE attack-free patients by Week 17 
• PK parameters, including, but not limited to:  maximum observed plasma 
concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time 
curve (AUC), and half-life (t½) 
• Potential exposure response analysis using relevant exposure parameters and 
biomarkers 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Hereditary angioedema is a rare genetic disorder that is characterized by disabling recurrent 
episodes of local skin swellings, painful abdominal attacks, and, occasionally, laryngeal attacks 
that can be life-threatening.  The disorder is classified in 3 subtypes.  Hereditary angioedema 
Type I (HAE-1) and Type II (HAE-2) are caused by an autosomal dominant mutation in the 
SERPING1 gene, resulting in either decreased levels of C1-INH (HAE-1) or loss-of-function of 
this protein (HAE-2) (Bissler et al. 1997).  The third form of HAE is associated with normal 
levels and function of C1-INH (HAE-nC1-INH).  This form is currently categorized as 
4 subtypes, with either specific genetic mutations in the factor XII gene, the plasminogen gene, 
or the angiopoietin-1 gene, or due to an unknown cause (Maurer et al. 2018).  Extensive 
evidence from in vitro and in vivo studies supports the key role of bradykinin (BK) in HAE 
attacks, although the data linking HAE-nC1-INH with BK are less strong (Zuraw and 
Christiansen 2016).  Diagnosing HAE-nC1-INH can be challenging given the large heterogeneity 
of this patient population, the lack of diagnostic tests, and the fact that specific genetic mutations 
account only partially for the occurrence of this type of HAE.  Recently, a threshold-stimulated 
kallikrein activity assay was shown to discriminate BK-mediated angioedema from histamine-
mediated angioedema (Lara‑Marquez et al. 2018).  
 
 
 
Treatment options for HAE include on-demand treatment of attacks and prophylaxis.  
On-demand options include supplementation of C1-INH (either plasma-derived or recombinant 
C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist).  In 
addition, tranexamic acid may relieve symptoms in non-severe angioedema attacks.  
Prophylactic regimens for HAE include plasma-derived C1-INH concentrate (administered either 

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intravenously or subcutaneously [SC]), attenuated androgens, antifibrinolytics and a recently 
Food and Drug Administration-approved monoclonal antibody directed against plasma kallikrein 
(PKa).  Kallikrein circulates in plasma as a zymogen (i.e., PKK) which is bound to one of its 
main substrates, high molecular weight kininogen (HK).  Prekallikrein is cleaved upon contact 
activation, forming the active protease PKa.  Plasma kallikrein cleaves HK in turn, thereby 
releasing BK and the split product cHK.  The binding of BK to the BK2 receptor leads to 
activation of various intracellular signaling pathways resulting in vasodilation, chemotaxis of 
neutrophils, and increased vascular permeability and fluid efflux, which typically characterize an 
angioedema attack (Zuraw and Christiansen 2016). 
2.2. 
Therapeutic Rationale 
 
Antisense technology is characterized by its 
high specificity in inhibiting a single-gene product, thereby diminishing the potential for 
off-target drug effects.  
 
 
 
  
 
 
 
The Phase 1 clinical data show that ISIS 721744 inhibits plasma PKK effectively in a 
dose-dependent manner without safety concerns. 
2.3. 
ISIS 721744 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with PKK ASO ISIS 546254, 
its 5ʹ-GalNAc3-conjugated mixed backbone variant ISIS 721744, and mouse surrogate PKK 
ASOs can be found in the Investigator’s Brochure. 
 
Results also strongly support that 
GalNAc3-conjugation of PKK ASO significantly increases the potency of ASO for inhibition of 
PKK hepatic mRNA and circulatory protein expression 
 
 
2.3.4. 
Clinical Experience 
ISIS 721744 has been evaluated in the clinical setting in a Phase 1 safety study 
(ISIS 721744-CS1).  All subjects have completed study procedures and final safety and PD data 
are available.  A summary is included below.  Please refer to the Investigator’s Brochure for a 
detailed description of the preclinical pharmacology, nonclinical toxicology and PK, as well as a 
description of previous clinical experience with other related 2′-MOE phosphorothioate 
oligonucleotides. 
ISIS 721744 has been studied in 32 healthy volunteers in a double-blind, multiple-dose, 
dose-escalation study.  Of these, 24 subjects received multiple doses of ISIS 721744.  The 
32 subjects were randomized into 4 cohorts (6 subjects each) to receive once-every-4-week SC 
doses of ISIS 721744 20, 40, 60, or 80 mg, or placebo (8 subjects) for a total of 12 weeks (4 total 
doses).  All subjects received all planned doses of Study Drug (ISIS 721744 or placebo).  The 
duration of Study Drug exposure was 84 days for each subject. 
No serious adverse events (SAEs) were reported in the ISIS 721744-CS1 study.  There were no 
early discontinuations from Study Drug or the study, and all subjects in the ISIS 721744 and 
placebo arms completed all study procedures.  Adverse events at the injection site (defined as 
any preferred term containing “injection site”) were the most commonly reported 
treatment-emergent adverse events (TEAEs) in the ISIS 721744 treatment arms; no injection 
site-related TEAEs were reported in the placebo arm.  There were no flu-like reactions or events 
of local cutaneous reaction at injection site (LCRIS) reported; LCRIS events were defined as 
(A) moderate or severe injection site erythema, swelling, pruritus, pain, or tenderness that started 
on the day of injection and persisted for at least 2 days; or (B) any AE at the injection site, 
regardless of severity, that led to discontinuation of Study Drug, where AE at the injection site 
was the principal reason for discontinuation.  No relationship between incidence of TEAEs and 
the dose administered was observed. 
Thirteen (13) AEs related to study treatment were reported for 4 (16.7%) subjects in the 
ISIS 721744 arm, and for 1 subject (2 events; 12.5%) in the placebo arm.  One (1) subject each 
in the ISIS 721744 and placebo arm reported AEs of ECG T wave inversion (preferred term) that 
were assessed as related.  Nine (9) of the total 13 related events with ISIS 721744 concerned 
injection site-related events and were reported by 1 subject in the 80 mg arm.  Additional related 
events were tinnitus (1 subject, 1 event in the 60 mg arm), headache (1 subject, 1 event in the 
60 mg arm), and epistaxis (1 subject, 1 event in the 20 mg arm).  All TEAEs related to study 
treatment were mild in severity, and none were serious. 

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ISIS 721744 resulted in a dose-dependent reduction of PKK concentration and plasma 
proenzyme activation.  The difference in absolute and percent change from Baseline for 
ISIS 721744 vs. placebo was statistically significant for PKK concentration for 40, 60, and 
80 mg (p ≤ 0.043) starting at Day 15, the first evaluation, and for 20 mg starting at Day 29, and 
for plasma proenzyme activation for all doses (p ≤ 0.002) starting at Day 15.  The nadir was 
generally reached around Day 71, when the percent reduction with the 80 mg dose was -93.2% 
for PKK concentration and -99.6% for plasma proenzyme activation. 
The difference in absolute and percent change from Baseline in cHK for ISIS 721744 vs. placebo 
was not statistically significant at any visit. 
Clinical data from other GalNAc3-conjugated 2ʹ-MOE-gapmer oligonucleotides suggest that 
enhanced delivery of ISIS 721744 to hepatocytes vs. non-parenchymal cells will result in similar 
PD results as ISIS 546254 at 1/10th to 1/30th of the dose (Viney et al. 2016). 
2.4. 
Rationale for Dose and Schedule of Administration 
The dose level of 80 mg every 28 days was selected based on the safety, tolerability, PK, and PD 
data from the ISIS 721744-CS1 study in healthy volunteers.  The Phase 1 study evaluated doses 
of 20, 40, 60, and 80 mg ISIS 721744 administered once every 4 weeks for a total of 12 weeks.  
All dose levels were generally well-tolerated and induced a dose- and exposure-dependent 
reduction in plasma PKK, a biomarker for BK and vascular permeability.  The highest dose level 
of 80 mg produced near-complete reduction of plasma PKK levels (a mean reduction of 93.6% 
from Baseline on Day 99 [2 weeks after the last dose]).  The estimated t½ from the Phase 1 PK 
data was approximately 4 to 5 weeks, supporting the once-every-28-day dosing regimen.  
Pharmacokinetic/PD analysis of the Phase 1 data suggested very minor differences in plasma 
PKK reductions at doses higher than 80 mg. 
2.5. 
Benefit-Risk Assessment 
2.5.1. 
Benefit Assessment 
The benefits of treatment of ISIS 721744 are currently unknown.  Due to its mechanism of 
action, ISIS 721744 has the potential to be efficacious for the treatment of patients with HAE. 
2.5.2. 
Risk Assessment 
The known potential risks to study participants associated with ISIS 721744 are elaborated on in 
the “Guidance to Investigator” section of the Investigator’s Brochure. 
There are no anticipated risks associated with reducing plasma PKK levels; however, a potential 
theoretical risk associated with PKK inhibition would be prolongation of activated partial 
thromboplastin time (aPTT).  This risk is informed by 80 cases of PKK deficiency that have been 
described in the literature (Girolami et al. 2010).  In these individuals, there is a discrepancy 
between an observed in vitro defect and an absence of bleeding.  Thus, it is believed that most 
cases go undetected or, if detected, go unreported.  Occasional bleeding or thrombosis has been 
reported in a few PKK deficient patients but these instances were due to the presence of 
associated risk factors.  Diagnosis is based on the prolongation of partial thromboplastin time 
and normal prothrombin time (PT) and thrombin time.  In these individuals, platelet and vascular 

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tests are normal and the long partial thromboplastin time has shown to be fully corrected by the 
addition of normal plasma or normal serum. 
In monkeys, doses of ISIS 721744 of up to 30 mg/kg/wk for 13 weeks were well-tolerated with 
the exception of thrombocytopenia observed in 1 female at 12 mg/kg/wk and 1 male at 
30 mg/kg/wk.  The monkey dose of 6 mg/kg/wk provides an approximate 20-fold margin relative 
to a human dose of 80 mg every 4 weeks and therefore there is sufficient therapeutic margin to 
assure the safe clinical use of ISIS 721744 at the proposed clinical dose and regimen. 
One (1) subject in the ISIS 721744-CS1 study had a confirmed platelet nadir count between 
100 × 103/µL and the lower limit of normal (LLN) (140 × 103/µL).  The subject received 
ISIS 721744 at 20 mg and had a platelet count of 139 × 103/µL on Study Day 99; all other 
reported values for this subject were within the reference range. 
Platelet counts will be monitored closely throughout the clinical study. 
More complete details can be found in the Investigator’s Brochure. 
2.5.3. 
Overall Assessment of Benefit:Risk 
No specific risks have been identified with ISIS 721744.  The AEs that occurred with the related 
drug ISIS 546254 were unrelated to reduction of PKK.  In addition, the conjugated nature of 
ISIS 721744 is anticipated to reduce systemic exposure even further.  Consequently, the platelet 
count reductions observed with the higher doses of the unconjugated molecule are not 
anticipated to occur at the dose tested in this study. 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ISIS 721744 are justified by the anticipated 
benefits that may be afforded to patients with HAE. 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This Phase 2a study will be conducted at multiple Study Centers worldwide to assess the efficacy 
of ISIS 721744 in approximately 24 patients with HAE.  Part A of the study will be randomized, 
double-blind, and placebo-controlled; Part B of the study will be open-label. 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will be 
allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or 
HAE-nC1-INH in Part B).  Part A is randomized, double-blind, and placebo-controlled; and 
Part B is open-label.  The study visit schedule and procedures are nearly identical in Part A and 
Part B, and thus are presented together; any differences are indicated where applicable. 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized to SC injections of 
ISIS 721744 80 mg or placebo in a 2:1 ratio (ISIS 721744:placebo).  In Part B, approximately 
6 patients with HAE-nC1-INH will be administered open-label SC injections of ISIS 721744 
80 mg.  Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study 
Centers are unable to enroll sufficient patients; this will not impact the completion of Part A. 

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Patients who discontinue treatment will remain in the study and attend the Early Termination 
(ET) Visit unless consent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A.  
Appendix B includes a list of laboratory analytes required for the study. 
3.2. 
Number of Study Centers 
This study will be conducted at multiple Study Centers worldwide. 
3.3. 
Number of Patients 
A total of approximately 24 patients in Parts A and B combined will be administered SC 
injections of ISIS 721744 80 mg or placebo every 4 weeks.  Patients will be allocated into Part A 
or Part B according to type of HAE, (i.e., either HAE-1/HAE-2 or HAE-nC1-INH):  
approximately 18 patients with HAE-1/HAE-2 are planned to be enrolled in Part A of the study, 
and, in parallel, approximately 6 patients with HAE-nC1-INH are planned to be enrolled in 
Part B of the study.  Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended 
early if Study Centers are unable to enroll sufficient patients with HAE-nC1-INH; this will not 
impact completion of Part A. 
3.4. 
Overall Study Duration and Follow-up 
The study will consist of Screening, Treatment, and Post-Treatment Periods.  Please refer to the 
Schedule of Procedures in Appendix A. 
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Sponsor 
Medical Monitor in consultation with the Investigator. 
The length of each patient’s participation in the study is approximately 8 months, which includes 
an up to 8-week Screening Period, a 12-week Treatment Period (patients will receive fixed SC 
doses of Study Drug every 4 weeks during 4 on-site study visits), and a 4- to 13-week 
Post-Treatment Period as determined by whether a patient enrolls in the ISIS 721744-CS3 OLE 
study. 
3.4.1. 
Screening 
Patient eligibility for the study will be determined within 8 weeks (56 days) prior to study entry. 
3.4.2. 
Treatment Period 
Eligible patients will report to the Study Center for the first administration of Study Drug on 
Study Day 1 (Week 1 Visit) and will continue to receive Study Drug once every 4 weeks during 
the 12-week Treatment Period.  Patients will also return to the Study Center on Week 3 (or 
Home Healthcare (if available), as arranged by the Study Center personnel, per the Schedule of 
Procedures in Appendix A) for a safety monitoring visit. 

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3.4.3. 
Post-Treatment Period 
Patients are to return to the Study Center for post-treatment follow-up visits (or Home Healthcare 
(if available), as arranged by the Study Center personnel, per the Schedule of Procedures in 
Appendix A at Study Weeks 17, 21, and 26/ET.  Alternatively, patients who complete Study 
Visit Week 17, and meet eligibility requirements, may start the treatment period in the 
ISIS 721744-CS3 OLE study anytime after the Week 17 visit and discontinue participation in the 
CS2 Post-Treatment Evaluation Period.  Patients may be required to attend additional visits for 
monitoring of AEs or abnormal investigation results.  The frequency of additional monitoring 
will be determined by the Sponsor Medical Monitor in consultation with the Investigator.   
The final study visit, for patients not enrolling in the OLE, will be the Week 26/ET Visit.   
3.5. 
End-of-Study 
The End-of-Study is defined as the date of the last visit of the last patient in the study. 
3.6. 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be assembled to review safety, tolerability, 
and efficacy (as needed) data collected on ISIS 721744 during this study.  Based on its ongoing 
assessment of the safety and tolerability of ISIS 721744, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping, or continuing the study as planned.  
Details on the safety assessments, frequency of review, meeting schedules, and controlled access 
to unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1. 
Screening 
Before patients may be enrolled into the study, the Sponsor or designee requires a copy of the 
Study Center’s written Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
approval of the protocol, informed consent form (ICF), and all other patient information and/or 
recruitment material. 
Patients must sign the consent form before any screening tests or assessments, prior to screening 
blood draws, are performed.  At the time of consent, the patient 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, patients will be assigned a 
unique patient identification number.  This number will be used to identify the patient throughout 
the study and must be used on all study documentation related to that patient.  The screening 
number and patient identification number must remain constant throughout the entire study.   
In the event the patient is re-consented and re-screened, the patient must be given a new 
screening number.  Screening numbers, once assigned, will not be re-used. 

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4.2. 
Randomization 
Patients will be allocated into Part A or Part B according to type of HAE (i.e., either 
HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B).  Only Part A will be randomized and 
placebo-controlled.   
Patients will be enrolled and/or randomized (Part A only) at the Week 1 Visit, after all screening 
assessments have been completed and after the Investigator has verified that they are eligible per 
the criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to randomization 
(Part A only) and assignment of a unique patient identification number.   
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized via the Interactive 
Response Technology (IRT) system to SC injections of ISIS 721744 80 mg or placebo in a 
2:1 ratio (ISIS 721744:placebo).  In Part B, approximately 6 patients with HAE-nC1-INH will be 
enrolled via the IRT system to receive open-label SC injections of ISIS 721744 80 mg.  Due to 
the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are unable 
to enroll sufficient patients; this will not impact the completion of Part A. 
Randomization information will be concealed from the Investigators and patients until the end of 
the study, with the exception of an emergency situation involving a patient that requires 
unblinding of the treatment assignment. 
Both ISIS 721744 and placebo will be provided as injections for SC administration and will be 
identical in appearance. 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
Patients whose randomization code has been broken will not be replaced. 
4.4. 
Unblinding of Treatment Assignment 
For Part A, the Sponsor and all patients, monitors, and Study Center personnel related to the 
study will be blinded throughout the study.  However, if a patient has suffered an SAE (as 
defined in Section 9.3.3), and/or when knowledge of the treatment assignment will impact the 
clinical management of the patient, the Investigator will have the ability to unblind the treatment 
assignment for that patient via the IRT system. 
In the case of unblinding, the IRT system will send a blinded notification to the Sponsor or 
designee within 24 hours to let them know that a patient was unblinded.  In addition, all 
suspected unexpected serious adverse reactions (SUSARs) will be unblinded by the Sponsor or 
designee for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the ET study procedures and observations 
(see Appendix A) prior to unblinding, as knowledge of the treatment arm could influence patient 
assessment. 

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5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 8 weeks (56 days) of the Week 1 Visit (Study Day 1) or at the time point specified in the 
eligibility criteria listed. 
5.1. 
Inclusion Criteria 
1. Patients must provide written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements for the duration 
of the study. 
2. Patients must be aged ≥ 18 years at the time of informed consent. 
3. Patients must have a documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or 
HAE-nC1-INH (for inclusion in Part B) as defined below: 
a. Documented diagnosis of HAE-1/HAE-2 based upon ALL of the following: 
i. Documented clinical history consistent with HAE (SC or mucosal, non-pruritic 
swelling episodes without accompanying urticaria) (Maurer et al. 2018). 
ii. Diagnostic testing results that confirm HAE-1/HAE-2:  C1-INH functional level 
< 40% normal level.  Patients with a functional level of 40% to 50% of normal 
can be enrolled if their complement factor C4 (C4) level is below the LLN or if a 
known pathogenic mutation in the SERPING1 gene has been demonstrated. 
iii. At least 1 of the following:  age at reported HAE onset ≤ 30 years; a family 
history consistent with HAE-1/HAE-2; or complement component 1q within the 
normal range. 
b. Documented diagnosis of HAE-nC1-INH based upon documented clinical history 
consistent with HAE (SC or mucosal, non-pruritic swelling episodes without 
accompanying urticaria) (Maurer et al. 2018) AND any 1 of the following:  
i. A clinical diagnosis of BK-mediated angioedema as confirmed with 
threshold-stimulated kallikrein activity and Investigator-confirmed response to 
acute use of a BK targeted treatment (icatibant or ecallantide). 
ii. One (1) of the established mutations (c.1032C>A, Thr309Lys; c.1032C>G, 
Thr309Arg; c.971_1018+24del72*; or c.892_909dup) in the factor XII gene. 
iii. The established mutation in the plasminogen gene (c.988A>G, p.Lys330Glu). 
iv. The established mutation in the angiopoietin-1 gene (c.355G>T, p.A119S). 
4. Patients must: 
a. Experience a minimum of 2 HAE attacks (assessed by the Angioedema Activity 
Score [AAS] and confirmed by the Investigator) during the Screening Period. 
b. Complete the AAS questionnaire on a daily basis (minimum of 4 daily assessments 
per week) for the duration of the Screening Period. 

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5. Patients must have access to, and the ability to use, ≥ 1 acute medication(s) 
(e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) 
to treat angioedema attacks. 
6. Female patients must be non-pregnant (and not planning a pregnancy during the study) 
and non-lactating, and be either: 
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy). 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years of age, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating hormone 
[FSH] levels in the post-menopausal range for the laboratory involved). 
c. Abstinent (only acceptable as true abstinence, i.e., when in line with the preferred and 
usual lifestyle of the patient; periodic abstinence [e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods], declaration of abstinence for the duration 
of the study, or withdrawal are not acceptable methods of contraception). 
d. If engaged in sexual relations of childbearing potential, agree to use highly effective 
contraceptive methods (refer to Section 6.3.1) from the time of signing the ICF until 
at least 24 weeks after the last dose of Study Drug (ISIS 721744 or placebo). 
7. Male patients must be surgically sterile or, if engaged in sexual relations with a female of 
childbearing potential, the patient must agree to use a highly effective contraceptive 
method (refer to Section 6.3.1) from the time of signing the ICF until at least 24 weeks 
after the last dose of Study Drug (ISIS 721744 or placebo). 
5.2. 
Exclusion Criteria 
1. Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening or Study Periods. 
2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired or 
idiopathic angioedema. 
3. Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks. 
4. Any clinically significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion in the study.  The following values are exclusionary: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper 
limit of normal (ULN). 
b. Bilirubin > 1.5 × ULN unless due to Gilbert’s syndrome. 
c. Platelet count < LLN. 
d. Estimated glomerular filtration rate (eGFR) < 60 mL/min (as determined by the 
Cockcroft-Gault Equation for creatinine clearance). 
e. aPTT > 1.5 × ULN 

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5. Patients with a history of acquired coagulopathies or bleeding diathesis (e.g., 
thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver disease, 
drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting factor inhibitors) 
and inherited bleeding disorders (e.g., hemophilia A, hemophilia B, other clotting factor 
deficiencies, qualitative platelet disorders, inherited thrombocytopenia, vascular 
abnormalities). 
6. Any clinically significant renal or hepatic diseases. 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to dosing. 
8. Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial serological 
testing and confirmed with RNA testing, or prior treatment for hepatitis C.  Patients at 
Screening who test positive by serology, but negative by RNA may be allowed in 
consultation with the Sponsor Medical Monitor.  
9. 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. 
10. Treatment with another investigational drug or biological agent within 1 month or 
5 half-lives, whichever is longer, of Screening. 
11. Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening. 
b. Chronic prophylaxis with lanadelumab within 10 weeks prior to Screening. 
c. Oligonucleotides (including small interfering RNA) within 4 months of Screening if 
single dose received, or within 12 months of Screening if multiple doses received. 
12. Any condition that, in the opinion of the Investigator, may compromise the patient’s 
safety or compliance, preclude successful conduct of the study, or interfere with the 
interpretation of results. 
6. 
STUDY PROCEDURES 
6.1. 
Study Schedule 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will be 
allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or 
HAE-nC1-INH in Part B).  Part A is randomized, double-blind, and placebo-controlled; and 
Part B is open label.  The study visit schedule and procedures are nearly identical in Part A and 
Part B, and thus are presented together; any differences are indicated where applicable. 
All required study procedures are outlined in Appendix A. 
The safety of ISIS 721744 will be continually monitored throughout the study by the Investigator 
and the Sponsor Medical Monitor. 
The length of each patient’s participation from Screening to the last study visit is up to 
approximately 8 months (231 days). 

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6.1.1. 
Screening 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures, including screening procedures.  A 56-day period is provided for 
completing screening assessments and determining patient eligibility for the study.   
Safety labs may be retested for determination of patient eligibility at the Investigator’s discretion.  
The Sponsor Medical Monitor will be available for consultation, if needed. 
After providing written informed consent, patients will be screened for eligibility criteria.  
During the Screening Period, the following assessments will be performed:  demographics; 
medical history, including a detailed HAE history; prior and concomitant medications, including 
type of prophylaxis (if used) and type of acute treatment; HIV, hepatitis B, and hepatitis C 
screening; pregnancy testing for women of childbearing potential (WOCBP) and FSH testing for 
confirmation of menopause per inclusion criteria; quality of life as assessed by the AE-QoL 
questionnaire; attack frequency, as assessed by the AAS daily during up to 8 consecutive weeks, 
and confirmed by the Investigator; HAE attack assessment; physical examinations, including 
vital signs, body height, and weight; ECGs; AEs; PD blood sampling; inflammatory panel; and 
clinical laboratory assessments (chemistry, hematology, coagulation, and urinalysis). 
Threshold-stimulated kallikrein activity will be assessed only in patients who have 
HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 mutation.  
Genetic testing will be performed only for patients who do not have HAE genetic diagnostic 
testing results prior to Screening.  During the Screening Period, patients must experience a 
minimum of 2 HAE attacks (assessed by the AAS and confirmed by the Investigator) to be 
eligible for the study; patients will be instructed to report details of any HAE attack to the study 
site within 72 hours of the onset of the attack.  Throughout the Screening Period, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with the 
patient) in order to inquire about any attack that may have occurred.  If a patient experiences a 
third attack, the patient should be randomized as soon as possible, assuming all other screening 
activities have been completed and the patient meets all other eligibility requirements; in such 
cases, the Screening Period may be shorter than 8 weeks. 
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated.  Patients can be treated with on-demand therapy as 
determined by their treating physician. 
6.1.2. 
Treatment Period 
After a Screening Period of up to 8 weeks, those patients who had at least 2 documented attacks 
(assessed by the AAS and confirmed by the Investigator) during the Screening Period and met all 
other eligibility criteria will be administered Study Drug (ISIS 721744 or placebo).  Patients in 
Part A will be randomized to receive ISIS 721744 80 mg or placebo every 4 weeks for a total 
Treatment Period of 12 weeks.  Patients in Part B will all receive open-label ISIS 721744 80 mg 
every 4 weeks for a total Treatment Period of 12 weeks.   
Study Drug will be administered as SC injections in the abdomen, thigh, or outer area of the 
upper arm by qualified personnel at the Study Center or by Home Healthcare professional (if available 

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and after dosing instructions and training are provided by qualified site personnel).  The first dose of 
Study Drug will be administered at the Study Center on Study Day 1 (Week 1 Visit).  Study 
Center personnel (or Home Healthcare if available), will complete procedures per the Schedule 
of Procedures in Appendix A.  A ± 2-day excursion from the scheduled visit date is permitted for 
all visits (excluding the Week 1 Visit on Study Day 1) during the Treatment Period. 
During the study, patients will be instructed to report details of any HAE attack to the study site 
within 72 hours of the onset of the attack.  During the Treatment Period, the following data will 
be collected:  daily AAS and number of HAE attacks (assessed by the AAS and confirmed by the 
Investigator); number of HAE attacks that required on-demand treatment; HAE attack details, 
including localization, severity, course, and details of any required treatment (i.e., frequency and 
dose); and vital signs.  Throughout the Treatment Period, site personnel will contact the patient 
once a week (at approximately 7 days after the last contact with the patient) in order to inquire 
about any attack that may have occurred.  In addition, at study visit time points, site personnel 
will inquire about any new HAE attack information that was not provided through patient contact 
with the site.  See Section 6.2.1 for further information on the collection of data surrounding 
HAE attacks.  Additional assessments will be performed throughout the Treatment Period as 
indicated in the Schedule of Procedures table in Appendix A. 
Additionally, blood will be collected to assess PD and coagulation parameters, including, but not 
limited to:  plasma PKK, plasma proenzyme activation, cHK levels, D-dimer levels, aPTT, 
plasmin-antiplasmin complexes, C4 split products, and platelet counts.  Blood samples will also 
be collected regularly throughout the study for safety and PK/PD analyses.   
Patients who discontinue treatment will remain in the study and attend the ET Visit unless 
consent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A.  
Appendix B includes a list of laboratory analytes required for the study.  Detailed information 
regarding PK subgroups and collection times is provided in Appendix C. 
6.1.3. 
Post-Treatment Period 
Each patient will be followed for safety assessments for up to 13 weeks after the last dose of 
Study Drug.  During the Post-Treatment Period, patients will return to the Study Center (or have 
Home Healthcare (if available), as arranged by the Study Center personnel, per the Schedule of 
Procedures in Appendix A) for visits at Weeks 17, 21, and 26/ET for safety and clinical 
laboratory evaluations and for blood sampling for PK/PD analyses.  A ± 2-day excursion from 
the scheduled visit date is permitted for the visits at Weeks 17 and 21, and a ± 3-day excursion 
from the scheduled visit date is permitted for the visit at Week 26/ET.  Alternatively, after 
completion of the Week 13 visit, eligible patients may elect to enroll in the ISIS 721744-CS3 
OLE study, pending study approval by the IRB/IEC and the appropriate regulatory authority, and 
will need to sign the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved informed consent.  Patients who complete Study Visit Week 17, and meet eligibility 
requirements, may start the treatment period in the CS3 study anytime after the Week 17 visit 
and discontinue participation in the CS2 Post-Treatment Evaluation Period. 
During the Post-Treatment Period, the following data will be collected:  daily AAS and number 
of HAE attacks (assessed by the AAS and confirmed by the Investigator); number of HAE 

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attacks that required on-demand treatment; HAE attack details, including localization, severity, 
course, and details of any required treatment (i.e., frequency and dose); and vital signs.  
Throughout the Post-Treatment Period, site personnel will contact the patient once a week (at 
approximately 7 days after the last contact with the patient) in order to inquire about any attack 
that may have occurred.  In addition, during study visits, site personnel will inquire about any 
new HAE attack information that was not provided through patient contact with the site.  See 
Section 6.2.1 for further information on the collection of data surrounding HAE attacks. 
Additionally, blood will be collected to assess PD and coagulation parameters, including, but not 
limited to:  plasma PKK, plasma proenzyme activation, cHK levels, D-dimer levels, aPTT, 
plasmin-antiplasmin complexes, C4 split products, and platelet counts.  Blood samples will also 
be collected regularly throughout the study for safety and PK/PD analyses.  Additional 
assessments will be performed throughout the Post-Treatment Period as indicated in the 
Schedule of Procedures table in Appendix A. 
Patients who withdraw early from the study during the Treatment Period will be required to 
complete their End-of-Study evaluations following procedures listed for the Week 26/ET Visit; 
see Appendix A.   
6.2. 
Study Assessments 
6.2.1. 
Collection of Hereditary Angioedema Attack Details 
Historical HAE attack information will be collected at Screening.  During the study, patients will 
be instructed to report details of any HAE attack to the study site within 72 hours of the onset of 
the attack.  Throughout the Screening, Treatment, and Post-Treatment Periods, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with the 
patient) in order to inquire about any attack that may have occurred.  In addition, during study 
visits, site personnel will inquire about any new HAE attack information that was not provided 
through patient contact with the site. 
During the Screening, Treatment, and Post-Treatment Periods, detailed information on each 
HAE attack will be collected, and the number of HAE attacks that required on-demand 
treatment, and the details of any on-demand treatment used (frequency and dosing), will be 
assessed.  For each HAE attack, the following data will be collected:  
• Date/time of symptom onset 
• Description of symptoms 
• Location and description of symptoms: 
− Peripheral angioedema:  cutaneous swelling involving an extremity, face, neck, 
torso, and/or genitourinary region 
− Abdominal angioedema:  abdominal pain, with or without abdominal distension, 
nausea, vomiting, or diarrhea 
− Laryngeal angioedema:  stridor, dyspnea, difficulty speaking, difficulty 
swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx 

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• HAE attack severity: 
− Mild:  transient or mild discomfort 
− Moderate:  mild to moderate limitation in activity, some assistance needed 
− Severe:  marked limitation in activity, assistance required 
• Need for assistance, medical intervention, emergency room visit, or hospitalization 
• Medications to treat the attack 
• HAE attack course, including if the HAE attack(s) in question was a typical attack for 
the patient, or if there was an alternative diagnosis 
• Date/time symptoms resolved 
An HAE attack will be defined as an event with signs or symptoms consistent with an attack in at 
least 1 of the locations noted above.  A discrete attack will be counted if there is an at least 
24-hour symptom-free period between attacks. 
6.2.2. 
Patient-Reported Outcomes 
6.2.2.1. 
Angioedema Quality of Life Questionnaire 
Quality of life will be assessed by the AE-QoL questionnaire during Screening and at Weeks 1, 
9, 17, and 26/ET.   
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related quality 
of life impairment in patients suffering from recurrent angioedema (Weller et al. 2013).  The 
AE-QoL is a self-administered questionnaire that can be completed in less than 5 minutes; it 
comprises 17 questions across 4 domains:  functioning, fatigue/mood, fears/shame, and food.  
The AE-QoL can be used to calculate scores for the 4 individual domains, and can also be used 
to determine a total score.  The AE-QoL will be completed by the patient. 
6.2.2.2. 
Angioedema Activity Score 
Patients will be instructed on the use of the AAS questionnaire during Screening and will record 
their HAE attacks using the AAS questionnaire during the Screening Period to confirm study 
eligibility.  The AAS questionnaire will be completed by patients on a daily basis (minimum of 
4 daily assessments per week) for the duration of the study.   
During the Screening Period, patients must experience a minimum of 2 HAE attacks (assessed 
by the AAS and confirmed by the Investigator) to be eligible for the study. 
Enrolled patients will continue to record HAE attacks using the AAS questionnaire throughout 
the Treatment and Post-Treatment Periods. 
The AAS is a validated patient-reported outcome instrument to assess disease activity in patients 
with recurrent angioedema.  The AAS was designed as a diary-type tool, and is easy to 
administer and fast to complete.  Using the AAS questionnaire, patients score each of 5 key 
symptom-related factors from 0 to 3, resulting in a total daily score of 0 to 15.  Daily AAS can be 
summed to provide scores every 7 days, every 4 weeks, and every 12 weeks (Weller et al. 2013). 

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6.2.3. 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B.   
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) either in clinic or by Home Healthcare or 
local laboratory. 
6.3. 
Restriction on the Lifestyle of Patients 
6.3.1. 
Contraception Requirements 
All male patients and WOCBP must refrain from sperm/egg donation and either be abstinent† or 
use highly effective contraception from the time of signing the ICF until at least 24 weeks after 
their last dose of Study Drug.   
For male patients engaged in sexual relations with a WOCBP, if their female partner is using 
highly effective contraception from the time of the patient signing the informed consent until 
24 weeks after the patient’s last dose of study treatment, then it is not required for the male 
patient to also use a highly effective contraceptive method. 
For the purposes of this study, a WOCBP is defined as any female who has experienced 
menarche, and who does not meet 1 of the following conditions: 
• Post-menopausal:  12 months of spontaneous amenorrhea in females > 55 years of 
age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the post-menopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male patients: 
• Highly effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the non-pregnant female partner of childbearing potential 
uses a highly effective contraceptive method (defined below). 
• Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug. 
Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
For female patients and female partners of male patients, highly effective contraception methods 
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• Surgical sterilization (i.e., bilateral tubal occlusion); progestogen-only hormonal 
contraception associated with inhibition of ovulation; intrauterine contraception 
device or intrauterine hormone-releasing system. 
†Note: 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, or post-ovulation methods), declaration of abstinence for the 
duration of the study, or withdrawal are not acceptable methods of contraception. 
7. 
STUDY DRUG 
7.1. 
Study Drug Description 
Study Drug (ISIS 721744 or placebo) characteristics are listed in Table 1. 
 
 
 
 
During the Treatment Period, Study Drug (ISIS 721744 or placebo) will be administered as a 
single-SC injection every 4 weeks.  
Table 1: 
Study Drug Characteristics 
Study Drug 
ISIS 721744 
Placebo 
Strength 
100 mg/mL  
Not Applicable 
Volume/Formulation 
0.8 mL solution per vial  
0.8 mL solution per vial 
Route of Administration 
SC 
SC 
 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 721744 or placebo) 
labeled in accordance with specific country regulatory requirements. 
7.3. 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug (ISIS 721744 or placebo) supplies provided by the Sponsor according to Sponsor 
instruction and in accordance with institutional policy. 

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8. 
TREATMENT OF PATIENTS 
8.1. 
Study Drug Administration 
Study Drug (ISIS 721744 or placebo) will be administered as a single-SC injection once every 
4 weeks by blinded study staff during on-site visits at the Study Centers or by Home Healthcare 
professional (if available and after dosing instructions and training are provided by qualified site 
personnel).  Vials of Study Drug (ISIS 721744 or placebo) are for single use only. 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug (ISIS 721744 or placebo) preparation and administration. 
8.2. 
Other Protocol-Required Drugs 
Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived 
or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat angioedema attacks.  
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated.  Patients can be treated with on-demand therapy as 
determined by their treating physician. 
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.   
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 Study 
Day 1 value and the last value prior to Study 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 (ISIS 721744 or placebo). 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the retest results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 

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Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Section 8.6) are met, the patient will be permanently discontinued from further 
treatment with Study Drug (ISIS 721744 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 of the protocol.   
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. 
In the event of an ALT or AST measurement that is > 3 × ULN (or the greater of 2 × baseline 
value or 3 × 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 × ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 × ULN (or 
the greater of 2 × baseline value or 3 × ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase, international normalized ratio [INR], and 
total bilirubin) retested at least once-weekly until ALT and AST levels become ≤ 1.2 × ULN or 
1.2 × baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
• Obtain a more detailed history of symptoms and prior and concurrent diseases 
• Obtain further history for concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
• Obtain a history for exposure to environmental chemical agents and travel 
• Perform serology for viral hepatitis (hepatitis A virus immunoglobulin M ([IgM], 
hepatitis B surface antigen, hepatitis C virus antibody, cytomegalovirus IgM, and 
Epstein-Barr Virus antibody panel) 
• Perform serology for autoimmune hepatitis (e.g., antinuclear antibody) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computed tomography or magnetic resonance imaging scans, may be performed at the discretion 
of the Investigator, in consultation with the Sponsor Medical Monitor.  Repetition of the above 
evaluations should be considered if a patient’s ALT and/or AST levels reach 5 × ULN. 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results 
Please refer also to Table 2. 

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Platelet count will be monitored at least every 4 weeks during the Treatment and Post-Treatment 
Periods.  The Investigator should review all platelet count results within 48 hours of receipt.  
Any unreportable platelet count result must be rechecked ideally within 7 days and determined 
not to have met a stopping rule before dosing can continue.  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 8.6.2) should be followed. 
In the event of a platelet count < 75,000/mm3, additional laboratory investigations may be 
conducted in consultation with the Sponsor Medical Monitor. 
8.5.3. 
Safety Monitoring Rules for Renal Function Test Results 
If a patient’s results meet Criteria 1 or 2 below, the Investigator should confirm the results and 
initiate weekly monitoring if confirmed.  If the event of a persistent elevation is observed over 
2 consecutive weeks, then go to Section 8.6.3. 
1. Serum creatinine increase that fulfills all of the following:  ≥ 0.3 mg/dL (26.5 μmol/L) 
and ≥ 40% above baseline creatinine values and > ULN (refer to definition of Baseline in 
Section 8.6) 
2. Proteinuria, urine protein/creatinine ratio > 750 mg/g for baseline values ≥ 200 mg/g, or 
4 × baseline value for baseline values < 200 mg/g that are confirmed by repeated urine 
protein/creatinine ratio or by a quantitative total urine protein measurement of 
> 1.0 g/24 hours 
8.5.4. 
Safety Monitoring for Minor Bleeding Events 
If a bleeding event occurs, including minor bleeding events such as excess bruising, petechiae, or 
gingival bleeding on brushing teeth, the Investigator should notify the Sponsor Medical Monitor 
and additional testing of coagulation parameters (aPTT, PT, and 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 Study 
Day 1 value and the last value prior to Study 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 patient 
with Study Drug (ISIS 721744 or placebo) will be stopped permanently; values that are not 
confirmed due to failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 × ULN, which is confirmed 
2. ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 1.5 × ULN or INR > 1.5 

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4. ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × 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 Platelet Count Results 
Please refer also to Table 2. 
In the event of any platelet count < 25,000/mm3, dosing of the patient with Study Drug will be 
stopped permanently.  Platelet count should be monitored daily until 3 successive values 
> 25,000/mm3.  Then, monitor twice weekly until 3 successive values > 75,000/mm3.  Then, 
monitor weekly until 3 successive values > 100,000/mm3.  Consider more frequent monitoring if 
additional risk factors for bleeding are present (see Table 2).  Administration of steroids is 
strongly recommended for patients whose platelet count is < 25,000/mm3.  Treatment guidelines 
for immune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 
4 days every 2 to 4 weeks for 1 to 4 cycles; prednis(ol)one 0.5 to 2 mg/kg/day for 2 to 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 ≥ 25,000/mm3 to < 50,000/mm3, dosing of the patient with Study 
Drug will be stopped permanently.  Platelet count should be monitored twice weekly until 
3 successive values > 75,000/mm3.  Then, monitor weekly until 3 successive values 
> 100,000/mm3.  Consider more frequent monitoring and/or the administration of steroids if 
additional risk factors for bleeding are present (see Table 2). 
In the event of a platelet count ≥ 50,000/mm3 to ˂ 75,000/mm3, and in the absence of major 
bleeding or clinically relevant non-major bleeding (defined below), dosing with Study Drug 
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 Sponsor 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.  Platelet count must be 
measured twice weekly until 3 successive values > 75,000/mm3, then weekly until 3 successive 
values > 100,000/mm3.  Consider more frequent monitoring if additional risk factors for bleeding 
are present (see Table 2).  Any unreportable platelet count result must be rechecked, ideally 
within 7 days, 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, and/or 
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 g/dL (1.24 mmol/L) within 24 hours 

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Definition of Clinically Relevant Non-Major Bleeding Events 
Clinically relevant non-major bleeding 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 patient. 
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, or 
gingival bleeding on brushing teeth. 
If the subsequent test confirms the initial test result, then monitoring frequency and dosing 
should be adjusted as recommended in Table 2. 
Table 2: 
Actions in Patients with Low Platelet Count 
Platelet count 
(K/mm3) 
Dosing 
Monitoring frequency 
> 100 
Dosing every 4 weeks should be 
continued.   
At least every 4 weeks. 
≥ 75 to ≤ 100 
Dosing every 4 weeks should be 
continued. 
Every week. 
≥ 50 to < 75 
Pause dosing.  When platelet count 
returns to > 100K/mm3, restart 
dosing only if approved by the 
Sponsor Medical Monitor.   
Twice weekly until 3 successive 
values > 75K/mm3, then weekly until 
3 successive values > 100K/mm3. 
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
≥ 25 to < 50 
Permanently discontinue Study 
Drug. 
Consider corticosteroids if additional 
risk factors for bleeding are present.‡  
Twice weekly until 3 successive 
values > 75K/mm3, then weekly until 
3 successive values > 100K/mm3.   
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
< 25 
Permanently discontinue Study 
Drug. 
Corticosteroids strongly 
recommended.* 
Daily until 3 successive values 
> 25K/mm3, then twice weekly until 
3 successive values > 75K/mm3, then 
weekly until 3 successive values 
> 100K/mm3.   
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplatelet medicinal 
products, and/or prior history of major bleeding events. 
* It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives 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 2 to 4 weeks for 1 to 4 cycles; prednis(ol)one 0.5 to 2 mg/kg/day for 
2 to 4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days (Note:  patient may require continuation 
with oral steroids after methylprednisolone). 

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8.6.3. 
Temporary Stopping Rules for Renal Function Test Results 
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 Study Drug (ISIS 721744 or placebo) may be stopped 
temporarily: 
1. Serum creatinine increase that fulfills all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN (refer to definition 
of Baseline in Section 8.6) 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hours) 
The possible dosing reinitiation 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. 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
Adjustment of dose and/or schedule is not permitted. 
8.8. 
Discontinuation of Study Drug 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4. 
• The patient withdraws consent. 
• The patient withdraws from treatment (but does not withdraw consent). 
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug. 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1, 8.6.2, or 8.6.3. 
• The patient experiences an AE that necessitates unblinding of the Investigator or 
Sponsor to the patient’s treatment assignment. 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Patients who discontinue Study Drug will remain in the study and attend the ET Visit 
(Week 17 visit assessments), unless consent is withdrawn.  Any patient who discontinues early 
from the Treatment Period or from the Post-Treatment Follow-Up Period should be strongly 
encouraged to complete follow-up study visits, procedures and observations (see Appendix A). 
 
 

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8.9. 
Withdrawal of Patients from the Study Procedures 
Patients must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study may include the following: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for non-compliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures (Week 17 visit assessments) and observations 
at the time of withdrawal (see Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent, every effort should be 
made to complete the ET study procedures and observations at the time of withdrawal (see 
Appendix A). 
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol-specified drug or substance (including 
over-the-counter medications, herbal medications, and vitamin supplements) administered 
between Screening and the end of the Post-Treatment Period. 
Allowed Concomitant Therapy 
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated.  Patients can be treated with on-demand therapy as 
determined by their treating physician. 
All other stable medications (if not excluded below) are allowed, so long as the dose and type is 
not expected to change during the study. 
Disallowed Concomitant Therapy 
1. Chronic prophylaxis for angioedema attacks, except for a stable dose of androgens.  Any 
use of lanadelumab will not be permitted. 

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NOTE:  The use of acute medications (plasma-derived or recombinant C1-INH 
concentrate or BK2-receptor antagonist) to treat angioedema attacks is allowed as 
medically indicated. 
2. ACE inhibitors or any estrogen-containing medications with systemic absorption (such as 
oral contraceptive or hormonal replacement therapy). 
3. Any oligonucleotides (including small interfering RNA) other than ISIS 721744. 
4. Plasmapheresis. 
5. Any other investigational drug or device. 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the end of the Post-Treatment Period. 
8.11. 
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 or designee in 
accordance with the applicable Ionis and/or designee Standard Operating Procedures throughout 
the conduct of the clinical study. 
9.2. 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including SUSARs per the International Council for Harmonisation (ICH) 
guidelines E2A and ICH Good Clinical Practice (GCP).  Country-specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards/IECs will be notified of any SAE according to applicable 
regulations.  The DSMB will be notified of any SAE as specified in the DSMB Charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee 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 (ISIS 721744 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 or designee will unblind SUSARs for the purpose of 
regulatory reporting.  The Sponsor or designee will submit SUSARs to regulatory agencies in 
blinded or unblinded fashion according to local law.  The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 

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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An AE 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 
• 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 
• 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 
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, adverse drug reactions 
(ADRs) are defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered ADRs. 
The phrase “responses to a medicinal product” means that a causal relationship between the 
medicinal product and the AE 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. 

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9.3.3. 
Serious Adverse Event 
An SAE is any AE 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 patient 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 
• Results in a congenital anomaly or birth defect in the offspring of the patient 
(whether the patient 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 patient 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 AE 
(e.g., rated as mild, moderate, or severe according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [CTCAE]); 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 AE recorded on the eCRF. 
9.3.4. 
Adverse Events of Special Interest 
For the purpose of this study, severe reductions in platelet count < 50,000/mm3 accompanied by 
a major bleeding (MB) event or clinically relevant non-major bleeding (CRNMB) event, or 
platelet count of < 25,000/mm3 independent of a MB or CRNMB event, or any thrombotic 
episode are considered as AEs of special interest (AESIs) and  are subject to 15-day expedited 
reporting by the Sponsor to the regulatory agencies. 
9.4. 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 

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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 patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the ICF and will stop at the end of the patient’s Post-Treatment 
Period, which is defined as completion of the Week 26/ET Visit.  Serious adverse events should 
be reported using electronic SAE submission (via eDC) whenever possible.  In situations where 
electronic SAE submission is unavailable, a paper Initial Serious Adverse Event Form should be 
completed and a copy should be faxed or emailed to the Sponsor or designee.  The SAE 
reporting instructions, 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 as Follow-Up as soon as additional 
information becomes available.  All SAEs will be followed until resolution.  Serious adverse 
events that remain ongoing past the patient’s last protocol-specified follow-up visit will be 
evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree that the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the ICF and will stop at the 
end of the patient’s Post-Treatment Period, which is defined as completion of the Week 26/ET 
Visit.  The Investigator will monitor each patient closely and record all observed or volunteered 
AEs on the eCRF. 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the eCRF: 
9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 721744 or placebo) is characterized by 1 of the 
following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug 
(ISIS 721744 or placebo), e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ISIS 721744 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 (ISIS 721744 or placebo) administration and/or exposure suggests that 
a causal relationship is unlikely (for reporting purposes, Unlikely/Remote will be 
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• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and Study Drug (ISIS 721744 or 
placebo) 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site will be 
graded based on criteria from the 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 patient and does not affect the patient’s 
usual daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’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 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the study. 
Action taken with Study Drug (ISIS 721744 or placebo) due to an AE is characterized by 1 of the 
following: 
• None:  No changes made to Study Drug (ISIS 721744 or placebo) administration and 
dose 
• Not Applicable:  AE reported during the Screening Period prior to Study Drug 
(ISIS 721744 or placebo) administration 
• Permanently Discontinued:  Study Drug (ISIS 721744 or placebo) discontinued and 
not restarted 
• Temporarily Interrupted, Restarted – Same Dose:  Dosing and/or dosing 
frequency temporarily interrupted/changed or delayed due to the AE and restarted at 
the same dose 
9.4.3.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
eCRF.  Treatment should also be recorded on the concomitant treatment or ancillary procedures 
eCRF, as appropriate.  
9.4.3.5. 
Outcome of the Adverse Event 
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• AE Persists:  Patient terminates from the study and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious 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 patient 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 eCRF and in the patient’s medical 
record to facilitate source data verification.   
Investigators should follow-up, or support the Sponsor’s effort to follow up, with all pregnancies 
reported during the study from either the study patient or the female partner of the male study 
patient until pregnancy outcome is available.   
Sponsor Follow-up 
For SAEs and pregnancy cases in patients who have completed or terminated the 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, or autopsy reports) in order to perform an independent medical assessment of 
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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 Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
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 patient 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 patient’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 patient’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 (ISIS 721744 or placebo) dosing 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 patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing eCRF.  If the patient takes a dose of Study Drug 
(ISIS 721744 or placebo) that exceeds protocol specifications and the patient 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 AE, but 
it may result in an AE.  All AEs associated with an overdose or incorrect administration of Study 
Drug should be recorded on the Adverse Event eCRF.  If the associated AE fulfills seriousness 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event). 

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Should an overdose occur, the Investigator or designee should refer to the “Guidance for 
Investigator” section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use highly effective 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.   
Female patients:  If a suspected pregnancy occurs while on the study (including the 
Post-Treatment Period), a pregnancy test will be performed.  The patient with a confirmed 
pregnancy will be immediately withdrawn from treatment with Study Drug.  However, the 
patient will be encouraged to complete the Post-Treatment Period 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 patient 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 patients:  The progress of the pregnancy of a male patient’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. 
10. 
STATISTICAL CONSIDERATIONS 
The sections below indicate the overall structure and approach to the analysis of this study.  A 
detailed SAP incorporating these sections below will be prepared separately.  The SAP will 
outline all data handling conventions, including software, and specify additional statistical 
methods to be used for analysis.  The study objectives and endpoints are listed in Sections 1.1 
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10.1. 
Sample Size Considerations 
The study will enroll a total of approximately 24 patients with HAE.  Approximately 18 patients 
with HAE-1/HAE-2 are planned to be enrolled in Part A of the study and, in parallel, 
approximately 6 patients with HAE-nC1-INH are planned to be enrolled in Part B of the study.  
Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are 
unable to enroll sufficient patients; this will not impact completion of Part A.  Patients with 
HAE-1/HAE-2 (Part A) will be randomized to SC injections of ISIS 721744 80 mg or placebo 
administered every 4 weeks in a 2:1 ratio (ISIS 721744:placebo), and patients with 
HAE-nC1-INH (Part B) will be administered open-label SC injections of ISIS 721744 80 mg 
every 4 weeks. 
The sample size of 18 patients with HAE-1/HAE-2 (12 patients administered SC injections of 
ISIS 721744 80 mg and 6 patients administered placebo) is from clinical considerations for 
sufficient safety and tolerability evaluation.  The primary endpoint is the time-normalized 
number of HAE attacks (per month) from Week 1 to Week 17.  From historical data, the placebo 
group is estimated to have 6.8 HAE attacks per 4-month period.  If the ISIS 721744 80 mg group 
is assumed to have 2.8 HAE attacks per 4-month period, then with a 0.05 significance level and 
Poisson model, the sample size of 18 patients will provide at least 90% power for the primary 
endpoint, considering a 10% missing data or dropout rate for both active treatment and placebo.  
There is no statistical rationale for the sample size of 6 patients with HAE-nC1-INH. 
10.2. 
Populations 
The Safety Population will include all enrolled patients who receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo). 
The Intent-to-Treat (ITT) Population will include all enrolled or randomized patients. 
The Per-Protocol (PP) Population will include all patients in the ITT Population who are treated 
according to the protocol without any major deviations. 
The PK Population will include all patients who are enrolled and receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo) and have at least 1 evaluable PK sample. 
10.3. 
Definition of Baseline 
For platelets, Baseline will be defined as the average of all non-missing pre-dose assessments. 
For other assessments, if there are 2 or more pre-dose values available, Baseline will be defined 
as the average of the pre-dose Study Day 1 value and the last pre-dose value prior to Study 
Day 1.  If there is only 1 pre-dose measurement available, then it will be assigned as Baseline.   
10.4. 
Data and Safety Monitoring Board 
An independent DSMB will be established prior to the initiation of the study.  The DSMB will 
be responsible for monitoring the overall safe conduct of the study.  Based on its ongoing 
assessment of the safety and tolerability of ISIS 721744, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping, or continuing the study as planned.  

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Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data are outlined in the DSMB Charter and SAP. 
10.5. 
Interim Analysis 
No interim analysis is planned for this study. 
10.6. 
Planned Methods of Analysis 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Patient disposition will be summarized by treatment group.  All patients 
enrolled will be included in a summary of patient disposition. 
10.6.2. 
Safety Analysis 
The Safety Population will be used for all safety analyses.   
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of AEs; vital signs; ECGs; and clinical laboratory parameters.  
Safety results in patients dosed with ISIS 721744 will be compared to safety results in patients 
dosed with placebo. 
Treatment duration and amount of Study Drug (ISIS 721744 or placebo) received will be 
summarized by treatment group.  Patient incidence rates of all AEs will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA™) system organ class and by MedDRA preferred 
term.  Tables and/or narratives of treatment-emergent deaths and serious and significant AEs, 
including early withdrawals due to AEs, will also be provided. 
All TEAEs, all TEAEs potentially related to Study Drug, all treatment-emergent SAEs, and all 
treatment-emergent SAEs potentially related to Study Drug (ISIS 721744 or placebo) will be 
summarized. 
Laboratory tests to ensure patient safety, including chemistry panel, complete blood count with 
differential, coagulation panel, and complement, will be summarized by study visit for each 
treatment group.  These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ISIS 721744 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. 
Efficacy Analysis 
The ITT Population will be used for all efficacy analyses.  The PP Population will be used for a 
sensitivity analysis to assess robustness of the efficacy analysis results. 
The definition of an HAE attack, including discrete attacks, is provided in Section 6.2.1. 

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10.6.3.1. Primary Efficacy Analysis 
The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 1 
to Week 17. 
The Part A data will be analyzed using a Poisson regression model with treatment group as a 
fixed effect and the number of baseline HAE attacks as a covariate, and the logarithm of 
exposure in month will be used as the offset. 
The least-squares means, standard errors, and the 2-tailed 95% confidence intervals for the 
treatment group and placebo group will be presented. 
The Part B data will be summarized using descriptive statistics. 
10.6.3.2. Secondary Efficacy Analysis 
The secondary endpoints include the time-normalized number of HAE attacks (per month) from 
Week 5 to Week 17; the time-normalized number of moderate or severe HAE attacks (per 
month) from Week 5 to Week 17; the number of patients with a clinical response (defined as a 
≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate) by Week 17; the number 
of HAE attacks requiring acute therapy from Week 5 to Week 17; cHK levels at Weeks 9 and 17; 
PKK activity at Weeks 9 and 17; consumption of on-demand medication at Weeks 9 and 17; and 
AE-QoL questionnaire score at Weeks 9 and 17. 
For Part A, the time-normalized number of HAE attacks (per month) from Week 5 to Week 17 
and the time-normalized number of moderate or severe HAE attacks (per month) from Week 5 to 
Week 17 will be analyzed in a similar way to the primary efficacy endpoint. 
Continuous variables will be summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) by treatment group.  Continuous variables will also be 
analyzed using analysis of covariance or analysis of variance.  The least-squares means, standard 
errors, and the 2-tailed 95% confidence intervals for the treatment group and placebo group will 
be presented. 
Categorical variables will be summarized by frequency and percentage for the treatment group 
and placebo group.  Categorical variables will be analyzed using a Pearson’s Chi-square test or 
Cochran-Mantel-Haenszel test. 
The Part B data will be summarized using descriptive statistics. 
10.6.3.3. Exploratory Efficacy Analysis 
Exploratory efficacy endpoints include the number of HAE attack-free patients by Week 17 and 
potential exposure response analysis using relevant exposure parameters and biomarkers.  All 
exploratory efficacy endpoints will be analyzed using the same methods as described for the 
secondary efficacy endpoints. 
10.6.4. 
Pharmacokinetic Analysis 
The plasma PK of ISIS 721744 will be assessed following SC administration.  For all patients, 
Pre-Dose (trough) and Post-Treatment plasma ISIS 721744 concentrations will be determined 
and summarized using descriptive statistics.  Plasma terminal elimination half-life will also be 

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calculated using the Post-Treatment follow up ISIS 721744 plasma concentrations, if data 
permits.  For patients in the PK sub group, non-compartmental PK analysis of ISIS 721744 will 
be carried out on each individual patient dataset.   
Pharmacokinetic parameters include (but are not limited to) the following:  Cmax, Tmax, AUC, and 
t½.  Other plasma PK parameters, as appropriate, may be determined or calculated at the 
discretion of the PK scientist. 
Metabolite identification and profiling may be conducted on select plasma samples. 
Plasma PK parameters will be summarized using descriptive statistics.  Additional details 
regarding the PK analysis along with  immunogenicity (IM) analysis will be described in the 
SAP. 
Analysis of potential exposure-response relationship between biomarkers and PK measures may 
also be explored. 
Population PK and PK/PD analyses may be performed using PK data from this study, and/or 
combined with other ISIS 721744 clinical PK/PD data later in the development timeline. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or designee. 
Before a patient’s participation in the study, the Investigator is responsible for obtaining written 
informed consent from the patient 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 (ISIS 721744 or placebo) are administered.  The patient must be 
given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the ICF 
should be signed and personally dated by the patient and by the person who conducted the 
informed consent discussion (not necessarily an Investigator).  The original signed ICF 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 patient. 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current GCP as well as the demands of national drug 
and data protection laws and other applicable regulatory requirements must be followed.   
11.3. 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed ICF, other written patient information, and any proposed 
advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and ICF must be received by the Sponsor or designee before 

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recruitment of patients into the study and shipment of Study Drug.  A copy of the written 
approval of any other items/materials that must be approved by the Study Center or IEC/IRB 
must also be received by the Sponsor or designee before recruitment of patients into the study 
and shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP.  The Investigator should also notify the IEC/IRB of SAEs occurring at the Study Center 
and other AE reports received from the Sponsor or designee, in accordance with local 
procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
11.4. 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, patients should be identified by 
initials (if permitted by local law) and a patient identification number only.  Documents that are 
not for submission to the Sponsor or designee (e.g., signed ICFs) should be kept in strict 
confidence by the Investigator. 
In compliance with federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’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 patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the patients 
or the conduct of the study.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 

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12.2. 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the Study Center 
contract.  The Investigator/Sponsor or designee should notify the IEC/IRB in writing of the 
study’s completion or ET and send a copy of the notification to the Sponsor or designee. 
12.3. 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated study duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, imaging, and correspondence.  In this study, eCRFs 
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 or designee and/or 
applicable regulatory authorities.  Elements should include the following: 
• Patient files containing completed case report forms, informed consents, and 
supporting copies of source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IEC/IRB 
and the Sponsor or designee 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug 
Product Accountability Record, Return of Study Drug Product for Destruction, final 
Study Drug product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., case report forms and other pertinent data) provided that 
patient confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 

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consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the case report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or designees).  
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study 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 
patient data received by the Sponsor or designee.  During this review, patient data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and GCP.  To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor or designee. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English.  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 patients 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 studies and will follow 
applicable local compensation laws.  Patients 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 ICF. 
 

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13. 
REFERENCES 
Altmann K-H, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: From nuclease 
resistance to biological efficacy in animals. CHIMIA Int J Chem 1996; 50: 168‑176. 
Bissler JJ, Aulak KS, Donaldson VH, et al. Molecular defects in hereditary angioneurotic edema. Proc Assoc Am 
Physicians 1997; 109: 164‑173. 
Clinical Trial Facilitation Group 2014. Recommendations related to contraception and pregnancy testing in clinical 
trials. Heads of Medicines Agencies Website. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed December 5, 2019. 
Crooke ST, and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol Toxicol 1996; 
36: 107-129. 
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. 
Girolami A, Scarparo P, Candeo N, et al. Congenital prekallikrein deficiency. Expert Rev Hematol 2010; 3: 685-
695. 
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. 
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. 
Lara‑Marquez ML, Christiansen SC, Riedl MA, et al. Threshold-stimulated kallikrein activity distinguishes 
bradykinin- from histamine-mediated angioedema. Clin Exp Allergy 2018; 48: 1429‑1438. 
Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of 
hereditary angioedema-The 2017 revision and update. Allergy 2018; 73: 1575‑1596. 
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. 
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. 
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. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people 
with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388: 
2239-2253. 
Weller K, Groffik A, Magerl M, et al. Development, validation, and initial results of the Angioedema Activity 
Score. Allergy 2013; 68: 1185-1192. 
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. 
Zuraw BL, and Christiansen SC. HAE Pathophysiology and Underlying Mechanisms. Clin Rev Allergy Immunol 
2016; 51: 216-229. 
 
 

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14. 
APPENDICES 

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APPENDIX A. SCHEDULE OF PROCEDURES 
 

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Appendix A. Schedule of Procedures 
 
Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
Demographics and Medical 
History (including detailed 
HAE history) 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications (including HAE 
treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight and Height2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B, and 
Hepatitis C 
X 
 
 
 
 
 
 
 
 
FSH4 
X 
 
 
 
 
 
 
 
 
Pregnancy Test5 
X 
X 
 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Parameters (chemistry, 
hematology, complement, and 
coagulation)6, 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Appendix A. Schedule of Procedures Continued 
 
Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Threshold-Stimulated 
Kallikrein Activity 
(if applicable)8 
X 
 
 
 
 
 
 
 
 
Genetic Diagnostic Testing 
(if applicable)9 
X 
 
 
 
 
 
 
 
 
AE-QoL 
X 
X 
 
 
X 
 
X 
 
X 
Angioedema Activity 
Score10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAE Attack Assessment 
(including on-demand 
treatment)11, 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
 
 
X 
 
X 
 
X 
Randomization13 
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
(ISIS 721744 or placebo) 
 
X 
 
X 
X 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity Testing 
 
Xa 
X 
Xa 
Xa 
 
X 
 
X 
 
 

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Appendix A. Schedule of Procedures Continued 
 
Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
PK Blood Sampling14 
 
Xb 
X 
Xa 
Xa 
Xb 
X 
X 
X 
PD Blood Sampling15 
X 
Xa 
X 
Xa 
Xa 
Xa 
X 
X 
X 
Inflammatory Panel 
X 
Xa 
X 
Xa 
Xa 
Xa 
X 
X 
X 
Note: When multiple procedures are scheduled at the same visit, clinical assessments and procedures should be performed prior to Study Drug administration, 
unless otherwise indicated, and should proceed in the following order:  vital signs, physical examinations, patient-reported outcomes (such as the AAS and 
the AE-QoL questionnaire), ECGs, and collection of blood and/or urine for laboratory assessments.   
1 The Screening Period is up to 8 weeks in duration.  A patient may be randomized after fewer than 8 weeks of Screening if the patient experiences ≥ 2 HAE 
attacks in less than 8 weeks and has completed all other screening activities and has met all other eligibility requirements. 
2 Height will be measured at Screening only.  
3 Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and should be taken after sitting for at least 5 min.   
4 For confirmation of menopause at Screening per inclusion criteria. 
5 Only for women who are not surgically sterile or post-menopausal.  A serum pregnancy test will be performed during Screening and urine pregnancy tests 
will be performed at all other study visits.   
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 For a complete list of laboratory analytes, refer to Appendix B. 
8 Will be assessed only in patients who have HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 mutation.   
9 Will be performed only for patients who do not have HAE genetic diagnostic testing results prior to Screening. 
10 The AAS questionnaire will be completed by patients on a daily basis (minimum of 4 daily assessments per week) for the duration of the study.  Patients will 
be instructed on the use of the AAS during Screening and will record their HAE attacks using the AAS throughout the Screening Period (daily during up to 
8 consecutive weeks) to confirm study eligibility; patients are required to experience at least 2 HAE attacks (assessed by the AAS and confirmed by the 
Investigator) during the Screening Period to be eligible for enrollment.  If a patient experiences a third attack, the patient should be randomized as soon as 
possible, assuming all other screening activities have been completed and the patient meets all other eligibility requirements; in such cases, the Screening 
Period may be shorter than 8 weeks.  Enrolled patients will continue to record HAE attacks using the AAS throughout the Treatment and Post-Treatment 
Periods.  
 
 

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Legend Continued 
 
11 Historical HAE attack information will be collected at Screening.  During the study, patients will be instructed to report details of any HAE attack to the study 
site within 72 hours of the onset of the attack.  Throughout the Screening, Treatment, and Post-Treatment Periods, site personnel will contact the patient once 
a week (at approximately 7 days after the last contact with the patient) in order to inquire about any attack that may have occurred.  In addition, during study 
visits, site personnel will inquire about any new HAE attack information that was not provided through patient contact with the site. 
12 The following details relating to the localization, severity, and course of all HAE attacks that occured since the previous visit will be collected:  date/time of 
symptom onset; description of symptoms; location of symptoms (peripheral angioedema, abdominal angioedema, or laryngeal angioedema); impact of HAE 
attack on activity level; HAE attack severity (mild, moderate, or severe); need for assistance, medical intervention, emergency room visit, or hospitalization; 
medications to treat the attack; HAE attack course, including if the HAE attack(s) in question was a typical attack for the patient, or if there was an alternative 
diagnosis; and date/time symptoms resolved.  The number of HAE attacks that required on-demand treatment, and the frequency and dose of on-demand 
treatment, will also be recorded. 
13 After all screening assessments have been completed and the Investigator has verified that the patient is eligible. 
14 Refer to Appendix C for the PK Sampling Schedule. 
15 To be collected at each visit to assess plasma PKK, plasma proenzyme activation, and cHK levels. 
16 Patients who complete Study Visit Week 17, and meet eligibility requirements, may start the Treatment Period in the ISIS 721744-CS3 OLE study anytime 
after the Week 17 visit and discontinue participation in the CS2 Post-Treatment Evaluation Period.  
17 Assessments and procedures may be conducted by either a Home Healthcare professional (if available), or the Study Center as arranged by the Study Center 
personnel.  Physical Exam will be labeled Body Assessment if conducted by Home Healthcare professional.  Study Drug administration by Home Healthcare 
professional may be done only after study drug for home use is available. 
 
Time (time is in reference to Study Drug administration [ISIS 721744 or placebo]): 
a 
Pre-dose. 
b Pre-dose, 1, 2, 4, and 6 hours post-dose (PK Subgroup) or Pre-dose and 2-hours post-dose. 
 

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APPENDIX B. LIST OF LABORATORY ANALYTES 
 
 

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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 ISIS 721744 or other similar 
oligonucleotides. 
Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Cholesterol 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
• 
Creatine kinase 
• 
GGT 
Screening Tests 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (for 
confirmation of 
menopause at 
Screening per 
inclusion criteria) 
• 
Serum βhCG (only 
women who are not 
surgically sterile or 
post-menopausal) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
• 
Plasmin-antiplasmin 
complexes 
• 
D-dimer 
 
Complement 
• 
C5a 
• 
Bb 
• 
C4 split products 
• 
C4 
 
Pharmacodynamics 
Panel 
• 
Plasma PKK 
• 
Plasma proenzyme 
activation 
• 
cHK 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
(WBC) 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1 
• 
ISIS 721744 
concentration in plasma 
 
Immunogenicity 
• 
Anti-ISIS 721744 
antibodies 
Inflammatory 
• 
hs-CRP  
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein/creatinine ratio 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
eGFR 
• 
Microscopic 
examination2 
 
 
1 Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 721744 with plasma 
constituents. 
2 Will be performed on abnormal findings unless otherwise specified. 
 

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APPENDIX C. PHARMACOKINETIC SAMPLING SCHEDULE  
 
 

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Appendix C Pharmacokinetic Sampling Schedule  
PK samples on Day 1 and Day 85 will be collected pre-dose, and 1, 2, 4, and 6 hours post-dose 
in PK subgroup only (approximately 6 patients) while pre-dose and 2 hours post-dose samples on 
Day 1 and Day 85 will be collected for all other patients.  The rest of the sampling schedule will 
be the same for both sets of pateints (see table below): 
 
Pharmacokinetic Sampling Schedule 
 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 176 
PK 
Subgroup 
Blood:  
Pre-dose, 
1, 2, 4, 
and 
6 hours 
post-dose 
Blood: 
Anytime 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood:  
Pre-dose, 
1, 2, 4, 
and 
6 hours 
post-dose 
Blood:  
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
All 
Patients 
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime  
Blood: 
Pre-dose  
Blood: 
Pre-dose  
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime  
Blood 
Anytime  
Blood 
Anytime  
 
 

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APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 
 
 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities and 
adverse events at the injection site are based on the CTCAE Version 5.0, November 2017 with 
modifications outlined in the footnotes below. 
 
 
 

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Version: 1
Version Date: 05 May 2020
Title: A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the
Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense
Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema
Protocol

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
 
 
 
 
 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 721744-CS2 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study 
to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
 
Protocol Amendment 3 – 5 May 2020 
 
EudraCT No: 2019-001044-22 
 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number: 760-603-4665 
Fax Number: 760-603-2625 
 
Key Sponsor Contact: 
PPD 
 
Executive Director, Clinical Development 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number: PPD 
 

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
2 
 
 
 
ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
ISIS 721744-CS2 
Protocol Amendment 3 
EudraCT No: 2019-001044-22 
 
Clinical Phase: 2a 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study 
to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
 
Protocol History: 
Original Protocol: 
3 May 2019 
Amendment 1: 
21 October 2019 
Amendment 2: 
29 January 2020 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA 92010 
 
 See electronic signature and date attached at end of document  
 
PPD 
 
Vice President and Head of Clinical Development 
 
 
 
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. 

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
3 
 
 
 
ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
5 May 2020 
 
Protocol Signature Page 
 
 
Protocol Number: 
ISIS 721744-CS2 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to 
Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients with 
Hereditary Angioedema 
Amendment: 
Amendment 3 
Date: 
5 May 2020 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy 
of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in 
Patients with Hereditary Angioedema,” dated 5 May 2020, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonisation 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) 

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
4 
 
 
 
ISIS 721744-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ........................................................................................................... 8 
PROTOCOL SYNOPSIS ............................................................................................................... 12 
STUDY DESIGN AND TREATMENT SCHEMA ........................................................................ 21 
STUDY GLOSSARY ...................................................................................................................... 22 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................. 24 
1.1. 
Objectives .................................................................................................................... 24 
1.1.1. 
Primary Objective ....................................................................................................... 24 
1.1.2. 
Secondary Objectives .................................................................................................. 24 
1.1.3. 
Exploratory Objectives................................................................................................ 24 
1.2. 
Study Endpoints .......................................................................................................... 24 
1.2.1. 
Primary Endpoints ....................................................................................................... 24 
1.2.2. 
Secondary Endpoints ................................................................................................... 24 
1.2.3. 
Safety Endpoints .......................................................................................................... 25 
1.2.4. 
Exploratory Endpoints ................................................................................................ 25 
2. 
BACKGROUND AND RATIONALE ....................................................................... 25 
2.1. 
Overview of Disease ................................................................................................... 25 
2.2. 
Therapeutic Rationale ................................................................................................. 26 
2.3. 
ISIS 721744 ................................................................................................................. 26 
2.3.1. 
Mechanism of Action .................................................................................................. 26 
2.3.2. 
Chemistry .................................................................................................................... 26 
2.3.3. 
Preclinical Experience .................................................................................................. 28 
2.3.4. 
Clinical Experience ..................................................................................................... 28 
2.4. 
Rationale for Dose and Schedule of Administration ................................................... 29 
2.5. 
Benefit-Risk Assessment ............................................................................................ 29 
2.5.1. 
Benefit Assessment ..................................................................................................... 29 
2.5.2. 
Risk Assessment ......................................................................................................... 29 
2.5.3. 
Overall Assessment of Benefit:Risk ............................................................................ 30 
3. 
EXPERIMENTAL PLAN ........................................................................................... 30 
3.1. 
Study Design ............................................................................................................... 30 
3.2. 
Number of Study Centers ............................................................................................ 31 
3.3. 
Number of Patients ...................................................................................................... 31 
3.4. 
Overall Study Duration and Follow-up ....................................................................... 31 
3.4.1. 
Screening ..................................................................................................................... 31 
3.4.2. 
Treatment Period ......................................................................................................... 31 
3.4.3. 
Post-Treatment Period ................................................................................................. 32 
3.5. 
End-of-Study ............................................................................................................... 32 
3.6. 
Data and Safety Monitoring Board ............................................................................. 32 
4. 
PATIENT ENROLLMENT.......................................................................................... 32 
4.1. 
Screening ..................................................................................................................... 32 

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Amendment 3 
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4.2. 
Randomization ............................................................................................................ 33 
4.3. 
Replacement of Patients .............................................................................................. 33 
4.4. 
Unblinding of Treatment Assignment ......................................................................... 33 
5. 
PATIENT ELIGIBILITY ............................................................................................ 34 
5.1. 
Inclusion Criteria ......................................................................................................... 34 
5.2. 
Exclusion Criteria ....................................................................................................... 35 
6. 
STUDY PROCEDURES .............................................................................................. 36 
6.1. 
Study Schedule ............................................................................................................ 36 
6.1.1. 
Screening ..................................................................................................................... 37 
6.1.2. 
Treatment Period ......................................................................................................... 37 
6.1.3. 
Post-Treatment Period ................................................................................................. 38 
6.2. 
Study Assessments ...................................................................................................... 39 
6.2.1. 
Collection of Hereditary Angioedema Attack Details ................................................. 39 
6.2.2. 
Patient-Reported Outcomes ........................................................................................ 40 
6.2.2.1. 
Angioedema Quality of Life Questionnaire ................................................................ 40 
6.2.2.2. 
Angioedema Activity Score ........................................................................................ 40 
6.2.3. 
Laboratory Assessments .............................................................................................. 41 
6.3. 
Restriction on the Lifestyle of Patients ....................................................................... 41 
6.3.1. 
Contraception Requirements ....................................................................................... 41 
7. 
STUDY DRUG ............................................................................................................ 42 
7.1. 
Study Drug Description ................................................................................................ 42 
7.2. 
Packaging and Labeling .............................................................................................. 42 
7.3. 
Study Drug Accountability .......................................................................................... 42 
8. 
TREATMENT OF PATIENTS................................................................................... 43 
8.1. 
Study Drug Administration ......................................................................................... 43 
8.2. 
Other Protocol-Required Drugs .................................................................................. 43 
8.3. 
Other Protocol-Required Treatment Procedures ......................................................... 43 
8.4. 
Treatment Precautions ................................................................................................. 43 
8.5. 
Safety Monitoring Rules ............................................................................................. 43 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ................................................... 44 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results .................................................... 44 
8.5.3. 
Safety Monitoring Rules for Renal Function Test Results ......................................... 45 
8.5.4. 
Safety Monitoring for Minor Bleeding Events ........................................................... 45 
8.6. 
Stopping Rules ............................................................................................................ 45 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations ......................................................... 45 
8.6.2. 
Stopping Rules for Platelet Count Results .................................................................. 46 
8.6.3. 
Temporary Stopping Rules for Renal Function Test Results ...................................... 48 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................ 48 
8.8. 
Discontinuation of Study Drug ................................................................................... 48 
8.9. 
Withdrawal of Patients from the Study Procedures .................................................... 49 

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Amendment 3 
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8.10. 
Concomitant Therapy and Procedures ........................................................................ 49 
8.10.1. 
Concomitant Therapy .................................................................................................. 49 
8.10.2. 
Concomitant Procedures ............................................................................................. 50 
8.11. 
Treatment Compliance ................................................................................................ 50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 50 
9.1. 
Sponsor Review of Safety Information ....................................................................... 50 
9.2. 
Regulatory Requirements ............................................................................................. 50 
9.3. 
Definitions ................................................................................................................... 51 
9.3.1. 
Adverse Event ............................................................................................................. 51 
9.3.2. 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ............. 51 
9.3.3. 
Serious Adverse Event ................................................................................................ 52 
9.3.4. 
Adverse Events of Special Interest ............................................................................. 52 
9.4. 
Monitoring and Recording Adverse Events ................................................................ 52 
9.4.1. 
Serious Adverse Events .............................................................................................. 53 
9.4.2. 
Non-Serious Adverse Events ....................................................................................... 53 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) ......................................... 53 
9.4.3.1. 
Relationship to the Study Drug ................................................................................... 53 
9.4.3.2. 
Severity ....................................................................................................................... 54 
9.4.3.3. 
Action Taken with Study Drug ................................................................................... 54 
9.4.3.4. 
Treatment Given for Adverse Event ........................................................................... 54 
9.4.3.5. 
Outcome of the Adverse Event ................................................................................... 54 
9.4.3.6. 
Follow-up of Adverse Event ........................................................................................ 55 
9.5. 
Procedures for Handling Special Situations ................................................................ 56 
9.5.1. 
Abnormalities of Laboratory Tests ............................................................................. 56 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................. 56 
9.5.3. 
Dosing Errors .............................................................................................................. 56 
9.5.4. 
Contraception and Pregnancy ..................................................................................... 57 
10. 
STATISTICAL CONSIDERATIONS ........................................................................ 57 
10.1. 
Sample Size Considerations ........................................................................................ 58 
10.2. 
Populations .................................................................................................................. 58 
10.3. 
Definition of Baseline ................................................................................................. 58 
10.4. 
Data and Safety Monitoring Board ............................................................................. 58 
10.5. 
Interim Analysis .......................................................................................................... 59 
10.6. 
Planned Methods of Analysis ...................................................................................... 59 
10.6.1. 
Demographic and Baseline Characteristics ................................................................. 59 
10.6.2. 
Safety Analysis ........................................................................................................... 59 
10.6.3. 
Efficacy Analysis ........................................................................................................ 59 
10.6.3.1. 
Primary Efficacy Analysis .......................................................................................... 60 
10.6.3.2. 
Secondary Efficacy Analysis ...................................................................................... 60 
10.6.3.3. 
Exploratory Efficacy Analysis .................................................................................... 60 

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10.6.4. 
Pharmacokinetic Analysis ........................................................................................... 60 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................ 61 
11.1. 
Informed Consent ........................................................................................................ 61 
11.2. 
Ethical Conduct of the Study ...................................................................................... 61 
11.3. 
Independent Ethics Committee/Institutional Review Board ....................................... 61 
11.4. 
Patient Confidentiality ................................................................................................. 62 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............................................... 62 
12.1. 
Protocol Amendments ................................................................................................. 62 
12.2. 
Study Termination ....................................................................................................... 63 
12.3. 
Study Documentation and Storage .............................................................................. 63 
12.4. 
Study Monitoring ........................................................................................................ 63 
12.5. 
Language ..................................................................................................................... 64 
12.6. 
Compensation for Injury ............................................................................................. 64 
13. 
REFERENCES ............................................................................................................ 65 
14. 
APPENDICES ............................................................................................................ 66 
APPENDIX A. SCHEDULE OF PROCEDURES ...................................................................... 67 
APPENDIX B. LIST OF LABORATORY ANALYTES ........................................................... 72 
APPENDIX C. PHARMACOKINETIC SAMPLING SCHEDULE .......................................... 74 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES .............................................................. 76 
 
 
 
LIST OF TABLES 
Table 1: 
Study Drug Characteristics .......................................................................................... 42 
Table 2: 
Actions in Patients with Low Platelet Count ............................................................... 47 
 
 
 
LIST OF FIGURES 
Figure 1: 
Design of GalNAc3-Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer) .............................................................................. 27 

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ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
PROTOCOL AMENDMENT 
 
 
Protocol Number: 
ISIS 721744-CS2 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to 
Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
Amendment Number: 3 
Amendment Date: 
5 May 2020 
 
 
The following modifications to Protocol ISIS 721744-CS2 Amendment 2, dated 29 January 
2020, have been made. 
1) To adjust the length of time patients must not have received lanadelumab, prior to 
screening for ISIS 721744-CS2, from 6 months to 10 weeks (i.e., 5 times the ~14-day 
half life for lanadelumab). 
2) To decrease the burden of site visits where feasible for patients, Study Drug 
administration, assessements and procedures may be conducted by either a Home 
Healthcare professional (if available) or the Study Center, as arranged by the Study 
Center personnel, for visits as noted in Appendix A. 
3) To decrease the burden of PK sampling for patients, only a subgroup of approximately 
6 patients (rather than all patients) will have blood draws of pre-dose, 1, 2, 4, and 6 hours 
post-dose on Day 1 and Day 85. This, along with a pre-dose and a 2 hour post-dose 
blood collection on Day 1 and Day 85 in all patients, will provide enough information to 
determine PK parameters. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 

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Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
9 
 
 
 
The following table provides a summary list of major changes to the protocol: 
 
Protocol Section 
Description of Change 
Rationale 
PROTOCOL 
SYNOPSIS 
Study Population 
Exclusion Criteria 
Section 5.2.11.b 
Exclusion Criteria 
Deletions in strikeout and additions in bold: 
11.b Chronic prophylaxis with Llanadelumab within 
10 weeks 6 months prior to Screening 
To adjust the length of time 
patients must not have received 
lanadelumab, prior to screening 
for ISIS 721744-CS2, to 
5 times the ~14 day half life for 
lanadelumab. 
PROTOCOL 
SYNOPSIS 
Study Visit Schedule 
and Procedures 
Section 6.1.2 
Treatment Period 
Deletions in strikeout and additions in bold: 
The first dose of Study Drug will be administered at the 
Study Center on Day 1. ISIS 721744 Study Drug will be 
administered as a SC injection in the abdomen, thigh, or 
outer area of the upper arm by qualified personnel at the 
Study Center or Home Healthcare professional (if 
available and after dosing instructions and training are 
provided by qualified site personnel). The first dose of 
Study Drug will be administered at the Study Center on 
Day 1. Study visits Center personnel (or Home 
Healthcare if available), will complete procedures per 
the Schedule of Procedures in Appendix A. will be 
performed during the Treatment Period at Week 1 
(Administration 1), Week 3 (safety monitoring), Week 5 
(Administration 2), Week 9 (Administration 3), and Week 
13 (Administration 4); 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 
Section 6.1.3 
Post-Treatment 
Period 
Additions in bold: 
Each patient will be followed for safety assessments for up 
to 13 weeks after the last dose of Study Drug. During the 
Post-Treatment Period, patients will return to the Study 
Center (or have Home Healthcare (if available), as 
arranged by the Study Center personnel, per the 
Schedule of Procedures in Appendix A) for visits at 
Weeks 17, 21, and 26/ET for safety and clinical laboratory 
evaluations and for blood sampling for PK/PD analyses. 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 
Section 8.1 
Study Drug 
Administration 
Additions in bold: 
Study Drug (ISIS 721744 or placebo) will be administered 
as a single-SC injection once every 4 weeks by blinded 
study staff during on-site visits at the Study Centers or by 
Home Healthcare professional (if available and after 
dosing instructions and training are provided by 
qualified site personnel). 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients. 

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Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
10 
 
 
 
Protocol Section 
Description of Change 
Rationale 
Section 10.6.4 
Pharmacokinetics 
Analysis 
Deletions in strikeout and additions in bold: 
The plasma PK of ISIS 721744 will be assessed following 
SC administration. For all patients, pre-dose (trough) and 
post-treatment plasma ISIS 721744 concentrations will 
be determined and summarized using descriptive 
statistics. Plasma terminal elimination half-life will also 
be calculated using the Post-Treatment follow up 
ISIS 721744 plasma concentrations, if data permits. For 
patients in the PK sub group, nNon-compartmental PK 
analysis of ISIS 721744 will be carried out on each 
individual patient dataset. 
Added paragraph to define how 
PK data will be analyzed and 
described 
STUDY 
GLOSSARY 
Section 10.6.4 
Pharmacokinetics 
Analysis 
Additions in bold: 
Additional details regarding the PK analysis along with 
immunogenicity (IM) analysis will be described in the 
SAP. 
Added “along with IM 
analysis” to clarify that 
immunogenicity analysis will 
be performed 
Appendix A 
Footnote 
Added: 
17 Assessments and procedures may be conducted by either 
a Home Healthcare professional (if available), or the 
Study Center as arranged by the Study Center personnel. 
Physical Exam will be labeled Body Assessment if 
conducted by Home Healthcare professional. Study drug 
administration by Home Healthcare professional may be 
done only after study drug for home use is available 
Home healthcare provided to 
decrease the burden of site 
visits, where feasible, for 
patients 
Appendix A 
Footnote 
Additions in bold: 
b 
Pre-dose, 1, 2, 4, and 6 hours post-dose (PK Subgroup) 
or Pre-dose and 2-hours post-dose 
Added to note changes in PK 
schedule 
Appendix A 
Removed: 
Week 3 pregnancy test 
Pregnancy test only needed 
every 4 weeks 
Appendix B 
Removed 
Thyroid Panel 
TSH 
Free T4 
Free T3 
Thyroid panel is not a per 
protocol assessment 
Appendix C 
Added: 
PK samples on Day 1 and Day 85 will be collected pre-dose, 
and 1, 2, 4, and 6 hours post-dose in PK subgroup only 
(approximately 6 patients) while pre-dose and 2 hours post- 
dose samples on Day 1 and Day 85 will be collected for all 
other patients. The rest of the sampling schedule will be the 
same for both sets of pateints (see table below): 
Added to describe PK sampling 

 
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ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
 
Protocol 
Section 
Description of Change 
Rationale 
Appendix C 
Addions in bold: 
To decrease the 
burden of PK 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 176 
sampling for 
patients, only a 
subgroup of 
approximately 
6 patients (rather 
than all patients) 
All 
Patients 
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose, 
2 hours 
post-dose 
Blood 
Anytime 
Blood 
Anytime 
Blood 
Anytime 
PK 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
will have blood 
Subgroup 
Pre-dose, 
Anytime 
Pre-dose 
Pre-dose 
Pre-dose, 
Anytime 
Anytime 
Anytime 
draws of pre- 
1, 2, 4, 
1, 2, 4, 
dose, 1, 2, 4, and 
and 
and 
6 hours post- 
6 hours 
6 hours 
dose on Day 1 
post-dose 
post-dose 
and Day 85. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 

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ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
12 
 
 
 
 
PROTOCOL SYNOPSIS 
 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense 
Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema 
Study Phase 
2a 
Indication 
Hereditary angioedema (HAE) 
Primary 
Objective 
The primary objective of the study is to evaluate the clinical efficacy of antisense 
inhibitor of prekallikrein (ISIS 721744) in patients with HAE type 1 (HAE-1), HAE 
type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH). 
Secondary 
Objectives 
The secondary objectives of the study are to evaluate safety and tolerability of 
ISIS 721744 in patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1- 
INH) and to evaluate the effect of ISIS 721744 on plasma prekallikrein (PKK) and 
other relevant biomarkers. 
Exploratory 
Objectives 
The exploratory objectives of the study are to evaluate pharmacokinetics (PK) of 
ISIS 721744 (as a total full-length antisense oligonucleotide (ASO), including fully 
conjugated, partially conjugated, and unconjugated ISIS 721744) over time and to 
assess potential PK/pharmacodynamic (PD) correlations on relevant biomarkers and 
clinical outcomes, as appropriate. 
Study Design 
The study will be randomized, double-blind, and placebo-controlled in Part A and will 
be open-label in Part B. 
Number of 
Patients 
Approximately 24 patients with HAE are planned to be enrolled in the study: 
approximately 18 patients with HAE-1/HAE-2 are planned to be enrolled in Part A of 
the study, and, in parallel, approximately 6 patients with HAE-nC1-INH are planned to 
be enrolled in Part B of the study. Due to the rarity of HAE-nC1-INH, enrollment in 
Part B may be ended early if Study Centers are unable to enroll sufficient patients with 
HAE-nC1-INH; this will not impact completion of Part A. 

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Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
13 
 
 
 
PROTOCOL SYNOPSIS CONTINUED 
 
Study 
Population 
Inclusion Criteria 
1. Patients must provide written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements for the duration of the study. 
2. Patients must be aged ≥ 18 years at the time of informed consent. 
3. Patients must have a documented diagnosis of HAE-1/HAE-2 (for inclusion in 
Part A) or HAE-nC1-INH (for inclusion in Part B) as defined below: 
a. Documented diagnosis of HAE-1/HAE-2 based upon ALL of the following: 
i. Documented clinical history consistent with HAE (subcutaneous [SC] or 
mucosal, non-pruritic swelling episodes without accompanying urticaria) 
(Maurer et al. 2018). 
ii. Diagnostic testing results that confirm HAE-1/HAE-2: C1-INH functional 
level < 40% normal level. Patients with a functional level of 40% to 50% 
of normal can be enrolled if their complement factor C4 (C4) level is 
below the lower limit of normal (LLN) or if a known pathogenic mutation 
in the SERPING1 gene has been demonstrated. 
iii. At least 1 of the following: age at reported HAE onset ≤ 30 years; a 
family history consistent with HAE-1/HAE-2; or complement component 
1q within the normal range. 
b. Documented diagnosis of HAE-nC1-INH based upon documented clinical 
history consistent with HAE (SC or mucosal, non-pruritic swelling episodes 
without accompanying urticaria) (Maurer et al. 2018) AND any 1 of the 
following: 
i. A clinical diagnosis of bradykinin (BK)-mediated angioedema as 
confirmed with threshold-stimulated kallikrein activity and 
Investigator-confirmed response to acute use of a BK targeted treatment 
(icatibant or ecallantide-). 
ii. One (1) of the established mutations (c.1032C>A, Thr309Lys; 
c.1032C>G, Thr309Arg; c.971_1018+24del72*; or c.892_909dup) in the 
factor XII gene. 
iii. The established mutation in the plasminogen gene (c.988A>G, 
p.Lys330Glu). 
iv. The established mutation in the angiopoietin-1 gene (c.355G>T, 
p.A119S). 

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ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
14 
 
 
 
PROTOCOL SYNOPSIS CONTINUED 
 
Study 
Population 
Continued 
Inclusion Criteria Continued 
4. Patients must: 
a. Experience a minimum of 2 HAE attacks (assessed by the Angioedema 
Activity Score [AAS] and confirmed by the Investigator) during the 
Screening Period. 
b. Complete the AAS questionnaire on a daily basis (minimum of 4 daily 
assessments per week) for the duration of the Screening Period. 
5. Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., 
plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) 
to treat angioedema attacks. 
6. Female patients must be non-pregnant (and not planning a pregnancy during the 
study) and non-lactating, and be either: 
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years of age, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating 
hormone [FSH] levels in the post-menopausal range for the laboratory 
involved). 
c. Abstinent (only acceptable as true abstinence, i.e., when in line with the 
preferred and usual lifestyle of the patient; periodic abstinence [e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods], declaration of 
abstinence for the duration of the study, or withdrawal are not acceptable 
methods of contraception). 
d. If engaged in sexual relations of childbearing potential, agree to use highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of 
signing the informed consent form (ICF) until at least 24 weeks after the last 
dose of Study Drug (ISIS 721744 or placebo). 
7. Male patients must be surgically sterile or, if engaged in sexual relations with a 
female of childbearing potential, the patient must agree to use a highly effective 
contraceptive method (refer to Section 6.3.1) from the time of signing the ICF until 
at least 24 weeks after the last dose of Study Drug (ISIS 721744 or placebo). 
Exclusion Criteria 
1. Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening or Study Periods. 
2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired 
or idiopathic angioedema. 
3. Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks. 

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
PROTOCOL SYNOPSIS CONTINUED 
15 
 
 
 
 
 
Study 
Population 
Continued 
Exclusion Criteria Continued 
4. Any clinically significant abnormalities in screening laboratory values that would 
render a patient unsuitable for inclusion in the study. The following values are 
exclusionary: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 2.5 × upper limit of normal (ULN). 
b. Bilirubin > 1.5 × ULN unless due to Gilbert’s syndrome. 
c. Platelet count < LLN 
d. Estimated glomerular filtration rate (eGFR) < 60 mL/min (as determined by 
the Cockcroft Gault- Equation for creatinine clearance) 
e. aPTT > 1.5 × ULN 
5. Patients with a history of acquired coagulopathies or bleeding diathesis (e.g., 
thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver 
disease, drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting 
factor inhibitors) and inherited bleeding disorders (e.g., hemophilia A, hemophilia 
B, other clotting factor deficiencies, qualitative platelet disorders, inherited 
thrombocytopenia, vascular abnormalities). 
6. Any clinically significant renal or hepatic diseases. 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed prior to dosing. 
8. Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial 
serological testing and confirmed with RNA testing, or prior treatment for hepatitis 
C. Patients at Screening who test positive by serology, but negative by RNA may 
be allowed in consultation with the Sponsor Medical Monitor. 
9. 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. 
10. Treatment with another investigational drug or biological agent within 1 month or 
5 half-lives, whichever is longer, of Screening. 
11. Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening. 
b. Chronic prophylaxis with lanadelumab within 10 weeks prior to Screening. 
c. Oligonucleotides (including small interfering RNA) within 4 months of 
Screening if single dose received, or within 12 months of Screening if 
multiple doses received. 
12. Any condition that, in the opinion of the Investigator, may compromise the 
patient’s safety or compliance, preclude successful conduct of the study, or 
interfere with the interpretation of results 

721744-CS02 Protocol Amendment 05 May 2020 | 1.0 
ISIS 721744-CS2 
Protocol 
CONFIDENTIAL 
Amendment 3 
5 May 2020 
PROTOCOL SYNOPSIS CONTINUED 
16 
 
 
 
 
 
Prohibited 
Concomitant 
Medications 
The following medications/procedures will not be permitted during the study: 
• 
Chronic prophylaxis for angioedema attacks, except for a stable dose of 
androgens. Any use of lanadelumab will not be permitted. 
NOTE: The use of acute medications (plasma-derived or recombinant C1-INH 
concentrate or BK2-receptor antagonist) to treat angioedema attacks is allowed as 
medically indicated. 
• 
ACE inhibitors or any estrogen-containing medications with systemic absorption 
(such as oral contraceptive or hormonal replacement therapy). 
• 
Any oligonucleotides (including small interfering RNA) other than ISIS 721744. 
• 
Plasmapheresis. 
• 
Any other investigational drug or device. 
Treatment 
Groups 
A total of approximately 24 patients in Parts A and B combined will be administered 
SC injections of ISIS 721744 80 mg or placebo every 4 weeks. Patients will be 
allocated into Part A or Part B according to type of HAE, (i.e., either HAE-1/HAE-2 in 
Part A or HAE-nC1-INH in Part B) as follows: 
• 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized to 
SC injections of ISIS 721744 80 mg or placebo in a 2:1 ratio 
(ISIS 721744:placebo). 
• 
In Part B, approximately 6 patients with HAE-nC1-INH will be administered 
open-label SC injections of ISIS 721744 80 mg. Due to the rarity of 
HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are 
unable to enroll sufficient patients; this will not impact the completion of Part A. 
Study Drug 
Dosage and 
Administration 
The Study Drug (ISIS 721744 or placebo) is contained in 2-mL stoppered glass vials. 
The Study Drug (ISIS 721744 or placebo) and its storage and preparation instructions 
will be provided by the Sponsor or designee. The Study Drug (ISIS 721744 or 
placebo) must be stored securely at 2 °C to 8 °C and be protected from light. 
During the Treatment Period, Study Drug (ISIS 721744 or placebo) will be 
administered as a single SC injection every 4 weeks. 

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Rationale for 
The dose level of 80 mg every 28 days was selected based on the safety, tolerability, 
Dose and 
PK, and PD data from the ISIS 721744-CS1 study in healthy volunteers. The Phase 1 
Schedule 
study evaluated doses of 20, 40, 60, and 80 mg ISIS 721744 administered once every 
Selection 
4 weeks for a total of 12 weeks. All dose levels were generally well-tolerated and 
induced a dose and exposure-dependent reduction in plasma PKK, a biomarker for BK 
and vascular permeability. The highest dose level of 80 mg produced near-complete 
reduction of plasma PKK levels (a mean reduction of 93.6% from Baseline on Day 99 
[2 weeks after the last dose]). The estimated half-life (t½) from the Phase 1 PK data 
was approximately 4 to 5 weeks, supporting the once-every-28-day dosing regimen. 
Pharmacokinetic/PD analysis of the Phase 1 data suggested very minor differences in 
plasma PKK reductions at doses higher than 80 mg. 
Adjustment of 
Dose and/or 
Treatment 
Schedule 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the 
study. 
Action taken with Study Drug (ISIS 721744 or placebo) due to an adverse event (AE) 
is characterized by 1 of the following: 
• 
None: No changes made to Study Drug (ISIS 721744 or placebo) administration 
and dose. 
• 
Not Applicable: AE reported during the Screening Period prior to Study Drug 
(ISIS 721744 or placebo) administration. 
• 
Permanently Discontinued: Study Drug (ISIS 721744 or placebo) discontinued 
and not restarted. 
• 
Temporarily Interrupted, Restarted – Same Dose: Dosing and/or dosing 
frequency temporarily interrupted/changed or delayed due to the AE and restarted 
at the same dose. 
Study Visit 
Schedule and 
Procedures 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will 
be allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 
in Part A or HAE-nC1-INH in Part B). Part A is randomized, double-blind, and 
placebo-controlled; and Part B is open-label. The study visit schedule and procedures 
are nearly identical in Part A and Part B, and thus are presented together; any 
differences are indicated where applicable. 
Patients will be screened for eligibility criteria following written informed consent. 
During the Screening Period, the following assessments will be performed: 
demographics; medical history, including a detailed HAE history; prior and 
concomitant medications, including type of prophylaxis (if used) and type of acute 
treatment; HIV, hepatitis B, and hepatitis C screening; pregnancy testing for women of 
childbearing potential and FSH testing for confirmation of menopause per inclusion 
criteria; quality of life as assessed by the angioedema quality of life (AE QoL) 
questionnaire; attack frequency, as assessed by the AAS daily during up to 
8 consecutive weeks, and confirmed by the Investigator; HAE attack assessment; 
physical examinations, including vital signs, body height, and weight; 
electrocardiograms (ECGs); AEs; PD blood sampling; inflammatory panel; and clinical 
laboratory assessments (chemistry, hematology, coagulation, and urinalysis). 

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Study Visit 
Schedule and 
Procedures 
Continued 
Threshold stimulated kallikrein activity will be assessed only in patients who have 
HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 
mutation. Genetic testing will be performed only for patients who do not have HAE 
genetic diagnostic testing results prior to Screening. 
During the Screening Period, patients must experience a minimum of 2 HAE attacks 
(assessed by the AAS and confirmed by the Investigator) to be eligible for the study; 
patients will be instructed to report details of any HAE attack to the study site within 
72 hours of the onset of the attack. Throughout the Screening Period, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with 
the patient) in order to inquire about any attack that may have occurred. If a patient 
experiences a third attack, the patient should be randomized as soon as possible, 
assuming all other screening activities have been completed and the patient meets all 
other eligibility requirements; in such cases, the Screening Period may be shorter than 
8 weeks. 
During the course of the study, the use of acute medications (plasma derived or 
recombinant C1 INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to 
treat angioedema attacks is allowed as medically indicated. Patients can be treated 
with on demand therapy as determined by their treating physician. 
After a Screening Period of up to 8 weeks, those patients who had at least 
2 documented attacks (assessed by the AAS and confirmed by the Investigator) during 
the Screening Period will be enrolled and/or randomized to receive ISIS 721744 80 mg 
or placebo (Part A) or open label ISIS 721744 80 mg (Part B) every 4 weeks for a total 
Treatment Period of 12 weeks. 
Study Drug will be administered as a SC injection in the abdomen, thigh, or outer area 
of the upper arm by qualified personnel at the Study Center or Home Healthcare 
professional (if available and after dosing instructions and training are provided by 
qualified site personnel). The first dose of Study Drug will be administered at the 
Study Center on Day 1. Study Center personnel (or Home Healthcare if available), 
will complete procedures per the Schedule of Procedures in Appendix A. After 
completion of the Week 13 visit, eligible patients may elect to enroll in the Open-Label 
Extension (OLE) Study (ISIS 721744-CS3), pending study approval by the IRB/IEC 
and the appropriate regulatory authority, and will need to sign the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approved informed consent. Patients 
who complete Study Visit Week 17, and meet eligibility requirements, may start the 
treatment period in the CS3 study anytime after the Week 17 visit and discontinue 
participation in the CS2 Post-Treatment Evaluation Period. 

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Study Visit 
Schedule and 
Procedures 
Continued 
During the study, patients will be instructed to report details of any HAE attack to the 
study site within 72 hours of the onset of the attack. During the Treatment and 
Post-Treatment Periods, the following data will be collected: daily AAS and number 
of HAE attacks (assessed by the AAS and confirmed by the Investigator); number of 
HAE attacks that required on-demand treatment; HAE attack details, including 
localization, severity, course, and details of any required treatment (i.e., frequency and 
dose); and vital signs. Throughout the Treatment and Post-Treatment Periods, site 
personnel will contact the patient once a week (at approximately 7 days after the last 
contact with the patient) in order to inquire about any attack that may have occurred. 
In addition, at study visit time points, site personnel will inquire about any new HAE 
attack information that was not provided through patient contact with the site. See 
Section 6.2.1 for further information on the collection of data surrounding HAE 
attacks. 
Additionally, blood will be collected at every visit during the Treatment and 
Post-Treatment Periods to assess PD and coagulation parameters, including, but not 
limited to: plasma PKK, plasma proenzyme activation, cleaved high molecular weight 
kininogen (cHK) levels, D-dimer levels, activated partial thromboplastin time (aPTT), 
plasmin-antiplasmin complexes, C4 split products, and platelet counts. Blood samples 
will also be collected regularly throughout the study for safety and PK/PD analyses. 
Additional assessments will be performed throughout the study as indicated in the 
Schedule of Procedures table in Appendix A. 
Patients who discontinue treatment will remain in the study and attend the Early 
Termination (ET) Visit unless consent is withdrawn. 
Detailed information regarding the CS2 procedures is presented in Section 6 and 
Appendix A. Appendix B includes a list of laboratory analytes required for the study. 
Primary 
Endpoint 
The primary endpoint is the time-normalized number of HAE attacks (per month) from 
Week 1 to Week 17. 
Secondary 
Endpoints 
Secondary endpoints include the following: 
• 
The time-normalized number of HAE attacks (per month) from Week 5 to 
Week 17 
• 
The time-normalized number of moderate or severe HAE attacks (per month) 
from Week 5 to Week 17 
• 
The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or 
≥ 90% reduction from Baseline in HAE attack rate) by Week 17 
• 
The number of HAE attacks requiring acute therapy from Week 5 to Week 17 
• 
cHK levels at Weeks 9 and 17 
• 
PKK activity at Weeks 9 and 17 
• 
Consumption of on-demand medication at Weeks 9 and 17 
• 
AE-QoL questionnaire score at Weeks 9 and 17 

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Exploratory 
Endpoints 
Exploratory endpoints include the following: 
• 
The number of HAE attack-free patients by Week 17 
• 
PK parameters, including, but not limited to: maximum observed plasma 
concentration (Cmax), time to Cmax, area under the plasma concentration-time 
curve, and t½ 
• 
Potential exposure-response analysis using relevant exposure parameters and 
biomarkers 
Safety 
Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the 
number, type, severity, and dose-relationship of AEs; vital signs; ECGs; and clinical 
laboratory parameters. Safety results in patients dosed with ISIS 721744 will be 
compared to safety results in patients dosed with placebo. 
Statistical 
Considerations 
The sample size of 18 patients with HAE-1/HAE-2 (12 patients administered 
SC injections of ISIS 721744 80 mg and 6 patients administered placebo) is from 
clinical considerations for sufficient safety and tolerability evaluation. The primary 
endpoint is the time-normalized number of HAE attacks (per month) from Week 1 to 
Week 17. From historical data, the placebo group is estimated to have 6.8 HAE 
attacks per 4-month period. If the ISIS 721744 80 mg group is assumed to have 
2.8 HAE attacks per 4-month period, then with a 0.05 significance level and Poisson 
model, the sample size of 18 patients will provide at least 90% power for the primary 
endpoint, considering a 10% missing data or dropout rate for both active treatment 
and placebo. There is no statistical rationale for the sample size of 6 patients with 
HAE-nC1-INH. 
An independent Data and Safety Monitoring Board (DSMB) will be established prior 
to the initiation of the study. The DSMB will be responsible for monitoring the 
overall safe conduct of the study. Based on its ongoing assessment of the safety and 
tolerability of ISIS 721744, the DSMB will provide recommendations to the Sponsor 
for modifying, stopping, or continuing the study as planned. Details on the safety 
assessments, frequency of review, meeting schedules and controlled access to 
unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan. 
Sponsor 
Ionis Pharmaceuticals, Inc. 

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POST-TREATMENT 
 
 
 
 
 
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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
.,_ 
◄ 
 
 
 
 
 
 
 
 
* The Screening Period is up to 8 weeks in duration. A patient may be randomized after fewer than 8 weeks of 
Screening if the patient experiences 
2 HAE attacks in less than 8 weeks and has completed all other screening 
activities and has met all other eligibility requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who complete 
Study Visit Week 17, 
and meet eligibility 
requirements, may start 
the Treatment Period in 
the ISIS 721744-CS3 
OLE study anytime 
after the Week 17 visit 
and discontinue 
participation in the CS2 
Post-Treatment 
Evaluation Period 
EARLY TERMINATION 
(ET) 
Follow Week 17 Schedule of 
Procedures at ET; Patient 
strongly encouraged to have 
post-treatment assessments 

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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AAS 
Angioedema Activity Score 
ACE 
angiotensin-converting enzyme 
ADR 
adverse drug reaction 
AE(s) 
adverse event(s) 
AE-QoL 
angioedema quality of life 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BK 
bradykinin 
BUN 
blood urea nitrogen 
C 
centigrade 
C1-INH 
C1-inhibitor 
C4 
complement factor C4 
C5a 
complement factor C5a (activated complement split product) 
cHK 
cleaved high molecular weight kininogen 
Cmax 
maximum observed plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
deciliter 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
ET 
Early Termination 
FSH 
follicle-stimulating hormone 
GalNAc3 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAE 
hereditary angioedema 
HAE-1 
hereditary angioedema type 1 
HAE-2 
hereditary angioedema type 2 
HAE-nC1-INH 
hereditary angioedema with normal C1-inhibitor 
HIV 
human immunodeficiency virus 
HK 
high molecular weight kininogen 
hs-CRP 
C-reactive protein measured by high sensitivity assay 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 

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IgM 
immunoglobulin M 
IM 
imunogenicity 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISIS 721744 
antisense inhibitor of prekallikrein 
ITT 
Intent-to-Treat 
LCRIS 
local cutaneous reaction at injection site 
LLN 
lower limit of normal 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PKa 
plasma kallikrein 
PKK 
prekallikrein 
PP 
Per-Protocol 
PT 
prothrombin time 
RNA 
ribonucleic acid 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
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 
ISIS 721744 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed plasma concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 

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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of antisense inhibitor of 
prekallikrein (ISIS 721744) in patients with hereditary angioedema (HAE) type 1 (HAE-1), HAE 
type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH). 
1.1.2. 
Secondary Objectives 
The secondary objectives of the study are to evaluate safety and tolerability of ISIS 721744 in 
patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1-INH) and to evaluate the 
effect of ISIS 721744 on plasma prekallikrein (PKK) and other relevant biomarkers. 
1.1.3. 
Exploratory Objectives 
The exploratory objectives of the study are to evaluate pharmacokinetics (PK) of ISIS 721744 
(as a total full-length antisense oligonucleotide [ASO], including fully conjugated, partially 
conjugated, and unconjugated ISIS 721744) over time and to assess potential 
PK/pharmacodynamic (PD) correlations on relevant biomarkers and clinical outcomes, as 
appropriate. 
1.2. 
Study Endpoints 
The definition of an HAE attack, including discrete attacks, is provided in Section 6.2.1. 
 
1.2.1. 
Primary Endpoints 
The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 1 
to Week 17. 
1.2.2. 
Secondary Endpoints 
Secondary endpoints include the following: 
• The time-normalized number of HAE attacks (per month) from Week 5 to Week 17 
• The time-normalized number of moderate or severe HAE attacks (per month) from 
Week 5 to Week 17 
• The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or 
≥ 90% reduction from Baseline in HAE attack rate) by Week 17 
• The number of HAE attacks requiring acute therapy from Week 5 to Week 17 
• Cleaved high molecular weight kininogen (cHK) levels at Weeks 9 and 17 
• PKK activity at Weeks 9 and 17 
• Consumption of on-demand medication at Weeks 9 and 17 
• Angioedema quality of life (AE-QoL) questionnaire score at Weeks 9 and 17 

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1.2.3. 
Safety Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of adverse events (AEs); vital signs; electrocardiograms (ECGs); 
and clinical laboratory parameters. Safety results in patients dosed with ISIS 721744 will be 
compared to safety results in patients dosed with placebo. 
 
1.2.4. 
Exploratory Endpoints 
Exploratory endpoints include the following: 
• The number of HAE attack-free patients by Week 17 
• PK parameters, including, but not limited to: maximum observed plasma 
concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time 
curve (AUC), and half-life (t½) 
• Potential exposure response analysis using relevant exposure parameters and 
biomarkers 
 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Hereditary angioedema is a rare genetic disorder that is characterized by disabling recurrent 
episodes of local skin swellings, painful abdominal attacks, and, occasionally, laryngeal attacks 
that can be life-threatening. The disorder is classified in 3 subtypes. Hereditary angioedema 
Type I (HAE-1) and Type II (HAE-2) are caused by an autosomal dominant mutation in the 
SERPING1 gene, resulting in either decreased levels of C1-INH (HAE-1) or loss-of-function of 
this protein (HAE-2) (Bissler et al. 1997). The third form of HAE is associated with normal 
levels and function of C1-INH (HAE-nC1-INH). This form is currently categorized as 
4 subtypes, with either specific genetic mutations in the factor XII gene, the plasminogen gene, 
or the angiopoietin-1 gene, or due to an unknown cause (Maurer et al. 2018). Extensive 
evidence from in vitro and in vivo studies supports the key role of bradykinin (BK) in HAE 
attacks, although the data linking HAE-nC1-INH with BK are less strong (Zuraw and 
Christiansen 2016). Diagnosing HAE-nC1-INH can be challenging given the large heterogeneity 
of this patient population, the lack of diagnostic tests, and the fact that specific genetic mutations 
account only partially for the occurrence of this type of HAE. Recently, a threshold-stimulated 
kallikrein activity assay was shown to discriminate BK-mediated angioedema from histamine- 
mediated angioedema (Lara‑Marquez et al. 2018). This technique may, therefore, enhance the 
identification of HAE-nC1-INH patients that are likely to benefit from inhibition of the contact 
activation pathway. 
Treatment options for HAE include on-demand treatment of attacks and prophylaxis. 
On-demand options include supplementation of C1-INH (either plasma-derived or recombinant 
C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist). In 
addition, tranexamic acid may relieve symptoms in non-severe angioedema attacks. 
Prophylactic regimens for HAE include plasma-derived C1-INH concentrate (administered either 

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intravenously or subcutaneously [SC]), attenuated androgens, antifibrinolytics and a recently 
Food and Drug Administration-approved monoclonal antibody directed against plasma kallikrein 
(PKa). Kallikrein circulates in plasma as a zymogen (i.e., PKK) which is bound to one of its 
main substrates, high molecular weight kininogen (HK). Prekallikrein is cleaved upon contact 
activation, forming the active protease PKa. Plasma kallikrein cleaves HK in turn, thereby 
releasing BK and the split product cHK. The binding of BK to the BK2 receptor leads to 
activation of various intracellular signaling pathways resulting in vasodilation, chemotaxis of 
neutrophils, and increased vascular permeability and fluid efflux, which typically characterize an 
angioedema attack (Zuraw and Christiansen 2016). 
 
2.2. 
Therapeutic Rationale 
ISIS 721744 is a second-generation, ligand-conjugated antisense oligonucleotide (ASO) drug 
designed to reduce the production of PKK mRNA. Antisense technology is characterized by its 
high specificity in inhibiting a single-gene product, thereby diminishing the potential for 
off-target drug effects. Furthermore, since ligand-conjugated ASOs require infrequent 
administration, ~once every month or even less often, the availability of a plasma PKK inhibitor 
could be of additional value to the arsenal of prophylactic drugs for the prevention of HAE 
attacks. The long t½ of second-generation antisense drugs and the lower frequency of 
administration afforded by ligand conjugation might provide additional benefit to patients. 
The Phase 1 clinical data show that ISIS 721744 inhibits plasma PKK effectively in a 
dose-dependent manner without safety concerns. 
 
2.3. 
ISIS 721744 
2.3.1. 
Mechanism of Action 
ISIS 721744 is an N-acetyl galactosamine (GalNAc3)-conjugated, second-generation ASO drug 
targeted to human PKK. It is complementary to the translated regions (Exon 9) of the PKK 
protein messenger ribonucleic acid (mRNA) and, following cleavage of the GalNAc3 moiety, 
binds to the mRNA by Watson and Crick base pairing. The hybridization (binding) of 
ISIS 721744 to the cognate mRNA results in the ubiquitous endonuclease that specifically 
hydrolyzes the RNA strand in RNA/DNA hybrids (RNase H1)-mediated degradation of the PKK 
mRNA, thus preventing production of the PKK protein. Maximal antisense-mediated reduction 
of target mRNA levels is typically greater than 90% of control levels in sensitive tissues (Crooke 
and Bennett 1996; Zhang et al. 2010). Furthermore, reduction in target mRNA levels using this 
approach correlates directly with a subsequent reduction in target protein levels. 
2.3.2. 
Chemistry 
Chemically, ISIS 721744 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone 
design). The nucleotide sequence of ISIS 721744 (Figure 1) is complementary to a 
20-nucleotide stretch within Exon 9 of the PKK protein mRNA. Structurally, the 
oligonucleotide has 4 regions. Two (2) of them, the 5 nucleotides at the 5′ end and the 
5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides. These 2′-MOE-modified nucleotides confer (1) increased affinity to the target 

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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 
(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 ISIS 721744 
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 ribonucleic acid (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, comprised of a triantennary cluster of GalNAc3 sugars, is linked to the 5ʹ end of 
ISIS 721744 via a phosphodiester linkage. The GalNAc3 cluster is a high-affinity ligand for the 
asialoglycoprotein receptor, a receptor expressed primarily on the surface of liver hepatocytes 
(Stockert 1995). The GalNAc3 cluster enhances delivery of ISIS 721744 to liver hepatocytes 
over other cell types and enhances potency. After internalization into cells, the GalNAc3 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 deoxyribonucleic acid (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 GalNAc3-conjugated ASOs. 
 
2′-MOE 
2′-Deoxy 
(RNase H1 sensitive) 
GsTsCsTsCsTsTsGsGsCs 
2′-MOE 
 
 
GalNAc3 = THA-GalNAc cluster 
2′-MOE = 2′-methoxylethyl RNA 
2′-Deoxy = DNA 
s = phosphorothioate linkage 
o = phosphodiester linkage 
 
 
Figure 1: 
Design of GalNAc3-Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer) 
The sequence of ISIS 721744 is shown. 
AoAoAsCsA 
oTsGsCoAoAs 
GalNAc3 

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2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with PKK ASO ISIS 546254, 
its 5ʹ-GalNAc3-conjugated mixed backbone variant ISIS 721744, and mouse surrogate PKK 
ASOs can be found in the Investigator’s Brochure. 
The results support the concept that inhibition of PKK through antisense mechanism may serve 
as a new and effective strategy for the prophylaxis of HAE. Results also strongly support that 
GalNAc3-conjugation of PKK ASO significantly increases the potency of ASO for inhibition of 
PKK hepatic mRNA and circulatory protein expression and thus these ASOs should be a useful 
therapeutic strategy for the prophylactic treatment of HAE. 
 
2.3.4. 
Clinical Experience 
ISIS 721744 has been evaluated in the clinical setting in a Phase 1 safety study 
(ISIS 721744-CS1). All subjects have completed study procedures and final safety and PD data 
are available. A summary is included below. Please refer to the Investigator’s Brochure for a 
detailed description of the preclinical pharmacology, nonclinical toxicology and PK, as well as a 
description of previous clinical experience with other related 2′-MOE phosphorothioate 
oligonucleotides. 
ISIS 721744 has been studied in 32 healthy volunteers in a double-blind, multiple-dose, 
dose-escalation study. Of these, 24 subjects received multiple doses of ISIS 721744. The 
32 subjects were randomized into 4 cohorts (6 subjects each) to receive once-every-4-week SC 
doses of ISIS 721744 20, 40, 60, or 80 mg, or placebo (8 subjects) for a total of 12 weeks (4 total 
doses). All subjects received all planned doses of Study Drug (ISIS 721744 or placebo). The 
duration of Study Drug exposure was 84 days for each subject. 
No serious adverse events (SAEs) were reported in the ISIS 721744-CS1 study. There were no 
early discontinuations from Study Drug or the study, and all subjects in the ISIS 721744 and 
placebo arms completed all study procedures. Adverse events at the injection site (defined as 
any preferred term containing “injection site”) were the most commonly reported 
treatment-emergent adverse events (TEAEs) in the ISIS 721744 treatment arms; no injection 
site-related TEAEs were reported in the placebo arm. There were no flu-like reactions or events 
of local cutaneous reaction at injection site (LCRIS) reported; LCRIS events were defined as 
(A) moderate or severe injection site erythema, swelling, pruritus, pain, or tenderness that started 
on the day of injection and persisted for at least 2 days; or (B) any AE at the injection site, 
regardless of severity, that led to discontinuation of Study Drug, where AE at the injection site 
was the principal reason for discontinuation. No relationship between incidence of TEAEs and 
the dose administered was observed. 
Thirteen (13) AEs related to study treatment were reported for 4 (16.7%) subjects in the 
ISIS 721744 arm, and for 1 subject (2 events; 12.5%) in the placebo arm. One (1) subject each 
in the ISIS 721744 and placebo arm reported AEs of ECG T wave inversion (preferred term) that 
were assessed as related. Nine (9) of the total 13 related events with ISIS 721744 concerned 
injection site-related events and were reported by 1 subject in the 80 mg arm. Additional related 
events were tinnitus (1 subject, 1 event in the 60 mg arm), headache (1 subject, 1 event in the 
60 mg arm), and epistaxis (1 subject, 1 event in the 20 mg arm). All TEAEs related to study 
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ISIS 721744 resulted in a dose-dependent reduction of PKK concentration and plasma 
proenzyme activation. The difference in absolute and percent change from Baseline for 
ISIS 721744 vs. placebo was statistically significant for PKK concentration for 40, 60, and 
80 mg (p ≤ 0.043) starting at Day 15, the first evaluation, and for 20 mg starting at Day 29, and 
for plasma proenzyme activation for all doses (p ≤ 0.002) starting at Day 15. The nadir was 
generally reached around Day 71, when the percent reduction with the 80 mg dose was -93.2% 
for PKK concentration and -99.6% for plasma proenzyme activation. 
The difference in absolute and percent change from Baseline in cHK for ISIS 721744 vs. placebo 
was not statistically significant at any visit. 
Clinical data from other GalNAc3-conjugated 2ʹ-MOE-gapmer oligonucleotides suggest that 
enhanced delivery of ISIS 721744 to hepatocytes vs. non-parenchymal cells will result in similar 
PD results as ISIS 546254 at 1/10th to 1/30th of the dose (Viney et al. 2016). 
2.4. 
Rationale for Dose and Schedule of Administration 
The dose level of 80 mg every 28 days was selected based on the safety, tolerability, PK, and PD 
data from the ISIS 721744-CS1 study in healthy volunteers. The Phase 1 study evaluated doses 
of 20, 40, 60, and 80 mg ISIS 721744 administered once every 4 weeks for a total of 12 weeks. 
All dose levels were generally well-tolerated and induced a dose- and exposure-dependent 
reduction in plasma PKK, a biomarker for BK and vascular permeability. The highest dose level 
of 80 mg produced near-complete reduction of plasma PKK levels (a mean reduction of 93.6% 
from Baseline on Day 99 [2 weeks after the last dose]). The estimated t½ from the Phase 1 PK 
data was approximately 4 to 5 weeks, supporting the once-every-28-day dosing regimen. 
Pharmacokinetic/PD analysis of the Phase 1 data suggested very minor differences in plasma 
PKK reductions at doses higher than 80 mg. 
 
2.5. 
Benefit-Risk Assessment 
2.5.1. 
Benefit Assessment 
The benefits of treatment of ISIS 721744 are currently unknown. Due to its mechanism of 
action, ISIS 721744 has the potential to be efficacious for the treatment of patients with HAE. 
2.5.2. 
Risk Assessment 
The known potential risks to study participants associated with ISIS 721744 are elaborated on in 
the “Guidance to Investigator” section of the Investigator’s Brochure. 
There are no anticipated risks associated with reducing plasma PKK levels; however, a potential 
theoretical risk associated with PKK inhibition would be prolongation of activated partial 
thromboplastin time (aPTT). This risk is informed by 80 cases of PKK deficiency that have been 
described in the literature (Girolami et al. 2010). In these individuals, there is a discrepancy 
between an observed in vitro defect and an absence of bleeding. Thus, it is believed that most 
cases go undetected or, if detected, go unreported. Occasional bleeding or thrombosis has been 
reported in a few PKK deficient patients but these instances were due to the presence of 
associated risk factors. Diagnosis is based on the prolongation of partial thromboplastin time 
and normal prothrombin time (PT) and thrombin time. In these individuals, platelet and vascular 

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tests are normal and the long partial thromboplastin time has shown to be fully corrected by the 
addition of normal plasma or normal serum. 
In monkeys, doses of ISIS 721744 of up to 30 mg/kg/wk for 13 weeks were well-tolerated with 
the exception of thrombocytopenia observed in 1 female at 12 mg/kg/wk and 1 male at 
30 mg/kg/wk. The monkey dose of 6 mg/kg/wk provides an approximate 20-fold margin relative 
to a human dose of 80 mg every 4 weeks and therefore there is sufficient therapeutic margin to 
assure the safe clinical use of ISIS 721744 at the proposed clinical dose and regimen. 
One (1) subject in the ISIS 721744-CS1 study had a confirmed platelet nadir count between 
100 × 103/µL and the lower limit of normal (LLN) (140 × 103/µL). The subject received 
ISIS 721744 at 20 mg and had a platelet count of 139 × 103/µL on Study Day 99; all other 
reported values for this subject were within the reference range. 
Platelet counts will be monitored closely throughout the clinical study. 
More complete details can be found in the Investigator’s Brochure. 
2.5.3. 
Overall Assessment of Benefit:Risk 
No specific risks have been identified with ISIS 721744. The AEs that occurred with the related 
drug ISIS 546254 were unrelated to reduction of PKK. In addition, the conjugated nature of 
ISIS 721744 is anticipated to reduce systemic exposure even further. Consequently, the platelet 
count reductions observed with the higher doses of the unconjugated molecule are not 
anticipated to occur at the dose tested in this study. 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ISIS 721744 are justified by the anticipated 
benefits that may be afforded to patients with HAE. 
 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This Phase 2a study will be conducted at multiple Study Centers worldwide to assess the efficacy 
of ISIS 721744 in approximately 24 patients with HAE. Part A of the study will be randomized, 
double-blind, and placebo-controlled; Part B of the study will be open-label. 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will be 
allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or 
HAE-nC1-INH in Part B). Part A is randomized, double-blind, and placebo-controlled; and 
Part B is open-label. The study visit schedule and procedures are nearly identical in Part A and 
Part B, and thus are presented together; any differences are indicated where applicable. 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized to SC injections of 
ISIS 721744 80 mg or placebo in a 2:1 ratio (ISIS 721744:placebo). In Part B, approximately 
6 patients with HAE-nC1-INH will be administered open-label SC injections of ISIS 721744 
80 mg. Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study 
Centers are unable to enroll sufficient patients; this will not impact the completion of Part A. 

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Patients who discontinue treatment will remain in the study and attend the Early Termination 
(ET) Visit unless consent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A. 
Appendix B includes a list of laboratory analytes required for the study. 
 
3.2. 
Number of Study Centers 
This study will be conducted at multiple Study Centers worldwide. 
 
3.3. 
Number of Patients 
A total of approximately 24 patients in Parts A and B combined will be administered SC 
injections of ISIS 721744 80 mg or placebo every 4 weeks. Patients will be allocated into Part A 
or Part B according to type of HAE, (i.e., either HAE-1/HAE-2 or HAE-nC1-INH): 
approximately 18 patients with HAE-1/HAE-2 are planned to be enrolled in Part A of the study, 
and, in parallel, approximately 6 patients with HAE-nC1-INH are planned to be enrolled in 
Part B of the study. Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended 
early if Study Centers are unable to enroll sufficient patients with HAE-nC1-INH; this will not 
impact completion of Part A. 
 
3.4. 
Overall Study Duration and Follow-up 
The study will consist of Screening, Treatment, and Post-Treatment Periods. Please refer to the 
Schedule of Procedures in Appendix A. 
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results. The frequency of additional monitoring will be determined by the Sponsor 
Medical Monitor in consultation with the Investigator. 
The length of each patient’s participation in the study is approximately 8 months, which includes 
an up to 8-week Screening Period, a 12-week Treatment Period (patients will receive fixed SC 
doses of Study Drug every 4 weeks during 4 on-site study visits), and a 4- to 13-week 
Post-Treatment Period as determined by whether a patient enrolls in the ISIS 721744-CS3 OLE 
study. 
3.4.1. 
Screening 
Patient eligibility for the study will be determined within 8 weeks (56 days) prior to study entry. 
 
3.4.2. 
Treatment Period 
Eligible patients will report to the Study Center for the first administration of Study Drug on 
Study Day 1 (Week 1 Visit) and will continue to receive Study Drug once every 4 weeks during 
the 12-week Treatment Period. Patients will also return to the Study Center on Week 3 (or 
Home Healthcare (if available), as arranged by the Study Center personnel, per the Schedule of 
Procedures in Appendix A) for a safety monitoring visit. 

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3.4.3. 
Post-Treatment Period 
Patients are to return to the Study Center for post-treatment follow-up visits (or Home Healthcare 
(if available), as arranged by the Study Center personnel, per the Schedule of Procedures in 
Appendix A at Study Weeks 17, 21, and 26/ET. Alternatively, patients who complete Study 
Visit Week 17, and meet eligibility requirements, may start the treatment period in the 
ISIS 721744-CS3 OLE study anytime after the Week 17 visit and discontinue participation in the 
CS2 Post-Treatment Evaluation Period. Patients may be required to attend additional visits for 
monitoring of AEs or abnormal investigation results. The frequency of additional monitoring 
will be determined by the Sponsor Medical Monitor in consultation with the Investigator. 
The final study visit, for patients not enrolling in the OLE, will be the Week 26/ET Visit. 
 
3.5. 
End-of-Study 
The End-of-Study is defined as the date of the last visit of the last patient in the study. 
 
3.6. 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be assembled to review safety, tolerability, 
and efficacy (as needed) data collected on ISIS 721744 during this study. Based on its ongoing 
assessment of the safety and tolerability of ISIS 721744, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping, or continuing the study as planned. 
Details on the safety assessments, frequency of review, meeting schedules, and controlled access 
to unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan (SAP). 
 
4. 
PATIENT ENROLLMENT 
4.1. 
Screening 
Before patients may be enrolled into the study, the Sponsor or designee requires a copy of the 
Study Center’s written Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
approval of the protocol, informed consent form (ICF), and all other patient information and/or 
recruitment material. 
Patients must sign the consent form before any screening tests or assessments, prior to screening 
blood draws, are performed. At the time of consent, the patient 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, patients will be assigned a 
unique patient identification number. This number will be used to identify the patient throughout 
the study and must be used on all study documentation related to that patient. The screening 
number and patient identification number must remain constant throughout the entire study. 
In the event the patient is re-consented and re-screened, the patient must be given a new 
screening number. Screening numbers, once assigned, will not be re-used. 

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4.2. 
Randomization 
Patients will be allocated into Part A or Part B according to type of HAE (i.e., either 
HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B). Only Part A will be randomized and 
placebo-controlled. 
Patients will be enrolled and/or randomized (Part A only) at the Week 1 Visit, after all screening 
assessments have been completed and after the Investigator has verified that they are eligible per 
the criteria in Sections 5.1 and 5.2. No patient may begin treatment prior to randomization 
(Part A only) and assignment of a unique patient identification number. 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized via the Interactive 
Response Technology (IRT) system to SC injections of ISIS 721744 80 mg or placebo in a 
2:1 ratio (ISIS 721744:placebo). In Part B, approximately 6 patients with HAE-nC1-INH will be 
enrolled via the IRT system to receive open-label SC injections of ISIS 721744 80 mg. Due to 
the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are unable 
to enroll sufficient patients; this will not impact the completion of Part A. 
Randomization information will be concealed from the Investigators and patients until the end of 
the study, with the exception of an emergency situation involving a patient that requires 
unblinding of the treatment assignment. 
Both ISIS 721744 and placebo will be provided as injections for SC administration and will be 
identical in appearance. 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
Patients whose randomization code has been broken will not be replaced. 
 
4.4. 
Unblinding of Treatment Assignment 
For Part A, the Sponsor and all patients, monitors, and Study Center personnel related to the 
study will be blinded throughout the study. However, if a patient has suffered an SAE (as 
defined in Section 9.3.3), and/or when knowledge of the treatment assignment will impact the 
clinical management of the patient, the Investigator will have the ability to unblind the treatment 
assignment for that patient via the IRT system. 
In the case of unblinding, the IRT system will send a blinded notification to the Sponsor or 
designee within 24 hours to let them know that a patient was unblinded. In addition, all 
suspected unexpected serious adverse reactions (SUSARs) will be unblinded by the Sponsor or 
designee for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the ET study procedures and observations 
(see Appendix A) prior to unblinding, as knowledge of the treatment arm could influence patient 
assessment. 

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5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 8 weeks (56 days) of the Week 1 Visit (Study Day 1) or at the time point specified in the 
eligibility criteria listed. 
5.1. 
Inclusion Criteria 
1. Patients must provide written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements for the duration 
of the study. 
2. Patients must be aged ≥ 18 years at the time of informed consent. 
3. Patients must have a documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or 
HAE-nC1-INH (for inclusion in Part B) as defined below: 
a. Documented diagnosis of HAE-1/HAE-2 based upon ALL of the following: 
i. Documented clinical history consistent with HAE (SC or mucosal, non-pruritic 
swelling episodes without accompanying urticaria) (Maurer et al. 2018). 
ii. Diagnostic testing results that confirm HAE-1/HAE-2: C1-INH functional level 
< 40% normal level. Patients with a functional level of 40% to 50% of normal 
can be enrolled if their complement factor C4 (C4) level is below the LLN or if a 
known pathogenic mutation in the SERPING1 gene has been demonstrated. 
iii. At least 1 of the following: age at reported HAE onset ≤ 30 years; a family 
history consistent with HAE-1/HAE-2; or complement component 1q within the 
normal range. 
b. Documented diagnosis of HAE-nC1-INH based upon documented clinical history 
consistent with HAE (SC or mucosal, non-pruritic swelling episodes without 
accompanying urticaria) (Maurer et al. 2018) AND any 1 of the following: 
i. A clinical diagnosis of BK-mediated angioedema as confirmed with 
threshold-stimulated kallikrein activity and Investigator-confirmed response to 
acute use of a BK targeted treatment (icatibant or ecallantide). 
ii. One (1) of the established mutations (c.1032C>A, Thr309Lys; c.1032C>G, 
Thr309Arg; c.971_1018+24del72*; or c.892_909dup) in the factor XII gene. 
iii. The established mutation in the plasminogen gene (c.988A>G, p.Lys330Glu). 
iv. The established mutation in the angiopoietin-1 gene (c.355G>T, p.A119S). 
4. Patients must: 
a. Experience a minimum of 2 HAE attacks (assessed by the Angioedema Activity 
Score [AAS] and confirmed by the Investigator) during the Screening Period. 
b. Complete the AAS questionnaire on a daily basis (minimum of 4 daily assessments 
per week) for the duration of the Screening Period. 

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5. Patients must have access to, and the ability to use, ≥ 1 acute medication(s) 
(e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) 
to treat angioedema attacks. 
6. Female patients must be non-pregnant (and not planning a pregnancy during the study) 
and non-lactating, and be either: 
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy). 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years of age, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating hormone 
[FSH] levels in the post-menopausal range for the laboratory involved). 
c. Abstinent (only acceptable as true abstinence, i.e., when in line with the preferred and 
usual lifestyle of the patient; periodic abstinence [e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods], declaration of abstinence for the duration 
of the study, or withdrawal are not acceptable methods of contraception). 
d. If engaged in sexual relations of childbearing potential, agree to use highly effective 
contraceptive methods (refer to Section 6.3.1) from the time of signing the ICF until 
at least 24 weeks after the last dose of Study Drug (ISIS 721744 or placebo). 
7. Male patients must be surgically sterile or, if engaged in sexual relations with a female of 
childbearing potential, the patient must agree to use a highly effective contraceptive 
method (refer to Section 6.3.1) from the time of signing the ICF until at least 24 weeks 
after the last dose of Study Drug (ISIS 721744 or placebo). 
5.2. 
Exclusion Criteria 
1. Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening or Study Periods. 
2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired or 
idiopathic angioedema. 
3. Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks. 
4. Any clinically significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion in the study. The following values are exclusionary: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper 
limit of normal (ULN). 
b. Bilirubin > 1.5 × ULN unless due to Gilbert’s syndrome. 
c. Platelet count < LLN. 
d. Estimated glomerular filtration rate (eGFR) < 60 mL/min (as determined by the 
Cockcroft-Gault Equation for creatinine clearance). 
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5. Patients with a history of acquired coagulopathies or bleeding diathesis (e.g., 
thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver disease, 
drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting factor inhibitors) 
and inherited bleeding disorders (e.g., hemophilia A, hemophilia B, other clotting factor 
deficiencies, qualitative platelet disorders, inherited thrombocytopenia, vascular 
abnormalities). 
6. Any clinically significant renal or hepatic diseases. 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to dosing. 
8. Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial serological 
testing and confirmed with RNA testing, or prior treatment for hepatitis C. Patients at 
Screening who test positive by serology, but negative by RNA may be allowed in 
consultation with the Sponsor Medical Monitor. 
9. 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. 
10. Treatment with another investigational drug or biological agent within 1 month or 
5 half-lives, whichever is longer, of Screening. 
11. Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening. 
b. Chronic prophylaxis with lanadelumab within 10 weeks prior to Screening. 
c. Oligonucleotides (including small interfering RNA) within 4 months of Screening if 
single dose received, or within 12 months of Screening if multiple doses received. 
12. Any condition that, in the opinion of the Investigator, may compromise the patient’s 
safety or compliance, preclude successful conduct of the study, or interfere with the 
interpretation of results. 
 
6. 
STUDY PROCEDURES 
6.1. 
Study Schedule 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will be 
allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or 
HAE-nC1-INH in Part B). Part A is randomized, double-blind, and placebo-controlled; and 
Part B is open label. The study visit schedule and procedures are nearly identical in Part A and 
Part B, and thus are presented together; any differences are indicated where applicable. 
All required study procedures are outlined in Appendix A. 
The safety of ISIS 721744 will be continually monitored throughout the study by the Investigator 
and the Sponsor Medical Monitor. 
The length of each patient’s participation from Screening to the last study visit is up to 
approximately 8 months (231 days). 

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6.1.1. 
Screening 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures, including screening procedures. A 56-day period is provided for 
completing screening assessments and determining patient eligibility for the study. 
Safety labs may be retested for determination of patient eligibility at the Investigator’s discretion. 
The Sponsor Medical Monitor will be available for consultation, if needed. 
After providing written informed consent, patients will be screened for eligibility criteria. 
During the Screening Period, the following assessments will be performed: demographics; 
medical history, including a detailed HAE history; prior and concomitant medications, including 
type of prophylaxis (if used) and type of acute treatment; HIV, hepatitis B, and hepatitis C 
screening; pregnancy testing for women of childbearing potential (WOCBP) and FSH testing for 
confirmation of menopause per inclusion criteria; quality of life as assessed by the AE-QoL 
questionnaire; attack frequency, as assessed by the AAS daily during up to 8 consecutive weeks, 
and confirmed by the Investigator; HAE attack assessment; physical examinations, including 
vital signs, body height, and weight; ECGs; AEs; PD blood sampling; inflammatory panel; and 
clinical laboratory assessments (chemistry, hematology, coagulation, and urinalysis). 
Threshold-stimulated kallikrein activity will be assessed only in patients who have 
HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 mutation. 
Genetic testing will be performed only for patients who do not have HAE genetic diagnostic 
testing results prior to Screening. During the Screening Period, patients must experience a 
minimum of 2 HAE attacks (assessed by the AAS and confirmed by the Investigator) to be 
eligible for the study; patients will be instructed to report details of any HAE attack to the study 
site within 72 hours of the onset of the attack. Throughout the Screening Period, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with the 
patient) in order to inquire about any attack that may have occurred. If a patient experiences a 
third attack, the patient should be randomized as soon as possible, assuming all other screening 
activities have been completed and the patient meets all other eligibility requirements; in such 
cases, the Screening Period may be shorter than 8 weeks. 
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated. Patients can be treated with on-demand therapy as 
determined by their treating physician. 
 
6.1.2. 
Treatment Period 
After a Screening Period of up to 8 weeks, those patients who had at least 2 documented attacks 
(assessed by the AAS and confirmed by the Investigator) during the Screening Period and met all 
other eligibility criteria will be administered Study Drug (ISIS 721744 or placebo). Patients in 
Part A will be randomized to receive ISIS 721744 80 mg or placebo every 4 weeks for a total 
Treatment Period of 12 weeks. Patients in Part B will all receive open-label ISIS 721744 80 mg 
every 4 weeks for a total Treatment Period of 12 weeks. 
Study Drug will be administered as SC injections in the abdomen, thigh, or outer area of the 
upper arm by qualified personnel at the Study Center or by Home Healthcare professional (if available 

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and after dosing instructions and training are provided by qualified site personnel). The first dose of 
Study Drug will be administered at the Study Center on Study Day 1 (Week 1 Visit). Study 
Center personnel (or Home Healthcare if available), will complete procedures per the Schedule 
of Procedures in Appendix A. A ± 2-day excursion from the scheduled visit date is permitted for 
all visits (excluding the Week 1 Visit on Study Day 1) during the Treatment Period. 
During the study, patients will be instructed to report details of any HAE attack to the study site 
within 72 hours of the onset of the attack. During the Treatment Period, the following data will 
be collected: daily AAS and number of HAE attacks (assessed by the AAS and confirmed by the 
Investigator); number of HAE attacks that required on-demand treatment; HAE attack details, 
including localization, severity, course, and details of any required treatment (i.e., frequency and 
dose); and vital signs. Throughout the Treatment Period, site personnel will contact the patient 
once a week (at approximately 7 days after the last contact with the patient) in order to inquire 
about any attack that may have occurred. In addition, at study visit time points, site personnel 
will inquire about any new HAE attack information that was not provided through patient contact 
with the site. See Section 6.2.1 for further information on the collection of data surrounding 
HAE attacks. Additional assessments will be performed throughout the Treatment Period as 
indicated in the Schedule of Procedures table in Appendix A. 
Additionally, blood will be collected to assess PD and coagulation parameters, including, but not 
limited to: plasma PKK, plasma proenzyme activation, cHK levels, D-dimer levels, aPTT, 
plasmin-antiplasmin complexes, C4 split products, and platelet counts. Blood samples will also 
be collected regularly throughout the study for safety and PK/PD analyses. 
Patients who discontinue treatment will remain in the study and attend the ET Visit unless 
consent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A. 
Appendix B includes a list of laboratory analytes required for the study. Detailed information 
regarding PK subgroups and collection times is provided in Appendix C. 
6.1.3. 
Post-Treatment Period 
Each patient will be followed for safety assessments for up to 13 weeks after the last dose of 
Study Drug. During the Post-Treatment Period, patients will return to the Study Center (or have 
Home Healthcare (if available), as arranged by the Study Center personnel, per the Schedule of 
Procedures in Appendix A) for visits at Weeks 17, 21, and 26/ET for safety and clinical 
laboratory evaluations and for blood sampling for PK/PD analyses. A ± 2-day excursion from 
the scheduled visit date is permitted for the visits at Weeks 17 and 21, and a ± 3-day excursion 
from the scheduled visit date is permitted for the visit at Week 26/ET. Alternatively, after 
completion of the Week 13 visit, eligible patients may elect to enroll in the ISIS 721744-CS3 
OLE study, pending study approval by the IRB/IEC and the appropriate regulatory authority, and 
will need to sign the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved informed consent. Patients who complete Study Visit Week 17, and meet eligibility 
requirements, may start the treatment period in the CS3 study anytime after the Week 17 visit 
and discontinue participation in the CS2 Post-Treatment Evaluation Period. 
During the Post-Treatment Period, the following data will be collected: daily AAS and number 
of HAE attacks (assessed by the AAS and confirmed by the Investigator); number of HAE 

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attacks that required on-demand treatment; HAE attack details, including localization, severity, 
course, and details of any required treatment (i.e., frequency and dose); and vital signs. 
Throughout the Post-Treatment Period, site personnel will contact the patient once a week (at 
approximately 7 days after the last contact with the patient) in order to inquire about any attack 
that may have occurred. In addition, during study visits, site personnel will inquire about any 
new HAE attack information that was not provided through patient contact with the site. See 
Section 6.2.1 for further information on the collection of data surrounding HAE attacks. 
Additionally, blood will be collected to assess PD and coagulation parameters, including, but not 
limited to: plasma PKK, plasma proenzyme activation, cHK levels, D-dimer levels, aPTT, 
plasmin-antiplasmin complexes, C4 split products, and platelet counts. Blood samples will also 
be collected regularly throughout the study for safety and PK/PD analyses. Additional 
assessments will be performed throughout the Post-Treatment Period as indicated in the 
Schedule of Procedures table in Appendix A. 
Patients who withdraw early from the study during the Treatment Period will be required to 
complete their End-of-Study evaluations following procedures listed for the Week 26/ET Visit; 
see Appendix A. 
 
6.2. 
Study Assessments 
6.2.1. 
Collection of Hereditary Angioedema Attack Details 
Historical HAE attack information will be collected at Screening. During the study, patients will 
be instructed to report details of any HAE attack to the study site within 72 hours of the onset of 
the attack. Throughout the Screening, Treatment, and Post-Treatment Periods, site personnel 
will contact the patient once a week (at approximately 7 days after the last contact with the 
patient) in order to inquire about any attack that may have occurred. In addition, during study 
visits, site personnel will inquire about any new HAE attack information that was not provided 
through patient contact with the site. 
During the Screening, Treatment, and Post-Treatment Periods, detailed information on each 
HAE attack will be collected, and the number of HAE attacks that required on-demand 
treatment, and the details of any on-demand treatment used (frequency and dosing), will be 
assessed. For each HAE attack, the following data will be collected: 
• Date/time of symptom onset 
• Description of symptoms 
• Location and description of symptoms: 
− Peripheral angioedema: cutaneous swelling involving an extremity, face, neck, 
torso, and/or genitourinary region 
− Abdominal angioedema: abdominal pain, with or without abdominal distension, 
nausea, vomiting, or diarrhea 
− Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty 
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• HAE attack severity: 
− Mild: transient or mild discomfort 
− Moderate: mild to moderate limitation in activity, some assistance needed 
− Severe: marked limitation in activity, assistance required 
• Need for assistance, medical intervention, emergency room visit, or hospitalization 
• Medications to treat the attack 
• HAE attack course, including if the HAE attack(s) in question was a typical attack for 
the patient, or if there was an alternative diagnosis 
• Date/time symptoms resolved 
An HAE attack will be defined as an event with signs or symptoms consistent with an attack in at 
least 1 of the locations noted above. A discrete attack will be counted if there is an at least 
24-hour symptom-free period between attacks. 
 
6.2.2. 
Patient-Reported Outcomes 
 
6.2.2.1. 
Angioedema Quality of Life Questionnaire 
Quality of life will be assessed by the AE-QoL questionnaire during Screening and at Weeks 1, 
9, 17, and 26/ET. 
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related quality 
of life impairment in patients suffering from recurrent angioedema (Weller et al. 2013). The 
AE-QoL is a self-administered questionnaire that can be completed in less than 5 minutes; it 
comprises 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. 
The AE-QoL can be used to calculate scores for the 4 individual domains, and can also be used 
to determine a total score. The AE-QoL will be completed by the patient. 
6.2.2.2. 
Angioedema Activity Score 
Patients will be instructed on the use of the AAS questionnaire during Screening and will record 
their HAE attacks using the AAS questionnaire during the Screening Period to confirm study 
eligibility. The AAS questionnaire will be completed by patients on a daily basis (minimum of 
4 daily assessments per week) for the duration of the study. 
During the Screening Period, patients must experience a minimum of 2 HAE attacks (assessed 
by the AAS and confirmed by the Investigator) to be eligible for the study. 
Enrolled patients will continue to record HAE attacks using the AAS questionnaire throughout 
the Treatment and Post-Treatment Periods. 
The AAS is a validated patient-reported outcome instrument to assess disease activity in patients 
with recurrent angioedema. The AAS was designed as a diary-type tool, and is easy to 
administer and fast to complete. Using the AAS questionnaire, patients score each of 5 key 
symptom-related factors from 0 to 3, resulting in a total daily score of 0 to 15. Daily AAS can be 
summed to provide scores every 7 days, every 4 weeks, and every 12 weeks (Weller et al. 2013). 

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6.2.3. 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. A list of these analytes is 
contained in Appendix B. 
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) either in clinic or by Home Healthcare or 
local laboratory. 
 
6.3. 
Restriction on the Lifestyle of Patients 
6.3.1. 
Contraception Requirements 
All male patients and WOCBP must refrain from sperm/egg donation and either be abstinent† or 
use highly effective contraception from the time of signing the ICF until at least 24 weeks after 
their last dose of Study Drug. 
For male patients engaged in sexual relations with a WOCBP, if their female partner is using 
highly effective contraception from the time of the patient signing the informed consent until 
24 weeks after the patient’s last dose of study treatment, then it is not required for the male 
patient to also use a highly effective contraceptive method. 
For the purposes of this study, a WOCBP is defined as any female who has experienced 
menarche, and who does not meet 1 of the following conditions: 
• Post-menopausal: 12 months of spontaneous amenorrhea in females > 55 years of 
age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the post-menopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male patients: 
• Highly effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the non-pregnant female partner of childbearing potential 
uses a highly effective contraceptive method (defined below). 
• Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug. 
Note: 
A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
For female patients and female partners of male patients, highly effective contraception methods 
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• Surgical sterilization (i.e., bilateral tubal occlusion); progestogen-only hormonal 
contraception associated with inhibition of ovulation; intrauterine contraception 
device or intrauterine hormone-releasing system. 
†Note: 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, or post-ovulation methods), declaration of abstinence for the 
duration of the study, or withdrawal are not acceptable methods of contraception. 
 
7. 
STUDY DRUG 
7.1. 
Study Drug Description 
Study Drug (ISIS 721744 or placebo) characteristics are listed in Table 1. 
The Study Drug (ISIS 721744 or placebo) is contained in 2-mL stoppered glass vials. The Study 
Drug (ISIS 721744 or placebo) and its storage and preparation instructions will be provided by 
the Sponsor or designee. The Study Drug (ISIS 721744 or placebo) must be stored securely at 
2 °C to 8 °C and be protected from light. 
During the Treatment Period, Study Drug (ISIS 721744 or placebo) will be administered as a 
single-SC injection every 4 weeks. 
Table 1: 
Study Drug Characteristics 
 
Study Drug 
ISIS 721744 
Placebo 
Strength 
100 mg/mL 
Not Applicable 
Volume/Formulation 
0.8 mL solution per vial 
0.8 mL solution per vial 
Route of Administration 
SC 
SC 
 
 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 721744 or placebo) 
labeled in accordance with specific country regulatory requirements. 
7.3. 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug (ISIS 721744 or placebo) supplies provided by the Sponsor according to Sponsor 
instruction and in accordance with institutional policy. 

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8. 
TREATMENT OF PATIENTS 
8.1. 
Study Drug Administration 
Study Drug (ISIS 721744 or placebo) will be administered as a single-SC injection once every 
4 weeks by blinded study staff during on-site visits at the Study Centers or by Home Healthcare 
professional (if available and after dosing instructions and training are provided by qualified site 
personnel). Vials of Study Drug (ISIS 721744 or placebo) are for single use only. 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug (ISIS 721744 or placebo) preparation and administration. 
8.2. 
Other Protocol-Required Drugs 
Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived 
or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat angioedema attacks. 
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated. Patients can be treated with on-demand therapy as 
determined by their treating physician. 
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. 
 
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 Study 
Day 1 value and the last value prior to Study 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 (ISIS 721744 or placebo). 
Re-dosing Guidance: Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the retest results are available. In general, patients who do not meet the 
stopping rules based upon retest may continue dosing. However, the Investigator and the 

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Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate. If any of the stopping criteria described 
below (refer to Section 8.6) are met, the patient will be permanently discontinued from further 
treatment with Study Drug (ISIS 721744 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 of the protocol. 
 
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. 
In the event of an ALT or AST measurement that is > 3 × ULN (or the greater of 2 × baseline 
value or 3 × 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 × ULN. 
Frequency of Repeat Measurements: Patients with confirmed ALT or AST levels > 3 × ULN (or 
the greater of 2 × baseline value or 3 × ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase, international normalized ratio [INR], and 
total bilirubin) retested at least once-weekly until ALT and AST levels become ≤ 1.2 × ULN or 
1.2 × baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations: For patients with confirmed ALT or AST 
levels > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
• Obtain a more detailed history of symptoms and prior and concurrent diseases 
• Obtain further history for concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
• Obtain a history for exposure to environmental chemical agents and travel 
• Perform serology for viral hepatitis (hepatitis A virus immunoglobulin M ([IgM], 
hepatitis B surface antigen, hepatitis C virus antibody, cytomegalovirus IgM, and 
Epstein-Barr Virus antibody panel) 
• Perform serology for autoimmune hepatitis (e.g., antinuclear antibody) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computed tomography or magnetic resonance imaging scans, may be performed at the discretion 
of the Investigator, in consultation with the Sponsor Medical Monitor. Repetition of the above 
evaluations should be considered if a patient’s ALT and/or AST levels reach 5 × ULN. 
 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results 
Please refer also to Table 2. 

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Platelet count will be monitored at least every 4 weeks during the Treatment and Post-Treatment 
Periods. The Investigator should review all platelet count results within 48 hours of receipt. 
Any unreportable platelet count result must be rechecked ideally within 7 days and determined 
not to have met a stopping rule before dosing can continue. 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 8.6.2) should be followed. 
In the event of a platelet count < 75,000/mm3, additional laboratory investigations may be 
conducted in consultation with the Sponsor Medical Monitor. 
 
8.5.3. 
Safety Monitoring Rules for Renal Function Test Results 
If a patient’s results meet Criteria 1 or 2 below, the Investigator should confirm the results and 
initiate weekly monitoring if confirmed. If the event of a persistent elevation is observed over 
2 consecutive weeks, then go to Section 8.6.3. 
1. Serum creatinine increase that fulfills all of the following: ≥ 0.3 mg/dL (26.5 μmol/L) 
and ≥ 40% above baseline creatinine values and > ULN (refer to definition of Baseline in 
Section 8.6) 
2. Proteinuria, urine protein/creatinine ratio > 750 mg/g for baseline values ≥ 200 mg/g, or 
4 × baseline value for baseline values < 200 mg/g that are confirmed by repeated urine 
protein/creatinine ratio or by a quantitative total urine protein measurement of 
> 1.0 g/24 hours 
 
8.5.4. 
Safety Monitoring for Minor Bleeding Events 
If a bleeding event occurs, including minor bleeding events such as excess bruising, petechiae, or 
gingival bleeding on brushing teeth, the Investigator should notify the Sponsor Medical Monitor 
and additional testing of coagulation parameters (aPTT, PT, and 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 Study 
Day 1 value and the last value prior to Study 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 patient 
with Study Drug (ISIS 721744 or placebo) will be stopped permanently; values that are not 
confirmed due to failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 × ULN, which is confirmed 
2. ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 1.5 × ULN or INR > 1.5 

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4. ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × 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 Platelet Count Results 
Please refer also to Table 2. 
In the event of any platelet count < 25,000/mm3, dosing of the patient with Study Drug will be 
stopped permanently. Platelet count should be monitored daily until 3 successive values 
> 25,000/mm3. Then, monitor twice weekly until 3 successive values > 75,000/mm3. Then, 
monitor weekly until 3 successive values > 100,000/mm3. Consider more frequent monitoring if 
additional risk factors for bleeding are present (see Table 2). Administration of steroids is 
strongly recommended for patients whose platelet count is < 25,000/mm3. Treatment guidelines 
for immune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 
4 days every 2 to 4 weeks for 1 to 4 cycles; prednis(ol)one 0.5 to 2 mg/kg/day for 2 to 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 ≥ 25,000/mm3 to < 50,000/mm3, dosing of the patient with Study 
Drug will be stopped permanently. Platelet count should be monitored twice weekly until 
3 successive values > 75,000/mm3. Then, monitor weekly until 3 successive values 
> 100,000/mm3. Consider more frequent monitoring and/or the administration of steroids if 
additional risk factors for bleeding are present (see Table 2). 
In the event of a platelet count ≥ 50,000/mm3 to ˂ 75,000/mm3, and in the absence of major 
bleeding or clinically relevant non-major bleeding (defined below), dosing with Study Drug 
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 Sponsor 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. Platelet count must be 
measured twice weekly until 3 successive values > 75,000/mm3, then weekly until 3 successive 
values > 100,000/mm3. Consider more frequent monitoring if additional risk factors for bleeding 
are present (see Table 2). Any unreportable platelet count result must be rechecked, ideally 
within 7 days, 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, and/or 
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 g/dL (1.24 mmol/L) within 24 hours 

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Definition of Clinically Relevant Non-Major Bleeding Events 
Clinically relevant non-major bleeding 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 patient. 
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, or 
gingival bleeding on brushing teeth. 
If the subsequent test confirms the initial test result, then monitoring frequency and dosing 
should be adjusted as recommended in Table 2. 
Table 2: 
Actions in Patients with Low Platelet Count 
 
Platelet count 
(K/mm3) 
Dosing 
Monitoring frequency 
> 100 
Dosing every 4 weeks should be 
continued. 
At least every 4 weeks. 
≥ 75 to ≤ 100 
Dosing every 4 weeks should be 
continued. 
Every week. 
≥ 50 to < 75 
Pause dosing. When platelet count 
returns to > 100K/mm3, restart 
dosing only if approved by the 
Sponsor Medical Monitor. 
Twice weekly until 3 successive 
values > 75K/mm3, then weekly until 
3 successive values > 100K/mm3. 
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
≥ 25 to < 50 
Permanently discontinue Study 
Drug. 
Consider corticosteroids if additional 
risk factors for bleeding are present.‡ 
Twice weekly until 3 successive 
values > 75K/mm3, then weekly until 
3 successive values > 100K/mm3. 
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
< 25 
Permanently discontinue Study 
Drug. 
Corticosteroids strongly 
recommended.* 
Daily until 3 successive values 
> 25K/mm3, then twice weekly until 
3 successive values > 75K/mm3, then 
weekly until 3 successive values 
> 100K/mm3. 
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present.‡ 
‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplatelet medicinal 
products, and/or prior history of major bleeding events. 
* It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives 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 2 to 4 weeks for 1 to 4 cycles; prednis(ol)one 0.5 to 2 mg/kg/day for 
2 to 4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days (Note: patient may require continuation 
with oral steroids after methylprednisolone). 

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8.6.3. 
Temporary Stopping Rules for Renal Function Test Results 
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 Study Drug (ISIS 721744 or placebo) may be stopped 
temporarily: 
1. Serum creatinine increase that fulfills all of the following criteria: ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN (refer to definition 
of Baseline in Section 8.6) 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hours) 
The possible dosing reinitiation 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. 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
Adjustment of dose and/or schedule is not permitted. 
 
8.8. 
Discontinuation of Study Drug 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant. Report the pregnancy according to instructions in 
Section 9.5.4. 
• The patient withdraws consent. 
• The patient withdraws from treatment (but does not withdraw consent). 
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug. 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1, 8.6.2, or 8.6.3. 
• The patient experiences an AE that necessitates unblinding of the Investigator or 
Sponsor to the patient’s treatment assignment. 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Patients who discontinue Study Drug will remain in the study and attend the ET Visit 
(Week 17 visit assessments), unless consent is withdrawn. Any patient who discontinues early 
from the Treatment Period or from the Post-Treatment Follow-Up Period should be strongly 
encouraged to complete follow-up study visits, procedures and observations (see Appendix A). 

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8.9. 
Withdrawal of Patients from the Study Procedures 
Patients must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study may include the following: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for non-compliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal. All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request. These patients should be 
encouraged to complete the ET study procedures (Week 17 visit assessments) and observations 
at the time of withdrawal (see Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent, every effort should be 
made to complete the ET study procedures and observations at the time of withdrawal (see 
Appendix A). 
 
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF. Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol-specified drug or substance (including 
over-the-counter medications, herbal medications, and vitamin supplements) administered 
between Screening and the end of the Post-Treatment Period. 
Allowed Concomitant Therapy 
During the course of the study, the use of acute medications (plasma-derived or recombinant 
C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat angioedema 
attacks is allowed as medically indicated. Patients can be treated with on-demand therapy as 
determined by their treating physician. 
All other stable medications (if not excluded below) are allowed, so long as the dose and type is 
not expected to change during the study. 
Disallowed Concomitant Therapy 
1. Chronic prophylaxis for angioedema attacks, except for a stable dose of androgens. Any 
use of lanadelumab will not be permitted. 

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NOTE: The use of acute medications (plasma-derived or recombinant C1-INH 
concentrate or BK2-receptor antagonist) to treat angioedema attacks is allowed as 
medically indicated. 
2. ACE inhibitors or any estrogen-containing medications with systemic absorption (such as 
oral contraceptive or hormonal replacement therapy). 
3. Any oligonucleotides (including small interfering RNA) other than ISIS 721744. 
4. Plasmapheresis. 
5. Any other investigational drug or device. 
 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the end of the Post-Treatment Period. 
 
8.11. 
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 or designee in 
accordance with the applicable Ionis and/or designee Standard Operating Procedures throughout 
the conduct of the clinical study. 
 
9.2. 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including SUSARs per the International Council for Harmonisation (ICH) 
guidelines E2A and ICH Good Clinical Practice (GCP). Country-specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards/IECs will be notified of any SAE according to applicable 
regulations. The DSMB will be notified of any SAE as specified in the DSMB Charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee 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 (ISIS 721744 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 or designee will unblind SUSARs for the purpose of 
regulatory reporting. The Sponsor or designee will submit SUSARs to regulatory agencies in 
blinded or unblinded fashion according to local law. The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 

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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An AE 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 
• 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 
• 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 
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, adverse drug reactions 
(ADRs) are defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered ADRs. 
The phrase “responses to a medicinal product” means that a causal relationship between the 
medicinal product and the AE 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. 

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9.3.3. 
Serious Adverse Event 
An SAE is any AE 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 patient 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 
• Results in a congenital anomaly or birth defect in the offspring of the patient 
(whether the patient 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 patient 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 AE 
(e.g., rated as mild, moderate, or severe according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [CTCAE]); 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 AE recorded on the eCRF. 
 
9.3.4. 
Adverse Events of Special Interest 
For the purpose of this study, severe reductions in platelet count < 50,000/mm3 accompanied by 
a major bleeding (MB) event or clinically relevant non-major bleeding (CRNMB) event, or 
platelet count of < 25,000/mm3 independent of a MB or CRNMB event, or any thrombotic 
episode are considered as AEs of special interest (AESIs) and are subject to 15-day expedited 
reporting by the Sponsor to the regulatory agencies. 
9.4. 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 

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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 patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event. The collection of SAEs will 
begin after the patient signs the ICF and will stop at the end of the patient’s Post-Treatment 
Period, which is defined as completion of the Week 26/ET Visit. Serious adverse events should 
be reported using electronic SAE submission (via eDC) whenever possible. In situations where 
electronic SAE submission is unavailable, a paper Initial Serious Adverse Event Form should be 
completed and a copy should be faxed or emailed to the Sponsor or designee. The SAE 
reporting instructions, 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 as Follow-Up as soon as additional 
information becomes available. All SAEs will be followed until resolution. Serious adverse 
events that remain ongoing past the patient’s last protocol-specified follow-up visit will be 
evaluated by the Investigator and Sponsor. If the Investigator and Sponsor agree that the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the ICF and will stop at the 
end of the patient’s Post-Treatment Period, which is defined as completion of the Week 26/ET 
Visit. The Investigator will monitor each patient closely and record all observed or volunteered 
AEs on the eCRF. 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the eCRF: 
9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 721744 or placebo) is characterized by 1 of the 
following: 
• Related: There is clear evidence that the event is related to the use of Study Drug 
(ISIS 721744 or placebo), e.g., confirmation by positive re-challenge test 
• Possible: The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ISIS 721744 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 (ISIS 721744 or placebo) administration and/or exposure suggests that 
a causal relationship is unlikely (for reporting purposes, Unlikely/Remote will be 
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• Not Related: The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and Study Drug (ISIS 721744 or 
placebo) 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site will be 
graded based on criteria from the 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 patient and does not affect the patient’s 
usual daily activities 
• Moderate: The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe: The event is incapacitating and causes considerable interference with the 
patient’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 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the study. 
Action taken with Study Drug (ISIS 721744 or placebo) due to an AE is characterized by 1 of the 
following: 
• None: No changes made to Study Drug (ISIS 721744 or placebo) administration and 
dose 
• Not Applicable: AE reported during the Screening Period prior to Study Drug 
(ISIS 721744 or placebo) administration 
• Permanently Discontinued: Study Drug (ISIS 721744 or placebo) discontinued and 
not restarted 
• Temporarily Interrupted, Restarted – Same Dose: Dosing and/or dosing 
frequency temporarily interrupted/changed or delayed due to the AE and restarted at 
the same dose 
 
9.4.3.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
eCRF. Treatment should also be recorded on the concomitant treatment or ancillary procedures 
eCRF, as appropriate. 
 
9.4.3.5. 
Outcome of the Adverse Event 
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• AE Persists: Patient terminates from the study and the AE continues 
• Recovered: Patient recovered completely from the AE 
• Became Serious: The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable): AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing: SAE continuing 
• Persists (as non-serious AE): Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious 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 patient 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 eCRF and in the patient’s medical 
record to facilitate source data verification. 
Investigators should follow-up, or support the Sponsor’s effort to follow up, with all pregnancies 
reported during the study from either the study patient or the female partner of the male study 
patient until pregnancy outcome is available. 
Sponsor Follow-up 
For SAEs and pregnancy cases in patients who have completed or terminated the 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, or 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 Investigator and Sponsor 
Medical Monitor. Laboratory abnormalities deemed not clinically significant (NCS) by the 
Investigator should not be reported as AEs. Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports. The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
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 patient 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 patient’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 patient’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 (ISIS 721744 or placebo) dosing 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 patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing eCRF. If the patient takes a dose of Study Drug 
(ISIS 721744 or placebo) that exceeds protocol specifications and the patient 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 AE, but 
it may result in an AE. All AEs associated with an overdose or incorrect administration of Study 
Drug should be recorded on the Adverse Event eCRF. If the associated AE fulfills seriousness 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
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Should an overdose occur, the Investigator or designee should refer to the “Guidance for 
Investigator” section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use highly effective 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately. An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy. Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients: If a suspected pregnancy occurs while on the study (including the 
Post-Treatment Period), a pregnancy test will be performed. The patient with a confirmed 
pregnancy will be immediately withdrawn from treatment with Study Drug. However, the 
patient will be encouraged to complete the Post-Treatment Period 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 patient 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 patients: The progress of the pregnancy of a male patient’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. 
 
10. 
STATISTICAL CONSIDERATIONS 
The sections below indicate the overall structure and approach to the analysis of this study. A 
detailed SAP incorporating these sections below will be prepared separately. The SAP will 
outline all data handling conventions, including software, and specify additional statistical 
methods to be used for analysis. The study objectives and endpoints are listed in Sections 1.1 
and 1.2, respectively. 

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10.1. 
Sample Size Considerations 
The study will enroll a total of approximately 24 patients with HAE. Approximately 18 patients 
with HAE-1/HAE-2 are planned to be enrolled in Part A of the study and, in parallel, 
approximately 6 patients with HAE-nC1-INH are planned to be enrolled in Part B of the study. 
Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if Study Centers are 
unable to enroll sufficient patients; this will not impact completion of Part A. Patients with 
HAE-1/HAE-2 (Part A) will be randomized to SC injections of ISIS 721744 80 mg or placebo 
administered every 4 weeks in a 2:1 ratio (ISIS 721744:placebo), and patients with 
HAE-nC1-INH (Part B) will be administered open-label SC injections of ISIS 721744 80 mg 
every 4 weeks. 
The sample size of 18 patients with HAE-1/HAE-2 (12 patients administered SC injections of 
ISIS 721744 80 mg and 6 patients administered placebo) is from clinical considerations for 
sufficient safety and tolerability evaluation. The primary endpoint is the time-normalized 
number of HAE attacks (per month) from Week 1 to Week 17. From historical data, the placebo 
group is estimated to have 6.8 HAE attacks per 4-month period. If the ISIS 721744 80 mg group 
is assumed to have 2.8 HAE attacks per 4-month period, then with a 0.05 significance level and 
Poisson model, the sample size of 18 patients will provide at least 90% power for the primary 
endpoint, considering a 10% missing data or dropout rate for both active treatment and placebo. 
There is no statistical rationale for the sample size of 6 patients with HAE-nC1-INH. 
10.2. 
Populations 
The Safety Population will include all enrolled patients who receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo). 
The Intent-to-Treat (ITT) Population will include all enrolled or randomized patients. 
The Per-Protocol (PP) Population will include all patients in the ITT Population who are treated 
according to the protocol without any major deviations. 
The PK Population will include all patients who are enrolled and receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo) and have at least 1 evaluable PK sample. 
 
10.3. 
Definition of Baseline 
For platelets, Baseline will be defined as the average of all non-missing pre-dose assessments. 
For other assessments, if there are 2 or more pre-dose values available, Baseline will be defined 
as the average of the pre-dose Study Day 1 value and the last pre-dose value prior to Study 
Day 1. If there is only 1 pre-dose measurement available, then it will be assigned as Baseline. 
 
10.4. 
Data and Safety Monitoring Board 
An independent DSMB will be established prior to the initiation of the study. The DSMB will 
be responsible for monitoring the overall safe conduct of the study. Based on its ongoing 
assessment of the safety and tolerability of ISIS 721744, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping, or continuing the study as planned. 

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Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data are outlined in the DSMB Charter and SAP. 
10.5. 
Interim Analysis 
No interim analysis is planned for this study. 
 
10.6. 
Planned Methods of Analysis 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group. Patient disposition will be summarized by treatment group. All patients 
enrolled will be included in a summary of patient disposition. 
10.6.2. 
Safety Analysis 
The Safety Population will be used for all safety analyses. 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of AEs; vital signs; ECGs; and clinical laboratory parameters. 
Safety results in patients dosed with ISIS 721744 will be compared to safety results in patients 
dosed with placebo. 
Treatment duration and amount of Study Drug (ISIS 721744 or placebo) received will be 
summarized by treatment group. Patient incidence rates of all AEs will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA™) system organ class and by MedDRA preferred 
term. Tables and/or narratives of treatment-emergent deaths and serious and significant AEs, 
including early withdrawals due to AEs, will also be provided. 
All TEAEs, all TEAEs potentially related to Study Drug, all treatment-emergent SAEs, and all 
treatment-emergent SAEs potentially related to Study Drug (ISIS 721744 or placebo) will be 
summarized. 
Laboratory tests to ensure patient safety, including chemistry panel, complete blood count with 
differential, coagulation panel, and complement, will be summarized by study visit for each 
treatment group. These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ISIS 721744 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. 
Efficacy Analysis 
The ITT Population will be used for all efficacy analyses. The PP Population will be used for a 
sensitivity analysis to assess robustness of the efficacy analysis results. 
The definition of an HAE attack, including discrete attacks, is provided in Section 6.2.1. 

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10.6.3.1. Primary Efficacy Analysis 
The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 1 
to Week 17. 
The Part A data will be analyzed using a Poisson regression model with treatment group as a 
fixed effect and the number of baseline HAE attacks as a covariate, and the logarithm of 
exposure in month will be used as the offset. 
The least-squares means, standard errors, and the 2-tailed 95% confidence intervals for the 
treatment group and placebo group will be presented. 
The Part B data will be summarized using descriptive statistics. 
 
10.6.3.2. Secondary Efficacy Analysis 
The secondary endpoints include the time-normalized number of HAE attacks (per month) from 
Week 5 to Week 17; the time-normalized number of moderate or severe HAE attacks (per 
month) from Week 5 to Week 17; the number of patients with a clinical response (defined as a 
≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate) by Week 17; the number 
of HAE attacks requiring acute therapy from Week 5 to Week 17; cHK levels at Weeks 9 and 17; 
PKK activity at Weeks 9 and 17; consumption of on-demand medication at Weeks 9 and 17; and 
AE-QoL questionnaire score at Weeks 9 and 17. 
For Part A, the time-normalized number of HAE attacks (per month) from Week 5 to Week 17 
and the time-normalized number of moderate or severe HAE attacks (per month) from Week 5 to 
Week 17 will be analyzed in a similar way to the primary efficacy endpoint. 
Continuous variables will be summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) by treatment group. Continuous variables will also be 
analyzed using analysis of covariance or analysis of variance. The least-squares means, standard 
errors, and the 2-tailed 95% confidence intervals for the treatment group and placebo group will 
be presented. 
Categorical variables will be summarized by frequency and percentage for the treatment group 
and placebo group. Categorical variables will be analyzed using a Pearson’s Chi-square test or 
Cochran-Mantel-Haenszel test. 
The Part B data will be summarized using descriptive statistics. 
 
10.6.3.3. Exploratory Efficacy Analysis 
Exploratory efficacy endpoints include the number of HAE attack-free patients by Week 17 and 
potential exposure response analysis using relevant exposure parameters and biomarkers. All 
exploratory efficacy endpoints will be analyzed using the same methods as described for the 
secondary efficacy endpoints. 
 
10.6.4. 
Pharmacokinetic Analysis 
The plasma PK of ISIS 721744 will be assessed following SC administration. For all patients, 
Pre-Dose (trough) and Post-Treatment plasma ISIS 721744 concentrations will be determined 
and summarized using descriptive statistics. Plasma terminal elimination half-life will also be 

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calculated using the Post-Treatment follow up ISIS 721744 plasma concentrations, if data 
permits. For patients in the PK sub group, non-compartmental PK analysis of ISIS 721744 will 
be carried out on each individual patient dataset. 
Pharmacokinetic parameters include (but are not limited to) the following: Cmax, Tmax, AUC, and 
t½. Other plasma PK parameters, as appropriate, may be determined or calculated at the 
discretion of the PK scientist. 
Metabolite identification and profiling may be conducted on select plasma samples. 
Plasma PK parameters will be summarized using descriptive statistics. Additional details 
regarding the PK analysis along with immunogenicity (IM) analysis will be described in the 
SAP. 
Analysis of potential exposure-response relationship between biomarkers and PK measures may 
also be explored. 
Population PK and PK/PD analyses may be performed using PK data from this study, and/or 
combined with other ISIS 721744 clinical PK/PD data later in the development timeline. 
 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or designee. 
Before a patient’s participation in the study, the Investigator is responsible for obtaining written 
informed consent from the patient 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 (ISIS 721744 or placebo) are administered. The patient must be 
given sufficient time to consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the ICF 
should be signed and personally dated by the patient and by the person who conducted the 
informed consent discussion (not necessarily an Investigator). The original signed ICF 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 patient. 
 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current GCP as well as the demands of national drug 
and data protection laws and other applicable regulatory requirements must be followed. 
 
11.3. 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed ICF, other written patient information, and any proposed 
advertising material must be submitted to the IEC/IRB for written approval. A copy of the 
written approval of the protocol and ICF must be received by the Sponsor or designee before 

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recruitment of patients into the study and shipment of Study Drug. A copy of the written 
approval of any other items/materials that must be approved by the Study Center or IEC/IRB 
must also be received by the Sponsor or designee before recruitment of patients into the study 
and shipment of Study Drug. The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document. The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP. The Investigator should also notify the IEC/IRB of SAEs occurring at the Study Center 
and other AE reports received from the Sponsor or designee, in accordance with local 
procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study. Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
11.4. 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained. On the case report 
forms or other documents submitted to the Sponsor or designee, patients should be identified by 
initials (if permitted by local law) and a patient identification number only. Documents that are 
not for submission to the Sponsor or designee (e.g., signed ICFs) should be kept in strict 
confidence by the Investigator. 
In compliance with federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’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 patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee. 
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document. The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the patients 
or the conduct of the study. The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 

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12.2. 
Study Termination 
The Sponsor or designee reserves the right to terminate the study. The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the Study Center 
contract. The Investigator/Sponsor or designee should notify the IEC/IRB in writing of the 
study’s completion or ET and send a copy of the notification to the Sponsor or designee. 
 
12.3. 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated study duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s case report 
form data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, imaging, and correspondence. In this study, eCRFs 
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 or designee and/or 
applicable regulatory authorities. Elements should include the following: 
• Patient files containing completed case report forms, informed consents, and 
supporting copies of source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IEC/IRB 
and the Sponsor or designee 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug 
Product Accountability Record, Return of Study Drug Product for Destruction, final 
Study Drug product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator. Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., case report forms and other pertinent data) provided that 
patient confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 

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consistency of the data; and adherence to local regulations on the conduct of clinical research. 
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the case report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or designees). 
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study 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 
patient data received by the Sponsor or designee. During this review, patient data will be 
checked for consistency, omissions, and any apparent discrepancies. In addition, the data will be 
reviewed for adherence to the protocol and GCP. To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor or designee. 
The Principal Investigator will sign and date the indicated places on the case report form. These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English. 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 patients 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 studies and will follow 
applicable local compensation laws. Patients 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 ICF. 

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13. 
REFERENCES 
Altmann K-H, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: From nuclease 
resistance to biological efficacy in animals. CHIMIA Int J Chem 1996; 50: 168‑176. 
Bissler JJ, Aulak KS, Donaldson VH, et al. Molecular defects in hereditary angioneurotic edema. Proc Assoc Am 
Physicians 1997; 109: 164‑173. 
Clinical Trial Facilitation Group 2014. Recommendations related to contraception and pregnancy testing in clinical 
trials. Heads of Medicines Agencies Website. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed December 5, 2019. 
Crooke ST, and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol Toxicol 1996; 
36: 107-129. 
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. 
Girolami A, Scarparo P, Candeo N, et al. Congenital prekallikrein deficiency. Expert Rev Hematol 2010; 3: 685- 
695. 
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. 
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. 
Lara‑Marquez ML, Christiansen SC, Riedl MA, et al. Threshold-stimulated kallikrein activity distinguishes 
bradykinin- from histamine-mediated angioedema. Clin Exp Allergy 2018; 48: 1429‑1438. 
Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of 
hereditary angioedema-The 2017 revision and update. Allergy 2018; 73: 1575‑1596. 
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. 
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. 
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. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people 
with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388: 
2239-2253. 
Weller K, Groffik A, Magerl M, et al. Development, validation, and initial results of the Angioedema Activity 
Score. Allergy 2013; 68: 1185-1192. 
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. 
Zuraw BL, and Christiansen SC. HAE Pathophysiology and Underlying Mechanisms. Clin Rev Allergy Immunol 
2016; 51: 216-229. 

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14. 
APPENDICES 

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APPENDIX A. SCHEDULE OF PROCEDURES 

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Appendix A. Schedule of Procedures 
 
Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Demographics and Medical 
History (including detailed 
HAE history) 
X 
Prior/Concomitant 
Medications (including HAE 
treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight and Height2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B, and 
Hepatitis C 
X 
FSH4 
X 
Pregnancy Test5 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Parameters (chemistry, 
hematology, complement, and 
coagulation)6, 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Threshold-Stimulated 
Kallikrein Activity 
(if applicable)8 
X 
Genetic Diagnostic Testing 
(if applicable)9 
X 
AE-QoL 
X 
X 
X 
X 
X 
Angioedema Activity 
Score10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAE Attack Assessment 
(including on-demand 
treatment)11, 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
Randomization13 
X 
Study Drug Administration 
(ISIS 721744 or placebo) 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity Testing 
Xa 
X 
Xa 
Xa 
X 
X 

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Screening1 
Treatment Period (12 Weeks) 
Post-Treatment Period16 
(13 Weeks) 
Study Week/Day 
Weeks -8 to -1 
Days -56 to -1 
Week 1 
Day 1 
Week 3 
Day 1517 
Week 5 
Day 2917 
Week 9 
Day 5717 
Week 13 
Day 8517 
Week 17 
Day 113 
or ET17 
Week 21 
Day 
14117 
Week 26 
Day 
17617 
Visit Window (Days) 
± 0 
± 0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
PK Blood Sampling14 
Xb 
X 
Xa 
Xa 
Xb 
X 
X 
X 
PD Blood Sampling15 
X 
Xa 
X 
Xa 
Xa 
Xa 
X 
X 
X 
Inflammatory Panel 
X 
Xa 
X 
Xa 
Xa 
Xa 
X 
X 
X 
Note: When multiple procedures are scheduled at the same visit, clinical assessments and procedures should be performed prior to Study Drug administration, 
unless otherwise indicated, and should proceed in the following order: vital signs, physical examinations, patient-reported outcomes (such as the AAS and 
the AE-QoL questionnaire), ECGs, and collection of blood and/or urine for laboratory assessments. 
1 
The Screening Period is up to 8 weeks in duration. A patient may be randomized after fewer than 8 weeks of Screening if the patient experiences ≥ 2 HAE 
attacks in less than 8 weeks and has completed all other screening activities and has met all other eligibility requirements. 
2 
Height will be measured at Screening only. 
3 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and should be taken after sitting for at least 5 min. 
4 
For confirmation of menopause at Screening per inclusion criteria. 
5 
Only for women who are not surgically sterile or post-menopausal. A serum pregnancy test will be performed during Screening and urine pregnancy tests 
will be performed at all other study visits. 
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 
For a complete list of laboratory analytes, refer to Appendix B. 
8 
Will be assessed only in patients who have HAE-nC1-INH without a factor XII mutation or the plasminogen or angiopoietin-1 mutation. 
9 
Will be performed only for patients who do not have HAE genetic diagnostic testing results prior to Screening. 
10 The AAS questionnaire will be completed by patients on a daily basis (minimum of 4 daily assessments per week) for the duration of the study. Patients will 
be instructed on the use of the AAS during Screening and will record their HAE attacks using the AAS throughout the Screening Period (daily during up to 
8 consecutive weeks) to confirm study eligibility; patients are required to experience at least 2 HAE attacks (assessed by the AAS and confirmed by the 
Investigator) during the Screening Period to be eligible for enrollment. If a patient experiences a third attack, the patient should be randomized as soon as 
possible, assuming all other screening activities have been completed and the patient meets all other eligibility requirements; in such cases, the Screening 
Period may be shorter than 8 weeks. Enrolled patients will continue to record HAE attacks using the AAS throughout the Treatment and Post-Treatment 
Periods. 

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Legend Continued 
 
11 Historical HAE attack information will be collected at Screening. During the study, patients will be instructed to report details of any HAE attack to the study 
site within 72 hours of the onset of the attack. Throughout the Screening, Treatment, and Post-Treatment Periods, site personnel will contact the patient once 
a week (at approximately 7 days after the last contact with the patient) in order to inquire about any attack that may have occurred. In addition, during study 
visits, site personnel will inquire about any new HAE attack information that was not provided through patient contact with the site. 
12 The following details relating to the localization, severity, and course of all HAE attacks that occured since the previous visit will be collected: date/time of 
symptom onset; description of symptoms; location of symptoms (peripheral angioedema, abdominal angioedema, or laryngeal angioedema); impact of HAE 
attack on activity level; HAE attack severity (mild, moderate, or severe); need for assistance, medical intervention, emergency room visit, or hospitalization; 
medications to treat the attack; HAE attack course, including if the HAE attack(s) in question was a typical attack for the patient, or if there was an alternative 
diagnosis; and date/time symptoms resolved. The number of HAE attacks that required on-demand treatment, and the frequency and dose of on-demand 
treatment, will also be recorded. 
13 After all screening assessments have been completed and the Investigator has verified that the patient is eligible. 
14 Refer to Appendix C for the PK Sampling Schedule. 
15 To be collected at each visit to assess plasma PKK, plasma proenzyme activation, and cHK levels. 
16 Patients who complete Study Visit Week 17, and meet eligibility requirements, may start the Treatment Period in the ISIS 721744-CS3 OLE study anytime 
after the Week 17 visit and discontinue participation in the CS2 Post-Treatment Evaluation Period. 
17 Assessments and procedures may be conducted by either a Home Healthcare professional (if available), or the Study Center as arranged by the Study Center 
personnel. Physical Exam will be labeled Body Assessment if conducted by Home Healthcare professional. Study Drug administration by Home Healthcare 
professional may be done only after study drug for home use is available. 
 
 
Time (time is in reference to Study Drug administration [ISIS 721744 or placebo]): 
a 
Pre-dose. 
b 
Pre-dose, 1, 2, 4, and 6 hours post-dose (PK Subgroup) or Pre-dose and 2-hours post-dose. 

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APPENDIX B. LIST OF LABORATORY ANALYTES 

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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 ISIS 721744 or other similar 
oligonucleotides. 
 
Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Cholesterol 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
• 
Creatine kinase 
• 
GGT 
Screening Tests 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (for 
confirmation of 
menopause at 
Screening per 
inclusion criteria) 
• 
Serum βhCG (only 
women who are not 
surgically sterile or 
post-menopausal) 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
• 
Plasmin-antiplasmin 
complexes 
• 
D-dimer 
Complement 
• 
C5a 
• 
Bb 
• 
C4 split products 
• 
C4 
Pharmacodynamics 
Panel 
• 
Plasma PKK 
• 
Plasma proenzyme 
activation 
• 
cHK 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
(WBC) 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Pharmacokinetics1 
 
• 
ISIS 721744 
concentration in plasma 
Immunogenicity 
• 
Anti-ISIS 721744 
antibodies 
Inflammatory 
• 
hs-CRP 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein/creatinine ratio 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
eGFR 
• 
Microscopic 
examination2 
1 Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 721744 with plasma 
constituents. 
2 Will be performed on abnormal findings unless otherwise specified. 

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APPENDIX C. PHARMACOKINETIC SAMPLING SCHEDULE 

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Appendix C Pharmacokinetic Sampling Schedule 
PK samples on Day 1 and Day 85 will be collected pre-dose, and 1, 2, 4, and 6 hours post-dose 
in PK subgroup only (approximately 6 patients) while pre-dose and 2 hours post-dose samples on 
Day 1 and Day 85 will be collected for all other patients. The rest of the sampling schedule will 
be the same for both sets of pateints (see table below): 
 
Pharmacokinetic Sampling Schedule 
 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 176 
PK 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Subgroup 
Pre-dose, 
Anytime 
Pre-dose 
Pre-dose 
Pre-dose, 
Anytime 
Anytime 
Anytime 
1, 2, 4, 
1, 2, 4, 
and 
and 
6 hours 
6 hours 
post-dose 
post-dose 
All 
Blood: 
Blood 
Blood: 
Blood: 
Blood: 
Blood 
Blood 
Blood 
Patients 
Pre-dose, 
Anytime 
Pre-dose 
Pre-dose 
Pre-dose, 
Anytime 
Anytime 
Anytime 
2 hours 
2 hours 
post-dose 
post-dose 

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APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities and 
adverse events at the injection site are based on the CTCAE Version 5.0, November 2017 with 
modifications outlined in the footnotes below. 
 

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ISIS 721744-CS2 
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Amendment Changes 
 
 
 
 
PROTOCOL AMENDMENTS 
 
 
Protocol Number: 
ISIS 721744-CS2 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to 
Assess the Clinical Efficacy of ISIS 721744, a Second-Generation Ligand- 
Conjugated Antisense Inhibitor of Prekallikrein, in Patients With 
Hereditary Angioedema 
 
 
 
A list of changes to the protocol are below: 
 
Amendment 
Description of Changes 
Dates 
Amendment 1 
The purpose of this protocol amendment is to implement 
the following modifications to Protocol ISIS 721744- 
CS2 date 03 May 2019: 
1. Specify a minimal compliance level in the inclusion 
criteria for completion of the Angioedema Activity 
Score, during the screening period, as a requirement 
prior to randomization to treatment in Part A, or 
initiation of treatment in Part B, of the study 
2. Broaden the exclusion criteria to include: elevated 
PTT, history of coagulopathy or bleeding diathesis, 
and renal and hepatic diseases 
3. Modify the exclusion criteria to allow for participants 
that test positive for hepatitis B or C enzyme but are 
non-reactive 
4. Provide the definition of an HAE attack and delineate 
how discrete attacks will be counted 
5. Designate adverse events of special interest (AESIs) 
6. Add anti-drug antibody testing at Day 15 and Day 29 
visits, and remove the requirement for a physical 
examination from the day 15 visit, in the Schedule of 
Procedures 
Minor changes have been made throughout the protocol 
to correct errors and/or to improve the overall clarity of 
the original 
21 October 2019 
Amendment 2 
The purpose of this protocol amendment is to implement 
the following modifications to Protocol ISIS 721744- 
CS2, Amendment 1, dated 21 October 2019: 
29 January 2019 

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1. To update the established mutations in the 
plasminogen and angiopoietin genes from the legacy 
description to the Human Genome Variation Society 
(HGVS) description in the diagnostic report. The 
plasminogen gene was changed from c.9886A>G to 
988A>G and the angiopoietin-1 gene from c.807G>T 
to 355G>T 
2. The duration of male and female contraceptive advice 
has been changed from at least 13 weeks to at least 
24 weeks. This will allow for near-complete 
elimination of ISIS 721744 as 24 weeks encompasses 
approximately 5 half-lives of ISIS 721744 and 1 
menstrual cycle (requested by the MHRA, to comply 
with CTFG guidance (Clinical Trial Facilitation 
Group 2014) 
3. To add language that patients who complete Study 
Visit Week 17, and meet eligibility requirements, 
may start the Treatment Period in the ISIS 721744- 
CS3 OLE study anytime after the Week 17 visit and 
discontinue participation in the CS2 Post-Treatment 
Evaluation Period at that time 
4. To remove as secondary endpoints the time 
normalized number of HAE attacks (per month) from 
Week 9 to Week 21 and the time normalized number 
of moderate or severe HAE attacks (per month) from 
Week 9 to Week 21, because patients will be allowed 
to rollover to the ISIS 721744-CS3 OLE study after 
the Week 17 visit in CS2 
5. To remove the requirement that patients must fast 
before visits that require blood sampling because 
none of the laboratories listed in Appendix B require 
fasting and, therefore, fasting is an unnecessary 
burden for the patient. 
Minor changes have been made throughout the protocol 
to correct errors and/or to improve the overall clarity of 
the original protocol but these changes do not impact 
subject safety, exposure, or the overall study design. 
Amendment 3 
The following modifications to Protocol ISIS 721744- 
CS2 Amendment 2, dated 29 January 2020, have been 
made: 
1. To adjust the length of time patients must not have 
received lanadelumab, prior to screening for ISIS 
721744-CS2, from 6 months to 10 weeks (i.e., 5 
times the ~14-day half life for lanadelumab). 
05 May 2020 

ISIS 721744-CS2 
Ionis Pharmaceuticals 
CONFIDENTIAL 
Protocol 
Amendment Changes 
 
2. To decrease the burden of site visits where feasible 
for patients, Study Drug administration, assessements 
and procedures may be conducted by either a Home 
Healthcare professional (if available) or the Study 
Center, as arranged by the Study Center personnel, 
for visits as noted in Appendix A. 
3. To decrease the burden of PK sampling for patients, 
only a subgroup of approximately 6 patients (rather 
than all patients) will have blood draws of pre-dose, 
1, 2, 4, and 6 hours post-dose on Day 1 and Day 85. 
This, along with a pre-dose and a 2 hour post-dose 
blood collection on Day 1 and Day 85 in all patients, 
will provide enough information to determine PK 
parameters. 
4. 
Minor changes have been made throughout the protocol 
to correct errors and/or to improve the overall clarity of 
the original protocol but these changes do not impact 
subject safety, exposure, or the overall study design. 

Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Feb 17, 2021 
ISIS 721744-CS2 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
ISIS 721744-CS2 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a 
Study to Assess the Clinical Efficacy of ISIS 721744, a Second- 
Generation Ligand-Conjugated Antisense Inhibitor of 
Prekallikrein, in Patients with Hereditary Angioedema 
 
 
 
Date: Feb 17, 2021 
 
Version: 1.0 
 
 
 
 
 
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. 

Ionis Pharmaceuticals, Inc. 
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Feb 17, 2021 
ISIS 721744-CS2 
CONFIDENTIAL 
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Statistical Analysis Plan Signature Page 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court Carlsbad, CA 92010 
 
Compound Name: 721744 
Protocol: 
CS2 
Study Title: 
Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study 
to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation 
Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients 
with Hereditary Angioedema 
 
Issue Date: 
5 May 2020 (Protocol Amendment 3) 
Signature:  
 Date:  
 
 
 
Assistant Director, Biometrics 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
Signature:  
 Date:  
 
 
 
Assistant Director, PK and Clinical Pharmacology 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Signature:  
 Date:  
 
 
 
 
Executive Director, Project Team Leader, Clinical Development 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 

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Table of Contents 
1 
INTRODUCTION .................................................................................................. 5 
1.1 
Study Overview .................................................................................................. 5 
1.2 
Objectives ........................................................................................................... 5 
1.2.1 
Primary Objective ........................................................................................... 5 
1.2.2 
Secondary Objectives ..................................................................................... 6 
1.2.3 
Exploratory Objectives ................................................................................... 6 
1.3 
Endpoints ............................................................................................................ 6 
1.3.1 
Primary Endpoints .......................................................................................... 6 
1.3.2 
Secondary Endpoints ...................................................................................... 6 
1.3.3 
Safety Endpoints............................................................................................. 6 
1.3.4 
Exploratory Endpoints .................................................................................... 7 
2 
PROCEDURES ...................................................................................................... 7 
2.1 
General Overview of Procedures........................................................................ 7 
2.2 
Randomization & Treatment Allocation ............................................................ 7 
2.3 
Conduct .............................................................................................................. 8 
2.4 
Data Monitoring ................................................................................................. 8 
2.4.1 
Safety Data Monitoring .................................................................................. 8 
2.4.2 
Data Monitoring Board .................................................................................. 8 
2.5 
Data Management .............................................................................................. 8 
2.5.1 
Case Report Form Data .................................................................................. 9 
2.5.2 
Laboratory Data .............................................................................................. 9 
2.5.3 
Pharmacokinetics Data ................................................................................... 9 
3 
ANALYTICAL PLAN ........................................................................................... 9 
3.1 
General Overview of Analyses ........................................................................... 9 
3.1.1 
Statistical Methods ......................................................................................... 9 
3.1.2 
Subject Population Analyzed ....................................................................... 12 
3.1.3 
Sample Size Consideration ............................................................................ 12 
3.1.4 
Planned Interim Analysis ............................................................................. 13 
3.1.5 
Incomplete or Missing Data .......................................................................... 13 
3.2 
Demographic and Baseline Characteristics and Patient Disposition ................ 14 
3.3 
Efficacy Analyses .............................................................................................. 15 

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3.3.1 
Analysis of Primary Endpoint ..................................................................... 15 
3.3.2 
Analysis of Secondary Endpoints ................................................................ 17 
3.3.2.1 
Time-normalized number of investigator-confirmed HAE attacks (per month) from 
Week 5to Week 17 .......................................................................................................... 17 
3.3.2.2 
Time-normalized number of moderate or severe investigator-confirmed HAE attacks 
(permonth) from Week 5 to Week 17 ............................................................................. 18 
3.3.2.3 
The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or ≥ 
90%reduction from Baseline in HAE attack rate) by Week 17 ........................................ 18 
3.3.2.4 
The number of investigator-confirmed HAE attacks requiring acute therapy from 
Week 5 to Week 17 ......................................................................................................... 18 
3.3.2.5 
Change and Percent Change in cHK and PKK levels at Week 5 to Week 17 .................. 19 
3.3.2.6 
Consumption of on-demand medication by Weeks 9 and 17 ........................................... 20 
3.3.2.7 
AE-QoL score at Weeks 9 and 17 .................................................................................... 20 
3.3.3 
Analysis of Exploratory Endpoints ............................................................. 21 
3.3.3.1 
The number of HAE attack-free patient by Week 17 ....................................................... 21 
3.4 
Safety Analyses ............................................................................................... 21 
3.4.1 
Exposure ...................................................................................................... 21 
3.4.2 
Adverse Events ............................................................................................ 22 
3.4.3 
Laboratory Measurements ........................................................................... 24 
3.4.4 
Vital Signs, Weight, and BMI ..................................................................... 26 
3.4.5 
Physical Examinations ................................................................................ 26 
3.4.6 
12-Lead Electrocardiograms (ECG) ............................................................ 26 
3.4.7 
Prior and Concomitant Medications ............................................................ 26 
3.4.8 
Angioedema Activity Score ........................................................................ 27 
3.5 
Pharmacokinetic Analysis ............................................................................... 27 
3.5.1 Plasma Concentration Data of Total Full Length Oligonucleotides ................. 28 
3.5.2 
Plasma Pharmacokinetic Parameters ........................................................... 28 
3.5.3 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis ............ 29 
3.4.5 
Immunogenicity (IM) Analysis ................................................................... 30 

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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 is a Phase 2a study, will be conducted at multiple Study Centers worldwide to assess the 
efficacy of ISIS 721744 in approximately 24 patients with HAE. Part A of the study will be 
randomized, double-blind, and placebo-controlled; Part B of the study will be open-label. 
The study will be conducted concurrently in 2 parts (Part A and Part B); patients will be 
allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A 
or HAE-nC1-INH in Part B). 
 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized to SC injections 
of ISIS 721744 80 mg or placebo in a 2:1 ratio (ISIS 721744:placebo). In Part B, approximately 
6 patients with HAE-nC1-INH will be administered open-label SC injections of ISIS 721744 
80 mg. Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early if study 
centers are unable to enroll sufficient patients; this will not impact the completion of Part A. 
 
The study will consist of Screening, Treatment, and Post-Treatment Periods. Please refer to the 
Schedule of Procedures in protocol Appendix A. Patients may be required to attend additional 
visits for monitoring of AEs or abnormal investigation results. The frequency of additional 
monitoring will be determined by the Sponsor Medical Monitor in consultation with the 
Investigator. The length of each patient’s participation in the study is approximately 8 months, 
which includes an up to 8-week Screening Period, a 12-week Treatment Period (patients will 
receive fixed SC doses of Study Drug every 4 weeks during 4 on-site study visits),and a 4 to 13- 
week Post-Treatment Period as determined by whether a patient enrolls in the ISIS 721744- 
CS3 OLE study. 
 
1.2 
Objectives 
 
1.2.1 Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of antisense inhibitor of 

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prekallikrein (ISIS 721744) in patients with hereditary angioedema (HAE) type 1 (HAE-1), 
HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (HAE-nC1-INH). 
 
1.2.2 Secondary Objectives 
The secondary objectives of the study are to evaluate safety and tolerability of ISIS 721744 in 
patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1-INH) and to evaluate 
the effect of ISIS 721744 on plasma prekallikrein (PKK) and other relevant biomarkers. 
 
1.2.3 Exploratory Objectives 
The exploratory objectives of the study are to evaluate pharmacokinetics (PK) of ISIS 721744 
(as a total full-length antisense oligonucleotide [ASO], including fully conjugated, partially 
conjugated, and unconjugated ISIS 721744) over time and to assess potential 
PK/pharmacodynamic (PD) correlations on relevant biomarkers and clinical outcomes, as 
appropriate. 
 
1.3 
Endpoints 
 
1.3.1 
Primary Endpoints 
The primary endpoint is the time-normalized number of investigator-confirmed HAE attacks 
(per month) from Week 1 to Week 17. 
 
1.3.2 Secondary Endpoints 
Secondary endpoints include the following: 
• The time-normalized number of investigator-confirmed HAE attacks (per month) 
from Week 5 to Week 17 
• The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or 
≥ 90% reduction from Baseline in Investigator-confirmed HAE attack rate) by Week 
17 
• The number of investigator-confirmed HAE attacks requiring acute therapy from 
Week 5 to Week 17 
• Cleaved high molecular weight kininogen (cHK) levels at Weeks 9 and 17 
• PKK activity at Weeks 9 and 17 
• Consumption of on-demand medication at Weeks 9 and 17 
• Angioedema quality of life (AE-QoL) questionnaire score at Weeks 9 and 17 
1.3.3 Safety Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 

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severity, and dose-relationship of adverse events (AEs); vital signs; electrocardiograms 
(ECGs); and clinical laboratory parameters. Safety results in patients dosed with ISIS 721744 
will be compared to safety results in patients dosed with placebo. 
 
1.3.4 Exploratory Endpoints 
• The number of HAE attack-free patients by Week 17 
• PK parameters, including, but not limited to maximum observed plasma 
concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time 
curve (AUC), and half-life (t½) 
• Potential exposure response analysis using relevant exposure parameters and 
Biomarkers 
 
1.3.5 Additional Endpoint 
• The time-normalized number of moderate or severe investigator-confirmed HAE 
attacks (per month) from Week 5 to Week 17 
 
 
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. 
Laboratory data will be transferred electronically to Ionis Pharmaceuticals, Inc. 
 
2.2 
Randomization & Treatment Allocation 
Patients will be allocated into Part A or Part B according to type of HAE (i.e., either 
HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B). Only Part A will be randomized and 
placebo-controlled. 
 
Patients will be enrolled and/or randomized (Part A only) at the Week 1 Visit, after all 
screening assessments have been completed and after the Investigator has verified that they 
are eligible per the criteria in protocol Sections 5.1 and 5.2. No patient may begin treatment 
prior to randomization (Part A only) and assignment of a unique patient identification 
number. 
 
In Part A, approximately 18 patients with HAE-1/HAE-2 will be randomized via the 
Interactive Response Technology (IRT) system to SC injections of ISIS 721744 80 mg or 
placebo in a 2:1 ratio (ISIS 721744:placebo). In Part B, approximately 6 patients with HAE- 
nC1-INH will be enrolled via the IRT system to receive open-label SC injections of ISIS 

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721744 80 mg. Due to the rarity of HAE-nC1-INH, enrollment in Part B may be ended early 
if Study Centers are unable to enroll sufficient patients; this will not impact the completion of 
Part A. 
 
Randomization information will be concealed from the Investigators and patients until the 
end of the study, with the exception of an emergency situation involving a patient that 
requires unblinding of the treatment assignment. 
 
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. 
 
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. 
 
2.4.2 Data Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be established to monitor the 
overall safe conduct of the study. Based on its ongoing assessment of the safety and tolerability 
of ISIS 721744, the DSMB will provide recommendations to the Sponsor for modifying, 
stopping or continuing the study as planned. Details on the safety assessments, frequency of 
review, meeting schedules, and controlled access to unblinded data are outlined in the DSMB 
Charter. 
 
2.5 Data Management 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) 
application will be used for this Study. 

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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 investigator 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 Pharmacokinetics Data 
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the plasma drug 
concentration data. Final data, which has been approved by Quality Assurance, will be stored 
in version-controlled repository 
 
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 the analyses, including by visit summaries, 
figures and abnormality summary. 

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PK parameters will be summarized using number of Subjects, mean, standard deviation, 
coefficient of variation (CV), geometric mean, geometric %CV, median, minimum, and 
maximum. 
General Presentation Considerations 
 
The minimum and maximum will be reported to the same number of decimal places as the raw 
data recorded in the database. The mean, median, lower quartile and upper quartile will be 
reported to one more decimal place than the raw data recorded in the database. The standard 
deviation will be reported to two more decimal places than the raw data recorded in the 
database. In general, the maximum number of decimal places reported shall be four for any 
summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. Any planned collapsing ofcategories 
will be detailed in the text and the data displays. 
Percentages will be presented to one decimal place and not be presented for zero counts. 
Percentages will be calculated using n as the denominator. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. 
P-values less than 0.001 will be presented as “<0.001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
Baseline definition 
 
For platelets, Baseline will be defined as the average of all non-missing pre-dose assessments. 
 
For other assessments, if there are 2 or more pre-dose values available, Baseline will be defined 
as the average of the pre-dose Study Day 1 value and the last pre-dose value prior to Study 
Day 1. If there is only 1 pre-dose measurement available, then it will be assigned as Baseline 
 
Run-in Period 
 
The run-in period is defined as the period from screening to first dose of study Drug 
administration. 
 
On-treatment and Post-treatment Periods 
• For HAE attack endpoints: 
o The on-treatment period spans the time during which the study treatment is 
administered until earliest date from 28 days after the last dose of medication 
and last contact date within the study. 

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o The post-treatment period starts on the day after the on-treatment period and 
ends on the day of the patient’s last contact date within the study. 
• For PD (cHK and PKK levels) and AE-QoL: 
o The on-treatment period spans the time during which the study treatment is 
administered until earliest date from 42 days after the last dose of medication 
and last contact date within the study. 
o The post-treatment period starts on the day after the on-treatment period and 
ends on the day of the patient’s last contact date within the study. 
 
 
Analytical visits 
PD (cHK, plasma proenzyme activation, and PKK levels) and AE-QoL data will be mapped to 
analysis visit specified in the table below. The intent of these visit windows is not to align with 
those prescribed for visit scheduling in the clinical study protocol but, rather, based on the 
protocol-defined target study day, to delineate mutually exclusive windows so that all 
assessments proximal to a particular study week can be integrated to best represent the patient’s 
status during that period of the study. Visits after Week 17 are part of the post-treatment 
assessment period and, due to the fact that most patients are expected to roll into the OLE Study 
ISIS 721744CS3, these data will only be provided in patient listings for evaluation of individual 
patient safety rather than being tabulated. Therefore, no visit windows are needed for data 
analysis for these visits. The PD and AE-QoL assessments that occurred during the post-
treatment period (as defined above) will not be included in the PD analyses/summaries, even 
if they occurred within one of the visit windows. If there are multiple assessments within a visit 
window, the visit nearest the scheduled date will be used unless 2 visits are equally near, in 
which case the average will be used. 
 
 
Assessments 
Mapped Visit 
(Week) 
Target Day 
Study Day 
Window 
PD 
3 
15 
2-22 
5 
29 
23-43 
9 
57 
44-71 
13 
85 
72-99 
17 
113 
100-127 
AE-QoL 
9 
57 
44-71 
17 
113 
100-127 
 
 
Other 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” will not 

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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. 
Safety Population 
The Safety Population will include all enrolled patients who receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo). 
Intent-to-Treat (ITT) Population 
The ITT Population will include all enrolled or randomized patients. 
Per Protocol Population 
The Per-Protocol (PP) Population will include all patients in the ITT Population who are 
treated according to the protocol without any major deviations. 
PK Population 
The PK Population will include all patients who are enrolled and receive at least 1 dose of 
Study Drug 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 
The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 
1 to Week 17. From historical data, the placebo group is estimated to have 6.8 HAE attacks 
per 4-month period. If the ISIS 721744 80 mg group is assumed to have 2.8 HAE attacks per 
4-month period, then with a 0.05 significance level and using Poisson model, the sample size 
of 18 patients (12 patients administered SC injections of ISIS 721744 80 mg and 6 patients 
administered placebo) will provide at least 90% power for the primary endpoint, considering a 
10% missing data or dropout rate for both active treatment and placebo. The sample size of 
18 patients with HAE-1/HAE-2 is also considered sufficient for safety and tolerability 
evaluation. 
 
There is no statistical rationale for the sample size of 6 patients with HAE-nC1-INH. 

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3.1.4 
Planned Interim Analysis 
No interim analysis is planned for this study. However, an independent Data Safety Monitoring 
Board (DSMB) will be established to provide ongoing, independent review and assessment of 
the safety data, and to safeguard the interests and safety of the participating subjects in the 
study. Analysis of the data for DSMB review will be conducted according to the DSMB 
Charter. Because no formal hypothesis testing for safety assessments is planned, multiplicity 
concerns regarding repeated analyses are not an issue. 
 
3.1.5 
Incomplete or Missing Data 
 
 
All available data will be included in the analysis. The length of observation time will be 
included as an offset variable in the Poisson model to adjust for differences in follow-up time. 
 
3.1.5.1 
Imputing Missing Start or End Date and Time for HAE Attacks 
 
In general, missing start time will be imputed as 0:00 and missing end time will be imputed as 
23:59. However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at 
least 24 hours in-between: 
• For HAE attacks with a missing start time and a non-missing start date one calendar 
day after the end date of the previous attack, the start time will be imputed using the 
end time of the previous HAE attack to ensure there are 24 hours in between the two 
attacks. 
• For HAE attacks with a missing start time and a non-missing end date/time within 24 
hours from the end date/time of the previous attack, the attack should be considered as 
one attack with the previous attack 
• For HAE attacks with missing end time and a non-missing end date one calendar day 
before the start date of the next attack, the end time will be imputed as the start time of 
the next HAE attack to ensure there are 24 hours in between the two attacks. 
• For HAE attacks with a missing end time and non-missing start date/time within 24 
hours from the start date/time of the next attack, the attack should be considered as one 
attack with the next attack. 
 
For HAE attacks with a non-missing start date and time and a missing stop date and time: 
• The stop date and time will be imputed as the earlier of the following two date and time: 
o Start date and time + 48 hours or study completion date and the stop time of 
23:59, whichever is later. 
o 24 hours before the start date and time of the next attack. 

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3.1.6 Unique HAE Attacks 
To be counted as a unique attack distinct from the previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms. 
 
Specifically, there must be at least 24 hours between the stop date/ time of the first event and 
the start date/time of the next event, for the attacks to be considered distinct. If there is less 
than 24 hours between the stop date/time of the first event and the start date/time of the next 
event, the events will be counted as one attack. 
 
When two or more attacks are combined for efficacy analysis, the parameters of the attacks 
will be conservatively chosen. The start date and time of the combined attack will take the 
earliest start date and time from the individual attacks; and the end date and time of the 
combined attack will take the latest end date and time of the individual attacks. The severity of 
the combined attack will take the highest severity from the individual attacks. The primary 
location of the combined attack will be determined by the primary location of the individual 
attacks, and by following the hierarchy of laryngeal attack, peripheral attack, and abdominal 
attack. One primary location will be taken; and all the other primary location(s) and secondary 
locations will be considered as secondary location for the combined attack. The rescue 
medications and supportive treatment for the combined attack will include all the records from 
individual attacks. Also, the combined attack will be considered as an investigator-confirmed 
attack if any of the individual attack being combined is an investigator-confirmed attack. 
 
3.2 
Demographic and Baseline Characteristics and Patient Disposition 
Baseline and demographic variables will be summarized descriptively by treatment group and 
overall for Part A, overall for Part B, and for each analysis population. 
 
Demographic and baseline characteristics to be presented include age, age category (18-<40, 
40 to 64, ≥65 years), gender, race, ethnicity, height, weight, BMI, type of genetic mutation. 
 
Age will be calculated as the difference between informed consent date and patient birth date 
divided by 365.25 and rounded down to the associated integer value. 
 
For race summary, if multiple races are recorded in database, ‘Multiple Race’ will be used in 
the summary table but details records in the listing. 
 
A separate table will be created for HAE history and will include family history of HAE, age 
at onset of angioedema symptoms, HAE type, type of attack(s) experienced, Lanadelumab use, 

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reason for discontinuation of Lanadelumab, number of attacks in the last 12 months, run-in 
period HAE attack rate (attacks/4 weeks), run-in period HAE attack rate group (1 to <2, 2 to 
<3, ≥3 attacks/4weeks). 
 
The run-in period HAE attack rate will be calculated for each subject as number of HAE attacks 
occurring during the run-in period divided by the number of days the subject contributed to the 
run-in period multiplied by 28 days. 
 
Medical history will be provided in the data listings. 
 
Subject enrollment and disposition will be summarized by treatment group and overall for Part 
A, and overall for Part B. 
 
The summaries will include: the total number of screened subjects, the number of randomized 
(Part A) or enrolled (Part B) subjects, the number of subjects in each analysis population (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 
Efficacy Analyses 
All efficacy analyses will be performed on the ITT population and Per-protocol population, 
with the former being the basis for the primary efficacy analysis. 
 
3.3.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the time-normalized number of investigator-confirmed HAE 
attacks per month (defined as 28 days) during the on-treatment period from Week 1 to Week 
17 (28 days after last dose administration), will be compared between ISIS 721744 80 mg and 
placebo in Part A using a Poisson regression model and Pearson chi-square scaling of standard 
errors to account for potential overdispersion. The model will include fixed effect for treatment 
group (categorical), the time normalized run-in period attack rate (continuous) as a covariate, 
and the logarithm of time in month (days from first dose date to 28 days after last dose 
administration divided by 28) that each subject was observed during the period will be used as 
an offset variable. 
 
The primary analysis of the primary endpoint will be conducted in the ITT population. 
See Section 3.2 for the calculation of the normalized run-in period attack rate. 

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From this model, the least squares mean rate and standard error for each treatment group as 
well as, the mean rate ratios relative to the placebo group and corresponding 95% confidence 
intervals will be estimated. The p-value of Wald-based chi-square test will also be reported. 
The percentage difference in mean investigator-confirmed HAE attack rate between ISIS 
721744 80 mg and placebo will be calculated as 100% * (mean rate ratio –1). Similarly, the 
estimated upper and lower confidence limits for the mean rate ratio can be transformed by 
subtracting 1 and multiplying by 100% to calculate 95% confidence intervals for the 
percentage change. 
 
Below is the SAS code for the primary analysis: 
 
PROC GENMOD; 
CLASS arm; 
MODEL no_attks = arm baserate / DIST=poisson LINK=log OFFSET=logmon PSCALE; 
LSMEANS arm/ DIFF CL EXP ILINK; 
RUN; 
Where: 
arm= treatment arm (categorical) 
no_attks = number of HAE attacks during the analysis period 
baserate = normalized HAE attack rate during the run-in period (continuous) 
logmon = logarithm of time in month each patient was observed during the analysis period. 
 
 
If one treatment group has 0 count, Fisher’s Exact Test will be used for the analysis instead of 
Poisson regression. The odds ratio, corresponding 95% CI, and p-value will be provided. 
 
The following sensitivity analyses will be performed on the primary efficacy endpoint to 
evaluate the robustness of the results. 
1. The primary analysis described above will be repeated in the PPS as a sensitivity 
analysis. 
 
2. The primary efficacy endpoint will be compared between ISIS 721744 80 mg and 
placebo in Part A using a Negative Binomial model. The model will include fixed 
effects for treatment group (categorical), the time normalized run-in period attack rate 
(continuous) as a covariate, and the logarithm of time in month (days from first dose 
date to 28 days after last dose administration divided by 28) that each patient was 
observed during the on-treatment period will be used as an offset variable. The analysis 
will be conducted in the ITT population. 
 
Below is the SAS code for the sensitivity analysis: 

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PROC GENMOD; 
CLASS arm; 
MODEL no_attks = arm baserate / DIST= NEGBIN OFFSET=logmon; 
LSMEANS arm/ DIFF CL EXP ILINK; 
RUN; 
Where: 
arm= treatment arm (categorical) 
no_attks = number of HAE attacks during the analysis period 
baserate = normalized HAE attack rate during the run-in period (continuous) 
logmon = logarithm of time in month each patient was observed during the analysis 
period 
 
The Part B data will be summarized using descriptive statistics. The exact 95% CI for mean 
based on the gamma distribution will be reported. 
 
In addition to the model-based analysis described above, unadjusted monthly investigator- 
confirmed HAE attack rates from Week 1 to Week 17 (end of the on-treatment period) as well 
as change and percent change from baseline will be summarized by treatment group and by 
Part. The monthly investigator-confirmed HAE attack rate will be calculated for each patient 
as the number of HAE attacks occurring during from Week 1 to Week 17 (end of the on- 
treatment period) divided by number of days the patient contributed to the period multiplied 
by 28 days. The mean percent change from baseline on HAE attacks by study month and 
treatment group will be plotted. 
 
The number of investigator-confirmed HAE attacks per month from Week 1 to Week 17 (end 
of the on-treatment period) will be also summarized descriptively by month (per 28-day 
interval) and treatment group and by Part. The summary will include the monthly investigator- 
confirmed HAE attack rate, change from run-in period, and percent change from run-in period 
of investigator-confirmed HAE attack rate. Investigator-confirmed HAE attacks will be 
grouped into 28-day intervals using the start date of the HAE attack. The date of the first 
exposure to study drug will be used as the start of the first interval and end of the interval will 
be the date of first exposure to study drug plus 28 days. Each successive interval will start the 
last day of the prior interval plus 1 day and end 28 days later. 
 
3.3.2 
Analysis of Secondary Endpoints 
 
3.3.2.1 
Time-normalized number of investigator-confirmed HAE attacks (per month) 
from Week 5 to Week 17 
It will be analyzed using the same method as described for the primary efficacy endpoint, will 
be conducted in both ITT and Per-protocol populations. Data summaries will parallel those 
described for the primary analysis of the primary efficacy endpoint. Only patients who 

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complete Week 5 ( 29 days) HAE assessments will be included in the analysis. The logarithm 
of time in month from Week 5 (Day 29) to Week 17 (end of the on-treatment period) for each 
patient will be used as an offset variable in the model. 
 
3.3.2.2 
Time-normalized number of moderate or severe investigator-confirmed HAE 
attacks (per month) from Week 5 to Week 17 
It will be analyzed using the same method as described for the primary efficacy endpoint, will 
be conducted in both ITT and Per-protocol populations. Only patients who complete Week 5 
(29 days) of HAE assessments will be included in the analysis. The logarithm of time in month 
from Week 5 (Day 29) to Week 17 (end of the on-treatment period) for each patient will be 
used as an offset variable in the model. 
 
3.3.2.3 
The number of patients with a clinical response (defined as a ≥ 50%, ≥ 70%, or ≥ 
90% reduction from Baseline in HAE attack rate) by Week 17 
For each patient, a treatment period HAE attack rate from Week 5 to Week 17 and run-in period 
HAE attack rate will be calculated. The percentage reduction will be calculated as the treatment 
period HAE attack rate from Week 5 to Week 17minus the run-in period HAE attackrate divided 
by the run-in period HAE attack rate. Patients who discontinued treatment early due to lack of 
efficacy or AEs will be considered as non-responders and included in the denominator for the 
calculation of the proportion in the ITT population. Patients who discontinued due to other 
reason will be excluded from analysis. 
 
Risk difference comparing ISIS 721744 80 mg group to the placebo group in Part A, and 
corresponding exact 95% confidence interval (Santner and Snell 1980) will be provided. The 
Fisher’s Exact test p-value will also be reported. The analysis will be conducted in both ITT 
and Per-protocol populations. 
 
Below is the SAS code for this analysis: 
 
PROC FREQ; 
TABLES arm*attack / RISKDIFF; 
EXACT RISKDIFF; 
RUN; 
 
3.3.2.4 
The number of investigator-confirmed HAE attacks requiring acute therapy from 
Week 5 to Week 17 
It will be analyzed using the same method as described for the primary efficacy endpoint, will 
be conducted in both ITT and Per-protocol populations. HAE attacks requiring acute therapy 
include those attacks with medical intervention or hospitalization marked on the CRFs. 

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3.3.2.5 
Change and Percent Change in cHK and PKK levels at Week 5 to Week 17 
The change and percent change from baseline in cHK and PKK levels at each visit during the 
treatment period will be compared between ISIS 721744 80 mg and placebo in Part A using 
the Mixed Effects Model with Repeated Measures (MMRM) model. The response variable is 
the change or percent change from baseline at post-baseline visit up to Week 17. For patients 
who terminate treatment early, only the data collected up to 42 days after last dose 
administration will be included. The MMRM model will include effects of treatment (ISIS 
721744 or placebo), time (categorical), treatment-by-time interaction, and baseline value. The 
analysis will be conducted in both ITT and Per-protocol populations. The unstructured 
covariance model will be used to model the within patient errors, shared across treatments and 
small sample adjustments to standard errors and tests will be made following the Kenward- 
Roger approach (Kenward, M. G. and Roger, J. H. (1997). If there are convergence problems 
with the repeated measures mixed model, this will be explored. For example, the SCORING=4 
option could be used in the PROC MIXED statement in SAS. This makes SAS use Fisher 
scoring for the first 4 iterations. If the convergence problem cannot be resolved the unstructured 
covariance matrix will be replaced by the compound symmetry covariance matrix (Type=CS in 
SAS). 
Below is the SAS code for this analysis: 
 
PROC MIXED; 
CLASS arm visit subject; 
MODEL endpoint=arm baseline visit arm*visit/ DDFM=kr; 
REPEATED visit / SUBJECT=subject TYPE=un; 
LSMEANS arm*visit / CL DIFF; 
RUN; 
 
The normality of each parameter will be examined using the Shapiro–Wilk test. The non- 
parametric Wilcoxon Rank Sum test will also be performed at each visit as the sensitivity 
analysis. Hodges-Lehmann estimates of the differences between ISIS 721744 80 mg group 
and the placebo group in Part A as well as distribution-free CIs based on the Wilcoxon Rank 
Sum Test will also be provided. 
 
CHK and PKK levels as well as the change and percent changes from baseline over time will 
also be summarized using descriptive statistics by visit, treatment group and by Part. 
 
The change and percent change in plasma proenzyme activation levels will also be analyzed. 

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3.3.2.6 
Consumption of on-demand medication by Weeks 9 and 17 
The number and percentage of patients who used on-demand medication by Week 9 (Day 57) 
and by Week 17 (end of the on-treatment period) will be tabulated by treatment group and by 
Part. On-demand medications will be identified based on manual review. 
 
3.3.2.7 
AE-QoL score at Weeks 9 and 17 
AE-QoL will be evaluated by determining its four individual domain scores and a total score. 
Each item answered by the patient scores between 0 and 4 points depending on the answer 
option chosen by the patient. The first answer option gets 0 points, the second option 1 point, 
the third option 2 points, etc. The AE-QoL domain scores and total score are calculated by 
using the following formula: 
(Sum of all completed items) / (maximum sum of all possible items)*100 
Computation of AE-QoL Total Score 
Example 1: All items were completed (maximum possible sum: 68 points) 
Sum of all 17 completed items: 41 points. 
Total score = 100*(41/68) = 60 (out of a possible 100 points) 
 
Example 2: 2 items were not completed (maximum possible sum: 60 points). 
Sum of all 15 completed items: 41 points. 
Total score = 100*(41/60) = 68 (out of a possible 100 points) 
 
Computation of Domain Scores (Example: Fears/Shame) 
Example: Sum of all 6 completed items: 14 points 
Maximum possible sum: 24 points 
Domain Score = 100*(14/24) = 58 (out of a possible 100 points) 
Remarks 
Since only answered items are included in the computation (and the calculated domain and 
total scores are not raw scores but linear transformations to a 0-to-100 scale), the calculated 
scores are not or only little influenced by missing items. 
 
An AE-QoL domain score should not be calculated if more than one item is left unanswered 
in that domain. The AE-QoL total score should not be calculated if more than 25% of items 
(>4 items) are left unanswered. 
The minimal and highest possible domain and total scores are 0 and 100, respectively. 
 
The AE-QoL total score and domain score will be analyzed using the same method as described 
for cHK, will be conducted in both ITT and Per-protocol population. 

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3.3.3 
Analysis of Exploratory Endpoints 
 
3.3.3.1 
The number of HAE attack-free patient by Week 17 
The number and percentage of patients who achieve investigator-confirmed HAE attack free 
(no investigator confirmed HAE attacks) by Week 17 (end of the on-treatment period) will be 
tabulated by treatment group and by Part. Patients who discontinued treatment early due to 
lack of efficacy or AEs will be considered as non-responders and included in the denominator 
for the calculation of the proportion in the ITT population. Patients who discontinued due to 
other reason will be excluded from analysis. The risk difference between ISIS 721744 80 mg 
group to the placebo group in Part A, and the corresponding exact 95% confidence interval 
will be provided. The Fisher’s Exact test p-value will also be reported. The analysis will be 
conducted in both ITT and Per-protocol population. 
 
The number and percentage of patients who achieve investigator-confirmed HAE attack free 
(no investigator confirmed HAE attacks) between Week 5 to the end of the on-treatment period, 
between Week 9 to the end of the on-treatment period, and between Week 13 to the end of the 
on-treatment period will also be tabulated and analyzed in a similar manner. 
 
 
3.3.4 
Analysis of Additional Endpoint 
 
3.3.4.1 Time-normalized number of moderate or severe investigator-confirmed HAE 
attacks (per month) from Week 1 to Week 17 
It will be analyzed using the same method as described for the primary efficacy endpoint, will 
be conducted in both ITT and Per-protocol populations. 
 
 
3.4 
Safety Analyses 
Safety analyses will be performed on the safety population. 
 
3.4.1 
Exposure 
 
Treatment duration, number of doses and amount of Study Drug will be summarized by Part 
and treatment group. 
 
The treatment duration (days) for each patient is defined as last dose date - first dose date +1. 

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3.4.2 
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. 
To determine the AE as treatment-emergent or not, if there is no “Formlink” link, and the AE 
(start date/time) occurs on or after the patient’s first dosing date/time, then the AE is treatment- 
emergent. Otherwise, if the AE (start date/time) occurs prior to the patient’s first dosing 
date/time, then the AE is not treatment-emergent. 
 
If there is a “Formlink” link between two AE records, then we compare them pairwise, and 
consider two cases, where we compare the AE severity (mild/moderate/severe) between the 
two records in the pair. We chronologically order the 2 records (by AE start date) and refer to 
the “first” and “second” AE. 
 
Case 1: The first AE record in the pair occurs before first dosing, and the second AE 
record occurs after first dosing. 
If the AE severity of the second record is worse than that of the first record, then only 
the second AE is deemed as a TEAE. Otherwise, neither record is considered as TEAE. 
 
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. 
 
All TEAEs identified based on the rules above will be summarized in the event number 
analysis. 
The most conservative approach will be used to determine if the event occurs after the 
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 complete 
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) preferred term and system organ class for: 

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• 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 
 
Local cutaneous reaction at injection site (LCRIS) is defined as (A) moderate or severe 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; or (B) any AE at the Study Drug injection site, regardless of severity, that 
leads to discontinuation of study drug, where AE at the Study Drug injection site is the principal 
reason for discontinuation. LCRIS will be summarized using the MedDRA coding system, by 
PT and by treatment group and Part. Patients with moderate, severe and any LCRIS will also be 
summarized. Discontinuations due to AE at the injection site will be summarized separately. 
Percentage of injections leading to those events will be summarized by PT and overall using 
the descriptive statistics. Additionally, percentage of injections leading to events will be 
summarized by moderate, severe severity and overall discontinuation of study drug due to AE 
at injection site. 
Percentage of injections leading to LCRIS at the injection site will be calculated as follows for 
each patient: (A/B)*100, where A=number of injections with a LCRIS, and B=total number of 
injections. Doses that are split across multiple injections are counted as a single injection. 
 
LCRIS will also be listed. 
 
Flu-like Reactions 

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Flu-like reactions are 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. 
Flu-like reactions will also be summarized using the MedDRA coding system, by preferred 
term and by treatment group and part. 
Percentage of injections leading to flu-like reactions will be summarized by treatment group 
and by Part using the descriptive statistics. 
Percentage of the injections leading to flu-like reactions will be calculated as follows for each 
patient: (A/B)*100, where A=number of injections leading to flu-like reactions, and B=total 
number of injections. 
Flu-like reactions will also be listed. 
Bleeding Adverse Events 
 
Bleeding AEs will be identified based on the Haemorrhages (SMQ) Export from MedDRA 
and summarized by MedDRA system organ class and preferred term and by treatment group 
and part. 
 
3.4.3 
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, glucose, BUN, creatinine, cholesterol, uric 
acid, total bilirubin, direct (conjugated) bilirubin, indirect (unconjugated) 
bilirubin, ALT, AST, alkaline phosphatase, creatine kinase, GGT, 
• Hematology: red blood cells, hemoglobin, hematocrit, platelets, MCV, MCH, 
MCHC, platelets, white blood cells (WBC), and WBC differential (percentage 
and absolute count) (basophils, eosinophils, lymphocytes, monocytes and 
neutrophils) 
• Coagulation: aPTT (sec): PT (sec), INR, Plasmin-antiplasmin complexes, D-dimer 
• Complement: Bb, C5a, C4 split products, C4 
• Inflammatory: Hs-CRP 
• Screening tests: hepatitis B surface antigen, hepatitis C antibody, HIV antibody, 
FSH (women only, if applicable), and serum βhCG (women only) The data will 
only be displayed in subject listings. 

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• Urinalysis (other): color, appearance, specific gravity, pH, P/C ratio, protein, blood, 
ketones, urobilinogen, glucose, bilirubin, , leukocyte esterase, nitrate, eGFR, 
microscopic examination. The data will only be displayed in subject listings. 
 
Missing WBC differential absolute counts and percentages will be derived: 
If WBC differential absolute counts are missing, and percentages are available, then absolute 
counts will be calculated by multiplying the percentage by total WBC count. Conversely, if 
absolute count is available, and percentage is missing, then percentage will be calculated by 
dividing absolute count by the total WBC count. If WBC differential absolute counts are 
missing, and manual count values are available, then manual count values will be used. If 
neutrophils count and percentages are missing, and segmented neutrophil and band neutrophil 
results are available, then neutrophils will be calculated by adding segmented neutrophils and 
band neutrophils, if only segmented neutrophil result is available, then neutrophils will be set 
to segmented neutrophils result. 
All lab data will be displayed in subject listings. 
Chemistry, hematology, coagulation, and complement, (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, the number and percentage of patients falling in each of the following categories 
based on the confirmed results will be tabulated by treatment group for 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. 
 
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. 

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3.4.4 
Vital Signs, Weight, and BMI 
Vital signs will include heart rate, respiratory rate, body temperature, systolic and diastolic 
blood pressure and pulse 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 values, weight, and BMI as well as the change and percent change 
from baseline at each study visits. 
 
3.4.5 
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. 
 
3.4.6 
12-Lead Electrocardiograms (ECG) 
Safety 12-lead ECG will be performed at the visits Screening, Day 1 (Pre-Dose), Day 57, Day 
113 and Day 176. The ECG data will include Ventricular Rate, PR Interval, QRS Duration, 
QTc, 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 
patient’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 
For the continuous variables above, descriptive statistics (n, mean, standard error, standard 
deviation, median, 25th percentile, 75th percentile, minimum and maximum) of the results at 
each study visit, as well as the changes and percent changes from Baseline to each study visit, 
will be presented in summary tables; for the categorical responses to overall interpretation, the 
results and the associated findings at each visit will be summarized by counts and percentages. 
 
All the safety ECG data collected will be listed. 
 
3.4.7 
Prior and Concomitant Medications 
Prior medications include medications started prior to the first dose of study medication 
regardless whether continued while on treatment or not. Concomitant medications include 
medications that patients are exposed to on or after the first dose of study medication. Partial 
or missing medication start date or end date will be imputed by the following imputation rules: 
 
Start date: 
• If year, month and day are all missing then assign the date of first dose of Study Drug 
• If month and day are missing and year is: 

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o earlier than the year of the first dose of Study Drug then assign December 31 
o otherwise, assign January 1 
• If only day is missing and month-year is: 
o earlier than the month-year of the first dose of Study Drug then assign the last day 
of the month 
o otherwise, assign the first day of the month 
End date: imputation will be performed for the end date only if the day or month is missing 
(i.e., year is present): 
• If month and day are missing, then assign December 31 
• If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to 
the imputed end date. 
Prior and concomitant medications will be coded using WHO Drug dictionary and 
summarized by ATC class, preferred name and by treatment group and Part. 
 
3.4.8 
Angioedema Activity Score 
The AAS consists of 5 questions as well as an opening question. A score between 0 and 3 is 
assigned to every answer field. The question scores are summed up to an AAS day sum score, 
7 AAS day sum scores to an AAS week sum score (AAS7), and 4 ASS week sum scores may 
be summed up to an AAS 4-week sum score (AAS28). Accordingly, the minimum and 
maximum possible AAS scores are 0-15 (AAS day sum score), 0-105 (AAS7), and 0-420 
(AAS28). Missing scores will be imputed using the LOCF method. 
 
The opening question may be used to count the number of angioedema affected days during 
the AAS documentation period but has no score. 
The AAS scores will be listed. The AAS 4-week sum score will also be summarized by 
treatment group and by Part over time. In addition, the AAS 4-week sum score will be 
analyzed using an ANCOVA model, including treatment group as effect, and baseline AAS 
score as covariate. 
 
3.5 
Pharmacokinetic Analysis 
The plasma pharmacokinetics of ISIS 721744 (as total full-length oligonucleotides or ISIS 
721744-equivalent, ISIS 721744-eq.) will be assessed following SC administration(s). 

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3.5.1 Plasma Concentration Data of Total Full Length Oligonucleotides 
Plasma concentrations of ISIS 721744 (ISIS 721744 eq.), along with the scheduled (nominal) 
and actual samples times (i.e., time from SC dosing) will be listed (when applicable) for each 
patient, by treatment group, nominal dose, and day. In addition, percent differences between 
scheduled and actual sampling times will also be listed for all patients. Percent differences 
between actual administered dose and nominal dose will also be listed. 
 
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 and %CV will be reported as not applicable. Summary 
statistics of the ISIS 721744 plasma concentrations will be tabulated by treatment group, 
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. 
 
ISIS 721744 eq. plasma concentration versus time (actual) profiles for each patient that 
received ISIS 721744 active treatment, as well as the mean (± SD or SE) plasma 
concentrations versus time (scheduled) profiles, will be presented graphically on linear and 
semilogarithmic scales. At the discretion of the pharmacokineticist and/or biostatistician, 
samples may be excluded from the mean plots if there are large deviations between 
scheduled and actual sampling times. 
 
3.5.2 Plasma Pharmacokinetic Parameters 
The plasma PK of ISIS 721744 (as total full-length oligonucleotides) will be assessed 
following SC administration. Non-compartmental PK analysis of ISIS 721744 (total full- 
length oligonucleotides) will be carried out on each individual subject data set using Phoenix 
WinNonlin version 8.0 or higher (Pharsight Corporation, Mountain View, CA). For 
calculation of PK parameters, all BLQ values will be set to zero. The plasma PK parameters 
for ISIS 721744-eq. will be calculated based on actual sampling times. The plasma PK 
parameters to be calculated or determined (when applicable) are listed in Table 1. Other 
plasma PK parameters, as appropriate, may be determined or calculated at the discretion of 
the PK scientist. 
 
Table 1 
Plasma Pharmacokinetic Parameters to be Calculated or Determined 

Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Feb 17, 2021 
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Parameter 
Definition/Method 
Day 1 
D85 
Cmax 
Maximum observed concentration 
X 
X 
Tmax 
Observed time at which Cmax occurs 
X 
X 
Tlast 
Time of last measurable (positive) concentration 
X 
X 
AUClast 
Area under the concentration-time curve from time zero to Tlast, calculated 
using linear-up log-down method. 
X 
AUC0-t 
Partial AUC: Area under the concentration-time curve from time zero to time 
t (e.g., t may be 24, 48, 72, 168 hrs or 28 days, as applicable), calculated using 
linear-up log-down method 
X 
X 
AUCτ 
Area under the concentration-time curve within the dosing interval (τ) at 
steady-state, calculated using linear-up log-down method 
X 
t1/2λz 
Terminal elimination half-life determined from the equation: ln 2/λz, where λz 
is the first-order rate constant associated with the terminal (log-linear) 
elimination phase. This is estimated via linear regression of time vs. log 
concentration. A minimum of three data points in the elimination phase will be 
used to define λz and the correlation of determination values (r2) had to be at or 
greater than 0.8 for the estimate to be accepted. 
X 
CLss/F 
Steady-state clearance divided by F (fraction of the dose absorbed) determined 
by Dose/AUCτ 
X 
CL0-t/F 
Clearance after first dose divided by F (fraction of the dose absorbed) 
determined by Dose/AUC0-t 
X 
Vz/F 
Volume of distribution (based on the terminal phase) divided by F (fraction of 
the dose absorbed) 
X 
Note: X designates parameters to be calculated or determined assuming sufficient data 
 
Plasma pharmacokinetic parameters will be summarized using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric %CV, median, minimum, and maximum) by 
treatment group, nominal dose, and day. Additionally, the relationship between dose and 
plasma exposure parameters (Cmax and AUC) of total full-length ASOs (ISIS 721744-eq.) 
will be evaluated using linear-regression analysis of the log-transformed mean data. Lastly, 
the relationship between individual subject trough data at selected time points and plasma 
exposure parameters (Cmax and AUC) will also be evaluated. 
 
3.5.3 Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis 
 
Exposure-response correlations may be explored graphically between plasma exposure (AUC, 
Cmax, Ctrough, as appropriate), and selected PD measures and outcomes, as well as other 
relevant biomarkers (such as plasma prekallikrein (PKK), etc.). In addition, the relationship 
between relevant PD markers and outcomes and plasma trough concentrations of ISIS 721744 
will be further evaluated with an inhibitory effect Emax model or another exposure-response 
model as appropriate. 

Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Feb 17, 2021 
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CONFIDENTIAL 
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Population PK and PKPD analysis may be performed using the PK and PD data from this 
Study, and/or combined with other ISIS 721744 clinical PK data later in the development 
timeline. 
 
3.4.5 Immunogenicity (IM) Analysis 
 
Immunogenicity (IM) analyses will be conducted in the Safety Population. Samples 
collected pre-dose on Days 1, 29 and 57 and anytime on Days 15, 113, and 176, including 
early termination samples for IM assessment, may be analyzed for anti-ISIS 721744 
antibodies (ADA). In addition, plasma samples collected at other time points (for PK 
purposes) may also potentially be evaluated if deemed of further interest and warranted by 
the pharmacokinetic scientist. An evaluable sample will be designated ‘IM positive’ based 
on both positive screening and confirmation assay results (i.e., confirmed positive result), and 
otherwise will be deemed ‘IM negative’. Sample IM results (screen positive/negative, 
confirmed positive/negative or unevaluable, and when applicable, titer of anti-ISIS 721744 
antibodies) before, during, and after treatment with study drug (ISIS 721744 or placebo) 
(sample IM status) will be listed by treatment and dose. The sample ADA incidence 
(number) and incidence rate (percent) at each evaluated study time point 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. 
Furthermore, titer over time will be also appropriately summarized (using descriptive 
statistics) as median, quartiles (25% and 75%), and range by treatment and dose. 
 
Study subjects’ overall ADA status will be assigned ‘IM positive’ status if they have at least 
one confirmed positive sample result at any time during the treatment or post-treatment 
evaluation periods. Study subjects will be assigned ‘IM negative’ status if all evaluated IM 
sample results during the treatment and post-treatment evaluation periods are IM negative and 
they have at least one evaluable IM result collected post study drug treatment. Otherwise, a 
study subject will be assigned ‘unknown’ IM status. Furthermore, subjects with positive overall 
ADA status will be further classified into different ADA types based on their baseline ADA 
status and change in ADA titer post treatment as described below (Shankar et al., 2014): 
• Treatment-Emergent ADA: sum of treatment-induced ADA and treatment-boosted 
ADA as described below: 
o 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) 
o 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 8-fold or more 

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• Treatment-Unaffected ADA: pre-existing ADA that were not affected (boosted) 
following biologic drug administration (i.e., any time after the initial drug 
administration the ADA titer is 4-fold or less) 
• ADA type would be not applicable (NA) if the subject overall ADA status is 
negative. 
• 
Other subject level IM parameters to be calculated/defined may include but not limited to: 
• Subject ADA Status at Baseline: "Positive" if the subject has Week 1 Day 1 pre-dose 
sample (baseline) tested as confirmed positive; "Negative" if the subject has Week 1 
Day 1 pre-dose sample (baseline) tested as confirmed negative; "Unknown" if the 
subject has Week 1 Day 1 pre-dose sample (baseline) unevaluable. 
• Onset of ADA: 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: 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 :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: the highest titer observed for the subject 
• Time to peak titer: 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: the total number of ADA samples being 
confirmed positive for the subject 
• Total number of ADA Samples evaluated: the total number of ADA samples being 
collected and analyzed successfully with reportable results for the subject 
 
Other immunogenicity data analysis may be conducted (e.g. classification as transient or 
persistent status for IM positive subjects) if there are a sufficient number of subjects with 
transient IM status. Transient and Persistent ADA definitions are defined below: 
Transient ADA response will be defined as: 
• 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. 

Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Feb 17, 2021 
ISIS 721744-CS2 
CONFIDENTIAL 
32 
 
 
 
Persistent ADA response will be defined as: 
• 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 
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, by treatment and dose. 
 
In addition to PK assessments (Section 3.5.2), selected safety (Section 3.4) and PD 
assessments (Section 3.6) may be further stratified by subject IM status (i.e., subject IM 
status being positive, negative or unknown) and presented in tables and/or graphically, as 
deemed appropriate or warranted by the designated study pharmacokineticist, medical 
monitor, and/or biostatistician. 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.