Clinical trial NCT03472040
Conditions: Hereditary Angioedema HAE Prophylaxis
Keywords: BCX7353 Hereditary Angioedema HAE
Sponsor: BioCryst Pharmaceuticals
Start date: 2018-02-16; Completion date: 2022-04-27
Enrollment: 387 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label study to evaluate the long term safety and effectiveness of oral treatment with BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II Hereditary Angioedema (HAE).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: BCX7353
Intervention descriptions: intervention 1: BCX7353 mg oral capsules administered once daily

Protocol documents:
Prot_000.pdf: 
Protocol 
BioCryst Pharmaceuticals, Inc. 
Version 9.0 
CONFIDENTIAL 
BCX7353-204 
1 
1.
TITLE PAGE
BIOCRYST 
PHARMACEUTICALS, INC. 
Protocol No. BCX7353-204 
AN OPEN-LABEL STUDY TO EVALUATE THE LONG-TERM 
SAFETY OF DAILY ORAL BCX7353 IN SUBJECTS WITH 
TYPE I AND II HEREDITARY ANGIOEDEMA 
Version 9.0 (United States): 23 March 2020 
IND No. 135,058 
EudraCT No. 2017-003281-27 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703 
Phone: (919) 859-1302 
Fax: (919) 851-1416 
The information in this document contains proprietary and confidential information belonging to 
BioCryst Pharmaceuticals, Inc. As a result, no part of this document should be copied, referred 
to, released, published or otherwise disclosed in any manner or media without prior written 
approval from BioCryst Pharmaceuticals, Inc. 
CONFIDENTIAL


Protocol 
BioCryst Pharmaceuticals, Inc. 
Version 9.0 
CONFIDENTIAL 
BCX7353-204 
 
2 
 
 
Protocol Number: 
BCX7353-204 
Study Title: 
An open-label study to evaluate the long-term safety of daily oral 
BCX7353 in subjects with Type I and II hereditary angioedema 
IND Number: 
135058 
EudraCT No. 
2017-003281-27 
Investigational Product: 
BCX7353 
Indication Studied: 
Hereditary Angioedema 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703, USA 
Sponsor Medical Monitor: Sylvia Dobo, MD 
Phone (24 hours): +1 919-859-7905  
Email Address: mm@biocryst.com 
Clinical Study Manager: 
Daniel Dix 
Senior Clinical Study Manager 
BioCryst Pharmaceuticals 
Office: +1 919-859-7933 
Email Address: ddix@biocryst.com 
Principal  Investigators: 
Global:  
Prof. Henriette Farkas MD, PhD, DSc 
Director of the Hungarian Angioedema Center 
3rd Department of Internal Medicine, Semmelweis University, 
Budapest, Hungary 
H-1125 Kutvolgyi ut 4 
Phone: +36-1-3251481 
Email Address: farkas.henriette@med.semmelweis-univ.hu 
United States: Dr. Aleena Banerji, MD 
Associate Professor 
Division of Rheumatology, Allergy and Immunology 
Massachusetts General Hospital 
100 Blossom Street, Cox 201 
Boston, Massachusetts, United States 02114 
Phone: +1 617-726-3850 
Email Address: abanerji@partners.org 


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Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and clinical 
research guidelines established by the Code of Federal Regulations 
(Title 21, CFR Parts 50, 56, and 312), International Council for 
Harmonisation Guidelines and all locally applicable regulations. Essential 
study documents are currently archived in accordance with applicable 
regulations 
Final Protocol Date: 
Version 9.0:  23 March 2020 
Previous Versions 
Version 8.0:  06 February 2020 
Version 7.0:  21 August 2019 
Version 6.0: 31 July 2019 (United States)  
Version 5.0: 07 February 2019 (United States) 
Version 4.0: 05 October 2018 
Version 3.0: 06 December 2017 
Version 2.0: 05 December 2017 
Version 1.0: 20 September 2017 


BioCryst Phart.ru1ceutkal~, Inc. 
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Protocol No: 
BCX7353-204 
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Melanie Cornpropst, P~~:~-;Jj ___ \ 
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Sylvia Dobo,, ~/iD 
ViCi: Pr~fiid.ent ~ledicai and Safety Scien,~ 
Bio-C~iy-st .Phi:rfl1ac.euti~<:!s~ !nc" 
EHiott Berger, PhD 
Senior \'ice Presid;:nt~ Re:~ulfitory~ ,'\.ffuirs 
Bi-oCryst Ph8.r:naceuti:;als~ Inc~ 
Date 
Date 
Date 


Protocol 
Version 9.0 
BioCryst Pharmaceuticals, Inc. 
CONFIDENTIAL 
1.1. 
Protocol Approval Signature Page 
Protocol No: 
BCX7353-204 
BCX7353-204 
Protocol Title: 
An open-label study to evaluate the long-term safety of daily oral BCX7353 in 
subjects with Type I and II hereditary angioedema 
Date; 
Version 9.0: 23 March 2020 
BioC1yst Pharmaceuticals, lnc. 
Reviewed and Approved by: 
Melanie Compropst, PharmD, PhD 
Vice President, Clinical Development 
BioCryst Pharmaceuticals, Inc. 
Sylv-ia'1nobo, MD 
Vice President., Medical and Safety Science 
BioCryst Pharmaceuticals, lnc. 
-
Elliott Berger, PhD 
Senior Vice President. Regulatory Affairs 
BioCryst Pharmaceuticals, Inc. 
Date 
Date 
Date 
4 


Protocol 
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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No: 
BCX7353-204 
Protocol Title: 
An open-label study to evaluate the long-term safety of daily oral BCX7353 in 
subjects with Type I and II hereditary angioedema 
 
Date: 
 
Version 9.0: 23 March 2020 
 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, International Council for Harmonisation guidelines for Good Clinical 
Practices, and all applicable regulatory requirements. 
 
 
_____________________________________________________________________ 
 Investigator’s Signature                                                            Date (DD MMM YYYY) 
 
 
_________________________________ 
Name (Print) 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. 
Name of Investigational Product: 
BCX7353 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-
3-(trifluoromethyl)-1H-pyrazole-5-carboxamide    
Title of Study:  
An open-label study to evaluate the long-term safety of daily oral BCX7353 in subjects with Type I and II 
hereditary angioedema 
Study center(s):  
Protocol Versions 1.0-4.0, 7.0: Multiple study centers in Asia-Pacific, Europe, Israel, and South Africa 
Protocol Versions 5.0, 6.0, 8.0, 9.0: Multiple centers in the United States (US) only    
Principal  Investigators:  
Global Principal  Investigator: Henriette Farkas MD, PhD, DSc 
United States Principal  Investigator: Aleena Banerji, MD 
Phase of development: 2 
Primary Objective:    
• 
To evaluate the long-term safety and tolerability of daily dosing of oral BCX7353 in subjects with hereditary 
angioedema (HAE)  
Secondary Objective: 
• 
To assess the effectiveness (ie, HAE attack frequency, severity and disease activity over time) of BCX7353 
during long-term administration 
• 
To evaluate quality of life (QoL) during long-term administration of BCX7353 
• 
To evaluate subject’s satisfaction with medication during long-term administration of BCX7353 
Methodology:  
This is a single-arm, open-label study to evaluate the long-term safety and effectiveness of orally administered 
BCX7353 in subjects with HAE who are expected to derive benefit from an oral treatment to prevent angioedema 
attacks.  
Subjects who meet the inclusion and exclusion criteria will be enrolled into the study for up to 96 weeks. 
Subjects enrolled under protocol versions 6.0 and 9.0 will receive BCX7353 150 mg administered orally once 
daily (QD). 
Study visits will occur at Screening, Baseline/Day 1, at Weeks 4, 12, 24, 48, 72, and 96 weeks, until the product 
is commercially available, or until the Sponsor discontinues development of the product for the prevention of 
angioedema attacks, whichever comes first. Any subject who discontinues androgen prophylaxis at the time of 
signing informed consent or at the screening visit will have an additional visit to measure alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase 
(LDH), gamma-glutamyltranspeptidase (GGT), and total and direct bilirubin 2 weeks (+7 days) after androgen 
discontinuation and before initiating treatment with BCX7353.  
Data from ongoing studies BCX7353-302 (Phase 3 study), BCX7353-301 (Phase 3 study) and the current study, 
BCX7353-204, are reviewed by the BCX7353 data monitoring committee (DMC) at protocol-specified intervals. 
The DMC may also be convened if a new clinically significant safety signal emerges or at other times as 
requested. The latest data review was conducted on 31 July 2019.  The recommendation of the DMC was that all 
3 studies proceed per protocol.  


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Study drug will be discontinued for subjects who are deriving no clinical benefit, are intolerant of study drug, or 
experience an unacceptable drug-related adverse event (AE). The study will be discontinued if ongoing 
regulatory or institutional review board/ethics committee approval is withdrawn, or in the event that technical or 
logistical factors prevent the ongoing conduct of the study. Safety and tolerability will be evaluated through 
assessments of AEs, laboratory analyses (clinical chemistry, hematology, coagulation and urinalysis), vital signs, 
electrocardiograms (ECGs), and physical examinations.  
The main study will be comprised of adult subjects (≥ 18 years of age); a substudy will be included that allows 
adolescent subjects ≥ 12 to 17 years of age to screen and enroll. Subjects will document all angioedema attacks 
that occur while on study. Angioedema attacks will be treated in accordance with the subject’s normal standard 
of care. Treatments for angioedema attacks will not be provided by the Sponsor. 
Patient-reported outcomes will be completed by subjects for the disease-specific Angioedema Quality of Life 
(AE-QoL) questionnaire and Treatment Satisfaction Questionnaire for Medication (TSQM), where validated 
translations are available. Subjects will be asked about time away from work or school. Additional data collection 
may be conducted by a specialty pharmacy to better understand the subject experience with the study drug during 
the subject’s participation in the study. 
Number of subjects (planned): Approximately 475 subjects globally (approximately 250 subjects are planned 
to be enrolled in the US) 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study: 
1) Males and non-pregnant, non-lactating females ≥ 18 years of age (main study) or ≥ 12 to 17 years of age 
(substudy)   
2) Subjects with a clinical diagnosis of HAE Type I or II who, in the opinion of the  Investigator, are expected 
to benefit from an oral treatment for the prevention of angioedema attacks. A clinical diagnosis of HAE Type 
I or II is defined as:  
• 
A C1 esterase inhibitor (C1-INH) functional level below the assay lower limit of normal as assessed 
during the screening period by chromogenic assay OR 
• 
Laboratory documentation of historical C1-INH functional level below the assay lower limit of normal 
OR 
• 
Subjects who currently use plasma derived or recombinant C1-INH based therapies for acute attacks or 
prophylaxis may use one of the following to confirm their diagnosis: 
o 
SERPING-1 gene mutation known or likely to be associated with HAE Type 1 or II as assessed 
during the screening period OR 
o 
A confirmed family history of C1-INH deficiency 
3) Subject weight ≥ 40 kg 
4)  Access to one or more targeted medications for the treatment of acute HAE attacks. The following are 
acceptable: icatibant, plasma-derived C1-INH (all forms), ecallantide, recombinant C1-INH.  
5) Female subjects must agree to use acceptable effective contraception, as defined in Section 8.2.1 
6) Able to provide written, informed consent. Subjects aged ≥ 12 to 17 years who are screened for the substudy 
must be able to read, understand, and be willing to sign an assent form in addition to a caregiver providing 
informed consent 
7) In the opinion of the  Investigator, the subject is able to adequately comply with all required study 
procedures for the duration of the study. The subject must demonstrate adequate compliance with all study 
procedures required including diary recording of HAE attacks 


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Exclusion Criteria 
Subjects must meet none of the following exclusion criteria to be eligible for participation in this study: 
1) Pregnancy or breastfeeding or planned pregnancy during the study period.  
2) Any clinically significant medical condition or medical history that, in the opinion of the  Investigator or 
Sponsor, would interfere with the subject’s safety or ability to participate in the study. Examples include 
active malignancy under treatment, uncontrolled cardiovascular disease (recent acute myocardial infarction, 
unstable angina), organ dysfunction such that supportive care is required (dialysis, oxygen therapy, cirrhotic 
care). 
3) Dementia, altered mental status or any psychiatric condition, that would prohibit the understanding or 
rendering of informed consent or participation in the study. 
4) Clinically significant abnormal ECG including but not limited to, a corrected QT interval using Fridericia’s 
method (QTcF) > 470 msec for women, a QTcF > 450 msec for men, or ventricular and/or atrial premature 
contractions that are more frequent than occasional, and/or as couplets or higher in grouping. 
5) Use of concomitant medications that are metabolized predominantly by CYP2D6 or CYP3A4 and that have a 
narrow therapeutic range as defined in Section 9.7.1.  
6) Use of oral androgens for treatment of HAE (prophylaxis or acute) within 28 days of the baseline visit or 
planned initiation during the study. 
7) Any laboratory parameter abnormality that, in the opinion of the  Investigator, is clinically significant and 
relevant for this study. 
8) Investigational drug exposure within 30 days prior to the screening visit. 
9) Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear 
etiology. 
10) History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or 
abuse (self-reported alcoholic intake > 3 units of alcohol/day). 
11) Current infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus. 
12)  Subjects with an immediate family relationship to either Sponsor employees, the  Investigator or employees 
of the study site who are named on the delegation log. 
13)  Subjects who are held in an institution by a government or judicial order. 
Investigational product, dosage and mode of administration:  
BCX7353 capsules, to be administered orally. Subjects will receive a dose of 150 mg QD.  
Reference therapy, dosage and mode of administration:  
Not applicable. 
Duration of treatment:  
Subjects will be eligible to receive study drug (BCX7353) for up to 96 weeks, until the product becomes 
commercially available, or until the Sponsor discontinues development of the product for the prevention of 
angioedema attacks, whichever comes first. Study drug will be discontinued for subjects who are deriving no 
clinical benefit, are intolerant of study drug, or experience an unacceptable drug-related AE. 
Criteria for evaluation: 
Safety: 


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Safety will be evaluated by AEs, laboratory analyses (clinical chemistry, hematology, coagulation, urinalysis), 
vital signs, ECGs, and physical examinations. An independent DMC will review safety data in accordance with a 
separate DMC Charter. 
Effectiveness: 
Effectiveness will be evaluated by the number of angioedema attacks and related details (timing, duration of 
symptoms, anatomical location, treatment), number of days with angioedema symptoms, assessment of attack 
severity, discontinuations due to lack of efficacy (through Week 48), and number of hospitalizations and clinic 
visits.  
Patient Reported Outcomes/Quality of Life: 
QoL will be assessed using the AE-QoL questionnaire and subject’s satisfaction with their medication using the 
TSQM. The number of days lost from school and/or work will also be assessed. 
Statistical methods: 
Analysis of Safety: Safety endpoints will be summarized by treatment group and will include the proportion of 
subjects: with treatment-emergent AEs (TEAEs); who discontinue due to a TEAE; who experience a 
treatment-emergent serious adverse event (SAE); who experience a Grade 3 or 4 TEAE; who experience a 
treatment-emergent, treatment-related AE consistent with a drug rash (eg, maculopapular rash, papular rash); and 
who experience Grade 3 or 4 laboratory abnormalities.  
AEs will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) and 
system organ classification (SOC). The occurrence of TEAEs will be summarized using MedDRA PT, SOC, and 
severity. In addition to severity, AEs and SAEs will be summarized based on  Investigator assessment of 
relationship to study drug.  
Time to discontinuation due to a TEAE and time to development of drug-related  Investigator-identified rash 
event of special interest (EOSI) will be estimated using the Kaplan-Meier method. For subjects with a 
drug-related  Investigator-identified rash EOSI, clinical and laboratory findings will be summarized as well as the 
proportion of subjects who successfully continued therapy following onset of rash. 
Descriptive statistics for vital signs, weight, and clinical laboratory results will be presented by study visit. 
Laboratory abnormalities will be graded and flagged automatically with a reference range scale. The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized. Laboratory 
toxicity shifts from baseline to the worst post-baseline value as well as the last visit will be summarized. The 
number and percentage of subjects who have elevations in ALT, AST, or bilirubin abnormalities in relation to 
fold above ULN will be summarized according to the US Food and Drug Administration’s Premarketing Clinical 
Evaluation on Drug-Induced Liver Injury Guidance for Industry. 
Clinically significant abnormal ECG findings will be summarized by study visit. Changes from baseline in ECG 
parameters will also be summarized by study visit. The number and proportion of subjects with clinically 
important absolute and change from baseline thresholds in QTcF will be summarized.  
Analysis of Effectiveness: Effectiveness endpoints will be analyzed by treatment group and will include 
angioedema attack rate, durability of response, number and proportion of days with angioedema symptoms, 
angioedema attack medication administrations, discontinuations due to lack of efficacy, and disease severity. The 
durability of response assessment will be based on attack rate trend over time.  
Additional related details of HAE attacks (e.g., symptoms, anatomical location, hospitalizations, emergency room 
visits, attack severity, attack duration) and number of days lost from work and/or school due to attacks will be 
listed and summarized using descriptive statistics. 
No formal tests of hypotheses will be conducted. 
Quality of Life Analyses: The baseline, follow-up, and change from baseline in the domain scores of the 
AE-QoL as well as the composite score of each instrument will be calculated and summarized by treatment 
group. Individual items will be analyzed to understand their contribution to the domain sub-scores. A TSQM 
global satisfaction score will be calculated as validated. Data on the global score as well as relevant subscales 
will be listed and summarized.  
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ..............................................................................................................1 
1.1. 
Protocol Approval Signature Page ................................................................................4 
1.2. 
Clinical Study Protocol Agreement ..............................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Background .................................................................................................................19 
5.2. 
Findings for BCX7353 ...............................................................................................19 
5.2.1. 
Summary of Study BCX7353-302 ..............................................................................19 
5.2.2. 
Summary of Interim Data of BCX7353-204 (Current Study) ....................................21 
5.3. 
Data Monitoring Committee Review of Ongoing Studies BCX7353-302, 
BCX7353-301 and BCX7353-204 .............................................................................25 
5.4. 
Rationale for Study .....................................................................................................25 
5.4.1. 
Rationale for Study Design .........................................................................................26 
5.4.2. 
Rationale for Study Drug Doses and Regimens .........................................................26 
5.4.3. 
Study Population Rationale ........................................................................................27 
5.4.4. 
Rationale for Allowance and Restriction of Concomitant Medications for 
HAE ............................................................................................................................28 
5.5. 
BCX7353 Risk/Benefit Analysis ................................................................................28 
5.6. 
Benefits of Trial Participation ....................................................................................29 
5.7. 
Overall Benefit-Risk Assessment ...............................................................................29 
6. 
TRIAL OBJECTIVES ................................................................................................29 
6.1. 
Objectives ...................................................................................................................29 
6.1.1. 
Primary Objective .......................................................................................................29 
6.1.2. 
Secondary Objectives .................................................................................................29 
7. 
OVERALL STUDY DESIGN AND PLAN ...............................................................30 
7.1. 
Endpoints ....................................................................................................................31 
7.1.1. 
Safety Endpoints .........................................................................................................31 


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7.1.2. 
Effectiveness Endpoints ..............................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
8.1. 
Number of Subjects ....................................................................................................32 
8.2. 
Subject Selection ........................................................................................................32 
8.2.1. 
Inclusion Criteria ........................................................................................................32 
8.2.2. 
Exclusion Criteria .......................................................................................................33 
8.3. 
Subject Discontinuation from the Study and from Study Drug ..................................34 
8.3.1. 
Subject Discontinuation from the Study .....................................................................34 
8.3.2. 
Subject Discontinuation from Study Drug .................................................................35 
9. 
TREATMENT OF SUBJECTS ..................................................................................36 
9.1. 
Description of Study Drug and Study Drug Product ..................................................36 
9.2. 
Description of Study Drug Packaging, Labeling, and Storage ...................................36 
9.3. 
Treatment Allocation and Study Drug Blinding .........................................................36 
9.4. 
Study Drug Administration and Treatment Compliance ............................................37 
9.5. 
Study Drug Dose Modification ...................................................................................37 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability ...............................37 
9.7. 
Concomitant Medications ...........................................................................................37 
9.7.1. 
Prohibited Medications ...............................................................................................38 
10. 
STUDY CONDUCT ...................................................................................................39 
10.1. 
Overview .....................................................................................................................39 
10.2. 
Schedule of Assessments ............................................................................................39 
10.3. 
Study Visits .................................................................................................................43 
10.3.1. 
Screening Visit ............................................................................................................43 
10.3.2. 
Baseline Visit (Day 1) ................................................................................................43 
10.3.3. 
Week 4 Visit ...............................................................................................................43 
10.3.4. 
Week 12, 24, 48, 72, and 96 Visits .............................................................................44 
10.3.5. 
End of Study Visit ......................................................................................................44 
11. 
ASSESSMENTS.........................................................................................................44 
11.1. 
Investigator-Completed Assessments .........................................................................44 
11.1.1. 
HAE Medical and Medication History .......................................................................45 
11.1.2. 
Physical Examination .................................................................................................45 
11.1.3. 
Weight/Body Mass Index ...........................................................................................45 
11.1.4. 
12-lead Electrocardiograms ........................................................................................45 


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11.1.5. 
Vital Signs ..................................................................................................................45 
11.1.6. 
Clinical Laboratory Evaluations .................................................................................46 
11.1.7. 
Screening for Human Immu nodeficiency Virus, Hepatitis B, and Hepatitis 
Serology ......................................................................................................................48 
11.1.8. 
Pregnancy Testing and Follicle-Stimulating Hormone ..............................................48 
11.1.9. 
HAE Diagnostic Criteria .............................................................................................48 
11.1.10. 
Other Laboratory Assessments ...................................................................................48 
11.1.11. 
Pharmacogenomic Testing ..........................................................................................49 
11.1.12. 
Rash Assessment ........................................................................................................49 
11.2. 
Subject-Completed Assessments ................................................................................50 
11.2.1. 
Patient-Reported Outcomes ........................................................................................50 
11.2.2. 
HAE Attack and Dosing Diary ...................................................................................50 
12. 
ADVERSE EVENT MANAGEMENT AND REPORTING .....................................51 
12.1. 
Adverse Events ...........................................................................................................51 
12.1.1. 
Definitions ..................................................................................................................51 
12.1.1.1. 
Adverse Event .............................................................................................................51 
12.1.1.2. 
Serious Adverse Event ................................................................................................52 
12.1.1.3. 
Adverse Events of Special Interest .............................................................................53 
12.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events .............................................................................53 
12.1.3. 
Definition of Severity .................................................................................................54 
12.1.4. 
Definition of Relationship to Study Drug ...................................................................54 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................55 
12.1.5.1. 
Reporting Events of Special Interest ..........................................................................56 
12.1.6. 
Pregnancy ...................................................................................................................56 
12.1.7. 
Serious Breaches of Good Clinical Practice ...............................................................57 
12.1.8. 
Treatment Interruptions ..............................................................................................57 
12.2. 
Toxicity Management .................................................................................................57 
12.2.1. 
Rash ............................................................................................................................57 
12.2.1.1. 
Study Drug Administration for Grade 1 or 2 Rashes Considered Related to 
Study Drug ..................................................................................................................58 
12.2.2. 
Aminotransferase (ALT or AST) Elevation ...............................................................58 
12.2.3. 
Overdose .....................................................................................................................59 


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12.3. 
Data Monitoring Committee .......................................................................................59 
13. 
STATISTICS ..............................................................................................................59 
13.1. 
Sample Size Considerations .......................................................................................60 
13.2. 
Stratification ...............................................................................................................60 
13.3. 
Statistical Methods ......................................................................................................60 
13.3.1. 
Analysis Populations ..................................................................................................60 
13.3.1.1. 
Screen Failures ............................................................................................................60 
13.3.1.2. 
Safety Population ........................................................................................................60 
13.3.1.3. 
Intent-to-Treat Population ..........................................................................................60 
13.3.2. 
General Considerations for Data Analysis .................................................................60 
13.3.3. 
Missing Data ...............................................................................................................61 
13.3.4. 
Subject Demographic and Disposition Data ...............................................................61 
13.3.5. 
Analysis of Safety Variables ......................................................................................61 
13.3.6. 
Analysis of Effectiveness Variables ...........................................................................62 
13.3.7. 
Interim and Final Analyses .........................................................................................63 
13.3.8. 
Quality of Life Analyses .............................................................................................63 
14. 
STUDY ADMINISTRATION ...................................................................................63 
14.1. 
Regulatory and Ethical Considerations ......................................................................63 
14.1.1. 
Regulatory Authority Approvals ................................................................................63 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals ...................................63 
14.1.3. 
Subject Informed Consent: Adults ..............................................................................64 
14.1.4. 
Subjects Informed Consent: Adolescents ...................................................................64 
14.1.5. 
Investigator Reporting Requirements .........................................................................65 
14.2. 
Study Monitoring ........................................................................................................65 
14.3. 
Quality Assurance .......................................................................................................65 
14.4. 
Study Termination and Site Closure ...........................................................................66 
14.5. 
Records Retention .......................................................................................................66 
14.6. 
Confidentiality of Information and Data ....................................................................67 
14.7. 
Study Publication ........................................................................................................67 
15. 
REFERENCES ...........................................................................................................68 
16. 
APPENDICES ............................................................................................................70 
16.1. 
DMID Adult Toxicity Table (DRAFT, Publish Date: November 2007) ....................70 
 


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LIST OF TABLES 
Table 1. 
Abbreviations and specialist terms .............................................................................16 
Table 2. 
Recommended Strategies for Switching to BCX7353 Prophylaxis from 
Another Therapy .........................................................................................................38 
Table 3. 
Schedule of Assessments: Study BCX7353-204 ........................................................40 
Table 4. 
Clinical Laboratory Evaluations .................................................................................47 


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LIST OF FIGURES 
Figure 1. 
Study Schema .............................................................................................................31 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1. 
Abbreviations and specialist terms 
Abbreviation  
Explanation 
ABW 
absolute body weight 
ACR 
spot urine microalbumin to creatinine ratio 
AE 
adverse event 
AE-QoL 
angioedema quality of life questionnaire 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the concentration vs. time curve 
AUCinf 
area under the concentration vs. time curve extrapolated to infinite time 
AUClast 
area under the concentration vs. time curve from time 0 to the last measurable 
concentration  
AUCtau 
area under the plasma concentration versus time curve over the dosing interval (tau) 
BCRP 
breast cancer resistance protein  
BK 
bradykinin 
BMI 
body mass index 
BMP 
di-docosahexaenoyl (22:6)- Bis(mono)acylglycerol phosphate 
C1-INH 
C1 esterase inhibitor 
CK 
creatine kinase 
Cmax 
maximum plasma concentration of the drug 
CRF 
case report form 
CRA 
clinical research associate 
CSR 
clinical study report 
Ctau 
observed drug concentration at the end of the dosing interval (tau) 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLCO 
diffusion capacity for carbon monoxide 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases 
ECxx 
concentration that elicits xx% response 
ECG 
electrocardiogram 
EOSI 
event of special interest  
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltranspeptidase 
GI 
gastrointestinal  
HAE 
hereditary angioedema 
HBV 
hepatitis B virus 


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Abbreviation  
Explanation 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HK 
high-molecular weight kininogen 
HLA 
human leukocyte antigen 
IB 
 Investigator’s brochure 
ICxx 
xx% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent to treat 
IUD 
intrauterine device 
IUS 
intrauterine system  
IV 
intravenous 
IXRS 
interactive (web or voice) response system  
LFT 
liver function test 
LLN 
lower limit of normal 
MATE 
multidrug toxin extrusion protein  
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein efflux pump 
PKK 
prekallikrein 
PLD 
phospholipidosis 
PR 
electrocardiographic interval occurring between the onset of the P wave and the QRS complex, 
representing time for atrial and ventricular depolarization, respectively 
PT 
preferred term 
QD 
once daily  
QoL 
quality of life 
QRS 
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave, representing the time for ventricular depolarization 
QT 
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur 
QTc 
corrected QT interval 
QTcF 
QT interval corrected by Fridericia's formula 
R 
correlation coefficient 
RR 
interval between successive heart beats using the R-wave peaks 
SAE 
serious adverse event 


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Abbreviation  
Explanation 
SAP 
statistical analysis plan 
SJS 
Stevens Johnson syndrome 
SOC 
system organ classification 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TpTe 
T peak to T end 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
US 
United States 


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5. 
INTRODUCTION 
5.1. 
Background 
Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is an autosomal 
dominant disorder characterized by recurrent episodes of swelling of the skin, pharynx, larynx, 
gastrointestinal (GI) tract, genitals, and extremities (Longhurst and Cicardi 2012). The frequency 
of attacks varies between subjects, from rarely in some patients to every few days in others. 
Angioedema attacks may or may not be precipitated by a stimulus (such as stress, trauma, or 
estrogen) and are typically rapid in onset, with symptoms subsiding gradually over the following 
3 to 5 days (Zuraw and Christiansen 2011). Oropharyngeal swelling can be life-threatening 
(Bork, Hardt et al. 2012), while attacks in other sites, including limbs, genitalia, face and 
intestines, can be painful, disabling, and disfiguring, and have a significant impact on 
functionality and quality of life (QoL) (Lumry, Castaldo et al. 2010). Although mortality risk 
from asphyxiation is much higher in undiagnosed patients with HAE, deaths still occur in 
diagnosed patients with access to care at centers of excellence (Bork, Hardt et al. 2012). 
Extensive evidence from animal models and clinical studies supports the role of bradykinin (BK) 
as the principal mediator of the signs and symptoms that characterize attacks of HAE (Kaplan 
2010, Zuraw and Christiansen 2011). Plasma kallikrein is a serine protease integral to the contact 
activation pathway (Saxena, Thompson et al. 2011). Kallikrein circulates in plasma as a 
zymogen, prekallikrein (PKK), bound to one of its main substrates, high-molecular-weight 
kininogen (HK). During contact activation, PKK is cleaved by activated factor XII, forming the 
active protease kallikrein. Kallikrein in turn cleaves HK, producing BK (Kaplan and 
Ghebrehiwet 2010). The activation of the BK B2 receptor by BK ultimately results in 
vasodilatation, increased vascular permeability, and smooth muscle contraction, all of which lead 
to the tissue swelling that characterizes HAE (Kaplan 2010).  
BCX7353 is a potent, synthetic, second-generation small molecule inhibitor of plasma kallikrein. 
In contrast to parenterally administered options commercially available for prophylaxis against 
HAE attacks, inhibition of kallikrein with an orally bioavailable small molecule such as 
BCX7353 offers the advantage of oral administration. 
5.2. 
Findings for BCX7353 
The principal results of non-clinical, clinical pharmacology, PK, clinical safety and efficacy 
studies of BCX7353 are described in the BCX7353  Investigator's brochure (IB).  
Two Phase 3 studies, BCX7353-301 and BCX7353-302, are ongoing but have results reported 
for the primary analysis.  Study BCX7353-302 Part 1 results are summarized below. Study 
BCX7353-301 had a safety profile and similar efficacy as Study BCX7353-302 and will not be 
individually discussed below. 
5.2.1. 
Summary of Study BCX7353-302 
BCX7353-302 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part 
study in subjects with Type I or II HAE. The primary objective of Part 1 of the study was to 
determine the efficacy of prophylactic BCX7353 150 and 110 mg administered orally once daily 
(QD) for 24 weeks compared to placebo in subjects with HAE. Part 3 is ongoing.  


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In Part 2, all subjects received active treatment with BCX7353 from Weeks 25 through 48, and 
Part 3 of the study extends treatment with BCX7353 through 96 weeks. Results for Part 1 are 
summarized herein.  
Overall, a total of 160 subjects were screened, 121 subjects were randomized (stratified by 
baseline attack rate, < 2 vs. ≥ 2 per 28 days), and 120 randomized subjects (99%) were treated. 
Of these, 108 subjects completed 24 weeks of study drug dosing in Part 1: 37 of 40 BCX7353 
150 mg subjects (93%), 37 of 41 BCX7353 110 mg subjects (90%), and 34 of 39 placebo 
subjects (87%). 
The mean baseline rate was 2.98 attacks per month. The majority of subjects (70%) had  
≥ 2 attacks per month at baseline, and the attack frequency was generally well distributed across 
the 3 treatment groups. 
The primary efficacy endpoint was the rate of  Investigator-confirmed HAE attacks during 
dosing in the entire 24-week treatment period. This study achieved its primary endpoint for both 
dose levels, with the 150 and 110 mg doses reducing HAE attacks by 44% (p < 0.001) and 
30% (p = 0.024), respectively, vs. placebo. The attack rate per 28 days over the 24-week Part 1 
dosing period was 1.31 for BCX7353 subjects on 150 mg QD, 1.65 for BCX7353 subjects on 
110 mg QD, and 2.35 for placebo subjects. These results were supported by sensitivity analyses 
and were consistent in subgroup analyses. Effects of BCX7353 in reducing attack rate were 
evident in the first 4 weeks and stable over the entire 24-week duration of Part 1. 
Secondary endpoints (change from baseline in the angioedema quality of life questionnaire 
[AE-QoL], number and proportion of days with angioedema symptoms, and rate of  
Investigator-confirmed HAE attacks during the effective dosing period [beginning on Day 8 
through Week 24]) were analyzed using hierarchical testing. Results for the first secondary 
endpoint, AE-QoL, were not statistically significant vs. placebo for either treatment group; 
therefore, inferential statistical testing was not performed on the descending secondary efficacy 
endpoints. 
BCX7353 significantly reduced the use of standard of care acute attack medication per 28 days 
vs. placebo by 53.6% (p < 0.001) for 150 mg and 46.3% (p < 0.001) for 110 mg. In responder 
analyses, 58%, 50%, and 23% of subjects receiving 150 mg BCX7353 had a ≥ 50%, ≥ 70% or 
≥ 90% reduction in their HAE attack rates compared to baseline vs. 25%, 15%, and 8% of 
placebo subjects, p = 0.005, p = 0.002, and p = 0.073 respectively.  
Administration of BCX7353 at doses of 150 and 110 mg QD for 24 weeks was safe and 
generally well tolerated. 
Overall 81.7% of subjects experienced a treatment-emergent adverse event (TEAE) on study: 
85.0% of 150 mg subjects, 82.9% of 110 mg subjects, and 76.9% of placebo subjects; 39.5% of 
BCX7353-treated subjects and 33.3% of placebo subjects experienced a drug-related TEAE. 
Five subjects discontinued study drug due to TEAEs: 1 (2.5%) on 150 mg, 3 (7.3%) on 110 mg, 
and 1 (2.6%) on placebo. No subjects on 150 mg, 1 subject on 110 mg (2.4%), and 3 subjects on 
placebo (7.7%) experienced serious adverse events (SAEs) on study; none of these events were 
drug related. All drug-related TEAEs were mild to moderate on placebo and in the 150 mg 
group, and the majority of TEAEs in the 110 mg group were mild to moderate; 3/41 (7.3%) 
110-mg subjects experienced Grade 3 drug-related TEAEs. Few subjects had treatment-emergent 
Grade 3 or 4 laboratory abnormalities. One subject on 150 mg BCX7353 who had previously 


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been exposed to androgens had Grade 4 alanine aminotransferase (ALT) elevation and Grade 3 
aspartate aminotransferase (AST) elevation without symptoms, which resolved after 
discontinuing study drug. 
The most common TEAEs across all arms were nasopharyngitis, nausea, and vomiting. Overall, 
50.0% and 41.5% of BCX7353 150 and 110 mg subjects, respectively, had gastrointestinal (GI) 
abdominal-associated TEAEs vs. 35.9% of placebo subjects. There were no drug-related rashes  
(events of special interest [EOSI]). 
Orally administered BCX7353 was a generally safe, well-tolerated, and effective treatment for 
the prevention of HAE attacks in Part 1 of this study, with better efficacy at the 150 mg dose 
compared to the 110 mg dose, and no increase in safety risk. 
5.2.2. 
Summary of Interim Data of BCX7353-204 (Current Study) 
An interim analysis of this current study has been completed.  As of the cut-off date of 
20 August 2019, a total of 100 and 127 subjects were treated with BCX7353 110 and 150 mg, 
respectively and were enrolled across 49 sites in 22 different countries in North America, 
Europe, Asia, Australia, and Africa. Of the 227 subjects treated with study drug, 103 subjects 
have completed dosing through Week 48 (30 subjects on BCX7353 110 mg and 73 subjects on 
BCX7353 150 mg).  
Of the 100 subjects initially allocated to BCX7353 110 mg, 22 subjects completed Week 48 
and have transitioned to BCX7353 150 mg; however, none of these subjects have data available 
from a regularly-scheduled study visit after transitioning to the BCX7353 150 mg dose since 
visits occur only on a quarterly basis. A total of 30 subjects reported 5 TEAEs after switching 
from BCX7353 110 to 150 mg; all 5 events were assessed by the  Investigator as not related to 
study drug.  
Except for race and ethnicity, the safety population was generally quite diverse. The mean age 
was 40.3 years (range 12 to 72 years), and most subjects were white (84.6%) and non-
Hispanic (93.0%). Overall 10 adolescent subjects (4.4%) ≥12 to 17 years of age and 5 elderly 
subjects (2.2%) ≥ 65 years of age were enrolled in the study.  
Overall, oral treatment with BCX7353 150 and 110 mg QD was safe and generally well 
tolerated. No new safety signals were identified, safety risks were consistent with the risks 
previously noted in the Phase 2 proof-of-concept Study 203 and consistent with safety seen in 
the Phase 3 pivotal Study 302 and the Phase 3 Study 301 conducted in Japan. Across both dose 
groups the mean (range) exposure to study drug was 282.7 (11 to 540) days. Safety monitoring 
revealed no cardiac, renal, hematologic or neurologic safety concerns.  Vital signs and ECG 
findings during the course of the study were unremarkable and consistent with normal 
variability. 
Fifty-nine subjects (26.0%) prematurely discontinued study drug; 57 subjects (25.1%) 
discontinued study drug before 48 weeks of dosing. The most common reasons for 
discontinuation of study drug were perceived lack of efficacy (12.3%) and laboratory 
abnormalities or TEAEs (8.4%). Overall, more subjects treated with BCX7353 110 mg 
compared to BCX7353 150 mg discontinued study drug due to perceived lack of efficacy; 17 of 
100 subjects (17.0%) vs. 11 of 127 subjects (8.7%). Overall, 19 subjects (8.4%) discontinued 
study drug due to TEAEs; 6 (6.0%) and 13 subjects (10.2%) in the BCX7353 110 and 150 mg 


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dose groups, respectively. TEAEs leading to discontinuation in > 1 subject were ALT increased 
(4 subjects [1.8%]), upper abdominal pain (3 subjects [1.3%]), vomiting (2 subjects [0.9%]), 
AST increased (2 subjects [0.9%]), hepatic enzyme increased (2 subjects [0.9%]), and liver 
function test (LFT) abnormal (2 subjects [0.9%]).  
The majority of subjects (91.0% and 90.6% of subjects in the BCX7353 110 and 150 mg dose 
groups, respectively) had at least 1 TEAE during the study. There was no effect of dose on the 
incidence of AEs. Overall, the most frequently reported TEAEs were nasopharyngitis (30.8%), 
headache (17.6%), abdominal pain (13.2%), and diarrhea (13.2%).   
Long term prior androgen use of ≥ 5 years and discontinuation of androgens within 2 weeks 
of BCX7353 initiation were correlated with a higher subject incidence of liver-related TEAEs, 
but not other types of TEAEs. Subjects who discontinued androgens in the 2 weeks prior to 
initiating BCX7353 (n = 40) experienced liver-related TEAEs in the investigations SOC more 
frequently than subjects who discontinued androgens ≥ 2 weeks before 
initiating BCX7353 (n = 113) or those subjects who had never used androgens (n = 74). In these 
groups, ALT increased, 25.0% vs. 2.7% and 1.4%, respectively; AST increased 17.5% vs. 2.7% 
and 1.4%, respectively; hepatic enzyme increased, 2.5% vs. 0.9% and 0, respectively; LFT 
abnormal, 5.0% vs. 0 and 0; and transaminase increased, 2.5% vs. 0 and 0.  
Overall, 49.8% of subjects had at least 1 TEAE assessed as drug-related by the  Investigator (ie, 
TEAEs possibly, probably, or definitely related to study drug). Most TEAEs were Grade 1 (mild) 
or Grade 2 (moderate) in severity. Overall, 15.0% of subjects experienced a Grade 3 or Grade 4 
TEAE. The most common Grade 3 or Grade 4 TEAEs were HAE (attacks) (3.5%), ALT 
increased (2.6%), hepatic enzyme increased (0.9%), LFT abnormal (0.9%), and pneumonia 
(0.9%). All other Grade 3 or Grade 4 TEAEs occurred in 1 subject each. Overall, long term prior 
androgen use of ≥ 5 years and discontinuation of androgens within 2 weeks 
of BCX7353 initiation was correlated with a higher frequency of Grade 3 or Grade 4 liver-related 
TEAEs.    
Overall, 13.2% of subjects experienced a treatment-emergent SAE. Treatment-emergent SAEs 
that occurred in > 1 subject were HAE attacks (12 subjects [5.3%]) and medical observation 
(3 subjects [1.3%]). Three subjects (1.3%) experienced 4 treatment emergent SAEs assessed by 
the  Investigator as related to study drug; G3 gastroenteritis and Grade 2 hepatic enzyme 
increased (n = 1), G3 abnormal LFT (n = 1), and G3 abdominal pain (n = 1). The 2 subjects 
with the treatment-emergent SAEs of gastroenteritis, hepatic enzyme increased, and abnormal 
LFT discontinued study drug. No subjects experienced a TEAE that led to death. 
Overall, 27 subjects (11.9%) interrupted study drug due to TEAEs. The most common TEAE 
that led to study drug interruption was HAE (attack) in 5 subjects (2.2%). Overall, TEAEs in the 
GI SOC led to study drug interruption in the greatest number of subjects; 8 subjects (6.3%) 
treated with BCX7353 150 mg and 2 subjects (2.0%) treated with BCX7353 110 mg. Overall, 
6 subjects (2.6%) discontinued study drug due to a GI TEAE; 2 subjects (2.0%) and 4 subjects 
(3.1%) in the BCX7353 110 and 150 mg dose groups, respectively.   
For this study, nonserious treatment-emergent rashes were considered EOSIs for  Investigator 
reporting purposes. Overall, 8 subjects (3.5%) had rash EOSIs assessed by the  Investigator as 
related to study drug but these rashes included non-specific urticaria and brief episodes of 
erythema. A total of 2 rash events were assessed by the Sponsor medical officer as likely related 


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to BCX7353 and consistent with delayed-type drug hypersensitivity, i.e. a diffuse maculo-
papular rash with pruritus but no systemic or mucosal symptoms. These rashes were consistent 
with those reported in prior studies, resolving quickly with no reoccurrence with study drug 
continuation or re-initiation (if drug was held).  
GI events were considered AEs of interest; however, they were not considered EOSIs for  
Investigator reporting purposes. Overall, 105 subjects (46.3%) experienced a GI abdominal 
TEAE and 6 subjects (2.6%) discontinued due to a GI abdominal event. The most common GI 
abdominal TEAEs were diarrhea (13.2%), abdominal pain (13.2%), and nausea (7.9%). No dose 
response was observed. Most events were Grade 1 or Grade 2 in severity. Two subjects (0.9%) 
experienced 3 serious GI abdominal events, abdominal pain in 1 subject and diarrhea and 
vomiting in the other subject. The event of abdominal pain was assessed as related to study drug 
but the diarrhea and vomiting were not because there was another more plausible etiology.   
The most common clinically significant chemistry abnormalities were liver-related 
abnormalities, and the most common abnormality was ALT increased. The majority 
of treatment-emergent liver abnormalities were Grade 1 or 2; however, 13 subjects (5.7%) 
experienced a treatment-emergent Grade 3 or 4 ALT laboratory abnormality, and all of these 
subjects had previously used androgens. All but 1 subject with a Grade 3 or 4 ALT stopped 
androgens 7 to 9 days from first dose of BCX7353; 1 subject stopped androgens < 2 months from 
the first dose of BCX7353. No subject had synthetic dysfunction or evidence of hepatitis. 
Subjects were mostly asymptomatic, although a few subjects had abdominal symptoms that 
overlapped with the GI symptoms reported with BCX7353 treatment; no subject had signs or 
symptoms of acute hepatitis. The Grade 3 or 4 ALT elevations in the 13 subjects were primarily 
laboratory abnormalities without clinical symptoms. All 13 subjects improved or 
recovered, 5 subjects while continuing on BCX7353; 2 subjects subsequently discontinued study 
drug for unrelated reasons (perceived lack of efficacy in both subjects). A total of 15 subjects had 
postbaseline ALT > 3 × upper limit of normal (ULN; 2 subjects with nontreatment emergent 
ALT values). Of the subjects who had stopped androgens within the previous 2 weeks before 
initiating BCX7353, the incidence of subjects with ALT > 3 × ULN was 32.5%. Of the subjects 
with ≥ 5 years of androgen use, the incidence of subjects with ALT > 3 × ULN was 13.0%. 
One subject had a bilirubin > 1.5 × ULN although no subject had a Grade 3 or Grade 4 bilirubin, 
and no subject had a concurrent elevation in bilirubin > 1.5 × ULN and ALT or AST > 3 × ULN. 
No subject met the criteria for Hy’s law during the study.   
In summary, BCX7353 was safe and generally well tolerated with no new safety signals 
observed. 
Subjects treated with BCX7353 110 or 150 mg QD had durably low attack rates, with no 
evidence for the development of tolerance to BCX7353. After 1 month of treatment, the 73 
subjects in the BCX7353 150 mg dose group who received BCX7353 through Week 48 had a 
mean (SD) attack rate of 1.18 (1.40) attacks per month. The mean rate of attacks held relatively 
steady during Months 2 to 12: 1.01 (1.26) attacks per month in Month 6 and 0.81 (1.03) attack 
per month in Month 12.  
The proportion of days with angioedema symptoms was generally similar for both dose groups 
and declined over time: during Month 1 the median proportion of days with symptoms was 7.1%; 
during Month 6 the median proportion of days with symptoms was 3.6%; and during Month 12 
the median proportion of days with symptoms was 0.0%.   


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During the first 24 weeks of study, 22 subjects (9.8%) treated with BCX7353 remained attack 
free, with slightly more subjects in the BCX7353 150 mg group (11.2%) remaining attack free 
compared with the BCX7353 110 mg dose group (8.0%). During the first 48 weeks of study, 
8 subjects (5.0%) treated with BCX7353 remained attack free, with slightly more subjects in 
the BCX7353 150 mg group (5.8%) remaining attack free compared with the BCX7353 110 mg 
dose group (3.6%).  
A total of 28 of 227 subjects (12.3%) discontinued treatment in the first 48 weeks of the study 
due to perceived lack of efficacy, with fewer subjects discontinuing treatment in 
the BCX7353 150 mg dose group compared to the 110 mg dose group (11 [8.7%] vs. 17 
[17.0%], respectively). Twenty of the 28 subjects who discontinued study drug due to a 
perceived lack of efficacy discontinued prior to Week 12. The proportions of subjects who 
discontinued BCX7353 due to a perceived lack of efficacy was higher for those subjects who had 
reported either that they had discontinued androgen use < 2 weeks prior to their first dose 
of BCX7353 (20.0%) or had used androgens for ≥ 10 years (18.2%), compared to subjects who 
had never used androgens (12.2%). Twelve of the 28 (42.9%) subjects who 
discontinued BCX7353 due to a perceived lack of efficacy had used androgen therapy for ≥ 10 
years before their first dose of BCX7353. Eight of the 28 (28.6%) subjects who 
discontinued BCX7353 due to a perceived lack of efficacy and had discontinued androgen 
therapy < 2 weeks before their first dose of BCX7353.  
The median duration of an attack was shorter for subjects treated with BCX7353 150 mg vs. 
110 mg (median of 17.7 vs. 28.0 hours). This difference was independent of attack location 
(ie, abdominal-only, peripheral-only, and mixed).   
Overall, subjects assessed about 34% of their attacks as negligible or mild in severity with 
approximately 60% of attacks resulting in no restriction or a slight restriction of daily activities. 
Overall, approximately 61% of attacks had no or a slight effect on the subject’s appearance. 
There were no notable differences between the dose groups.  
Of the on-study adjusted attacks, 85.4% were treated with any medication and 81.6% with SOC-
Rx. The most commonly used SOC-Rx were Berinert and Firazyr. There were no notable 
differences between the dose groups.  
Subject reported outcomes were assessed serially using the AE-QoL and TSQM questionnaires 
administered at study visits. MCID improvements (≥ 6 point improvement) in mean change from 
baseline AE-QoL total and all domain scores were observed at Week 4: an improvement of 8.9 
(19.0) and 11.2 (17.2) points from baseline in mean (SD) AE-QoL total score for the 110 and 
150 mg dose groups, respectively. The observed improvement in AE-QoL was durable, holding 
steady or further improving at all subsequent assessments; for example, at Week 48, the mean 
(SD) change from baseline improvements in AE-QoL total score were 12.8 (16.0) and 14.7 
(17.8) points for the 110 and 150 mg dose groups, respectively. Greater than MCID mean (SD) 
improvements in change from baseline were observed at Week 48 for the domains: functioning, 
16.1 (26.5) point improvement; fatigue/mood, 9.3 (19.0) point improvement; fear/shame, 19.9 
(22.2) point improvement; and nutrition, 9.4 (20.6) point improvement.  
The TSQM scores improved from baseline (assessment of the subject’s usual medication prior to 
starting BCX7353) to Week 48 on BCX7353 with mean (SD) change from baseline 


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improvements of 20.5 (24.7) points in convenience, 7.7 (24.2) points in side effects, 7.2 (29.6) 
points in effectiveness, and 3.6 (28.8) points in global satisfaction.   
In summary, subjects had low rates of attacks during the first month of treatment 
with BCX7353 that were maintained or improved over the 48 weeks. Subjects treated with     
150 mg of BCX7353 had a median of 6.5% of study days with angioedema symptoms, assessed 
about 36% of their attacks as negligible or mild in severity, assessed approximately 64% of 
attacks as resulting in no restriction or a slight restriction of daily activities, and assessed 
approximately 63% of attacks as having no or a slight effect on appearance. Attacks were 
generally shorter in duration for subjects treated with BCX7353 150 mg compared 
to BCX7353 110 mg, and BCX7353 150 mg QD also improved measures of QoL compared with 
baseline: at Week 48 a mean improvement > MCID in AE-QoL total score and functioning, 
fatigue/mood, fears/shame, and nutrition domain scores was observed along with improvements 
in all TSQM scores.  
5.3. 
Data Monitoring Committee Review of Ongoing 
Studies BCX7353-302, BCX7353-301 and BCX7353-204 
Data from ongoing studies BCX7353-302 (Phase 3 study), BCX7353-301 (Phase 3 study) and 
the current study, BCX7353-204, are reviewed by the BCX7353 data monitoring committee 
(DMC) at protocol-specified intervals. The DMC may also be convened  if a new clinically 
significant safety signal emerges or at other times as requested. 
The latest data review was conducted on 23 October 2019.   
The recommendation of the DMC was that all 3 studies proceed per protocol. 
5.4. 
Rationale for Study 
Currently, prophylactic treatments approved in most of the world for prevention of angioedema 
attacks in HAE are oral androgens and parenteral C1-INH therapies. In addition, the monoclonal 
antibody lanadelumab was recently approved as prophylactic therapy in some countries. While 
patient experience has improved with the expansion of approved therapies for HAE, an orphan 
disease, a 2013 survey of 245 United States (US) physicians that treat HAE indicated that their 
perception is that only 40% of their patients are fully satisfied with current HAE treatments 
(Aygoren-Pursun, Bygum et al. 2018). Regular IV infusions of C1-INH for prophylactic use in 
HAE may lead to an increase in complications over time, such as thrombosis, infection, pain, and 
limited venous access (Shire 2018). Even patients with HAE with no contraindications to 
androgens and who tolerate prophylactic androgens face long-term risks with continued 
treatment. Therefore, there remains a significant medical need to provide additional HAE 
treatment options that are efficacious, convenient, and well-tolerated. 
BCX7353 is an oral kallikrein inhibitor in development for prophylaxis of HAE Type I and II. 
BCX7353 has activity against plasma kallikrein at low nM concentrations that are attainable and 
sustained in humans following oral administration. In both the randomized, double blind, 24-
week, placebo-controlled Phase 3 study (BCX7353-302) and the proof-of-concept, 28-day, 
placebo-controlled, Phase 2 study (BCX7353-203), the rate of angioedema attacks in subjects 
randomized to BCX7353 was statistically significantly lower than in placebo subjects and 
BCX7353 was safe and generally well-tolerated. Subjects with HAE who have not previously 


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received BCX7353 will be offered the opportunity to participate in this study when, in the 
opinion of the  Investigator, they are expected to derive benefit from an oral treatment to prevent 
angioedema attacks. 
5.4.1. 
Rationale for Study Design  
This open-label safety study is designed to assess the long-term safety and effectiveness of 
1 dose level (150 mg QD) of BCX7353 in subjects who do not currently use prophylactic 
therapies and in subjects who are switching from other prophylactic therapies to BCX7353. This 
study offers subjects access to BCX7353 treatment for up to 96 weeks, until the product becomes 
commercially available, or until the Sponsor discontinues development of the product for the 
prevention of angioedema attacks, whichever comes first. This study will provide additional 
information on the long-term safety and effectiveness of the planned dose (150 mg QD) in US 
subjects. 
While there are approved therapies in many countries for prophylaxis against HAE attacks, 
including C1-INH infused intravenously or administered subcutaneously, the majority of patients 
globally are not being treated with prophylactic medications and the degree of individual benefit 
varies. Eligible subjects may enroll in the current study if the  Investigator assesses that they may 
benefit from daily administration of BCX7353.  
Acute attacks of angioedema will be treated in accordance with the subject’s normal standard of 
care. As appropriate, subjects will continue to use their prescribed acute attack medication to 
treat any acute attacks, as well as continue as needed with their approved prophylactic treatment 
for HAE attacks as prescribed under the medical management plan advised by their physician.  
Efficacy and safety data from the randomized, double-blind, placebo-controlled Phase 3 studies 
(BCX7353-302 and BCX7353-301) and accumulating safety data on subjects enrolled on earlier 
versions of the current study protocol (BCX7353-204) support long-term treatment with 
BCX7353 (Section 5.2).  At the writing of this version of the protocol, regulatory filings to both 
the US and Japan authorities have been completed towards the approval of BCX7353 for 
marketing. 
5.4.2. 
Rationale for Study Drug Doses and Regimens 
The BCX7353 dosage regimen selected for evaluation in this study is 150 mg BCX7353 
administered QD (equivalent to 175 mg QD [SN]).  
In Study BCX7353-203, the HAE attack rate was significantly lower vs. placebo in subjects who 
received daily doses of 125, 250, and 350 mg BCX7353 (SN) and the drug was well-tolerated. 
The plasma drug levels achieved at each dose were generally predictable and had an acceptable 
level of inter-subject variability. 
Two doses (150 and 110 mg QD) were studied in a pivotal Phase 3 clinical trial (BCX7353-302) 
and versions of the current study globally (BCX7353-204 Versions 1-5).  Study BCX7353-302, 
achieved its primary endpoint for both dose levels evaluated, with the 150 and 110 mg doses 
reducing HAE attacks by 44% (p < 0.001) and 30% (p = 0.024), respectively, vs. placebo. Orally 
administered BCX7353 was a safe, generally well-tolerated, and effective treatment for the 
prevention of HAE attacks in Part 1 of this study, with better efficacy at the 150 mg dose 
compared to the 110 mg dose, and no increase in safety risk. 


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Based on the results of BCX7353-302 of better efficacy and no increase in safety risk at the 
150 mg dose, the 150 mg dose will be assessed in the current study of BCX7353 for the 
prevention of attacks in HAE. 
5.4.3. 
Study Population Rationale  
The study will be limited to adults and adolescents ≥ 12 years of age of both sexes. Children <12 
years of age will be excluded from participation in BCX7353 clinical trials until the benefit-risk 
profile in adults and adolescents has been better characterized. Population PK modeling of PK 
data generated to date indicate that weight is a covariate on the bioavailability of BCX7353. 
Simulations of exposures by weight at clinically relevant doses indicated that a weight of < 40 kg 
is associated with exposures considered significantly higher (ie, > 20%) than those generated 
from an adult of 70 kg at doses to be studied in this protocol. Therefore, participation in the trial 
will be restricted to subjects who weigh at least 40 kg. At a weight of 40 kg, simulated exposure 
was well within the efficacious exposures identified in Study BCX7353-203 that were 
well-tolerated; therefore, it is anticipated that exposure in adolescent subjects will not exceed 
safe and tolerable exposures in adults. 
In the ongoing BCX7353-204 trial, asymptomatic and transient transaminase elevations have 
occurred almost exclusively in subjects who have recently (ie, < 2 weeks prior to starting 
BCX7353) discontinued androgens (BCX7353 IB). Currently the physiological and HAE attack 
changes that may occur with androgen cessation are not well described. Since androgen use 
(both current and past) is prevalant in the global HAE community, this protocol will provide data 
to better characterize androgen discontinuation in HAE patients and allow the development of 
guidance for treaters and patients who wish to switch from androgens to BCX7353. In order to 
reduce the incidence of transaminase elevations on study, subjects will be required to have last 
used androgens at least 28 days prior to initiation of BCX7353. 
To date, the BCX7353-204 trial has been conducted primarily outside of the US, including many 
areas where use of long-term prophylaxis for HAE attacks is uncommon. Since use of 
prophylactic therapy for HAE attacks is prevalent in the US HAE community, this protocol will 
provide data to allow the development of guidance for treaters and patients who wish to switch 
from another prophylactic therapy to BCX7353.  
Based on past and ongoing studies conducted in HAE subjects, it is anticipated that female 
subjects will comprise at least 50% of the subject population in this study. HAE affects both 
males and females, although the disease has a greater burden on females, with an increased 
frequency and severity of HAE attacks in women (Bork, Meng et al. 2006, Lumry, Castaldo et 
al. 2010). Estrogen appears to worsen the disease, as evidenced by an increased number of 
attacks reported following onset of puberty and when estrogen-containing therapy is initiated 
(Bouillet, Longhurst et al. 2008, Caballero, Farkas et al. 2012). Due to the gender distribution of 
HAE and the influence of hormones on the frequency of attacks, it is considered important to 
include both male and female subjects in this clinical study to gain an assessment of potential 
safety and population PK differences.  
Although there is no evidence of embryofetal developmental toxicity with BCX7353 in 
reproductive toxicology studies, appropriate precautions are still warranted with respect to 
administering BCX7353 to women of reproductive age, in accordance with International Council 
for Harmonisation (ICH) guidelines. Women of childbearing potential may be enrolled in this 


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study provided they meet the contraceptive requirements and have a negative pregnancy test 
(Section 8.2.1).  
Pregnant women will be excluded from participation in the current study. Additionally, any 
female subject who becomes pregnant on study will be required to immediately discontinue 
study drug, and will be followed through the end of the pregnancy.  
5.4.4. 
Rationale for Allowance and Restriction of Concomitant Medications for HAE 
All subjects must have access to appropriate treatments for the treatment of acute attacks (ie, 
icatibant, plasma-derived C1-INH [any form]), ecallantide, recombinant C1-INH). Each subject 
will continue to use their prescribed acute medication to treat any attacks, under the medical 
management plan advised by their physician, throughout the study. This is consistent with 
guidance documents that strongly support the position that all subjects with C1-INH deficiency 
should have access to medications for treating attacks (Cicardi, Bork et al. 2012, Zuraw, Banerji 
et al. 2013). 
While there are approved therapies in many countries for prophylaxis against HAE attacks, 
including C1-INH infused intravenously, consensus recommendations do not exist for either a 
standard of care for prophylactic treatment or a definition of indications for prophylaxis. A 
guideline published on the management of HAE by the US HAE Association Medical Advisory 
Board suggests that decisions on when to use prophylaxis should be individualized (Zuraw, 
Banerji et al. 2013):  
‘The decision about when to use long-term prophylactic treatment cannot be made on rigid 
criteria but should reflect the needs of the individual patient. Decisions regarding which 
patients should be considered for long-term prophylaxis should take into account attack 
frequency, attack severity, comorbid conditions, access to emergent treatment, and patient 
experience and preference.’  
Subjects may receive prophylactic therapies (eg, C1-INH, tranexamic acid, lanadelumab).  
Investigators may make modifications to the dose and schedule of the prophylactic therapy, 
including tapering or discontinuation of dosing, according to the degree of benefit of daily oral 
BCX7353 treatment. Recommended strategies for switching to BCX7353 prophylaxis from 
another therapy are provided in Section 9.7. 
Androgen use, however, is prohibited within 28 days of the baseline visit and at any time during 
the study to reduce the incidence of transaminase elevations (see Section 9.7.1). 
5.5. 
BCX7353 Risk/Benefit Analysis 
Given that BCX7353 is a small molecule kallikrein inhibitor with data available from completed 
Phase 1 single and multiple dose studies, a Phase 2 study in subjects with HAE, and two ongoing 
randomized, double-blind, placebo-controlled Phase 3 studies, there is an acceptably low risk of 
severe or serious adverse reactions. Potential risks and findings from nonclinical and clinical 
studies of BCX7353 are discussed in the Section 6 of the IB (Summary of Data and Guidance for 
the  Investigator).  


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5.6. 
Benefits of Trial Participation 
Study subjects will receive regular medical care for the duration of the study. Subjects may 
experience a reduction in the number of attacks while receiving BCX7353. BCX7353 produced a 
statistically significant and clinically meaningful reduction in the rate of HAE attacks compared 
to placebo for the primary endpoint in the ITT population of Study BCX7353-302.  
The development of BCX7353 may be of benefit to the wider community/patients with HAE.  
5.7. 
Overall Benefit-Risk Assessment 
The risks from daily oral administration of BCX7353 seen to date in both preclinical and clinical 
studies were primarily mild, monitorable, and reversible. Overall, the clinical efficacy and safety 
data support a favorable benefit risk profile for BCX7353.  In the 24-week, adequate, well-
controlled pivotal efficacy and safety trial in adolescents and adults with Type I or II HAE, 
BCX7353 150 mg QD treatment for 24 weeks versus placebo resulted in statistically significant 
and clinically meaningful reductions in monthly HAE attack rate, monthly rate of HAE attacks 
requiring acute rescue therapy, the monthly rate of moderate or severe HAE attacks, and the 
monthly rate of laryngeal HAE attacks. Results of sensitivity and subgroup analyses of the HAE 
attack rate were consistent with those of the primary efficacy analysis. The safety data from 
controlled trials and long-term open-label studies is sufficient to assess the safety of BCX7353 in 
the proposed rare disease HAE population. Important potential risks are delayed-type 
hypersensitivity reactions (rash) and transaminase elevations. Hypersensitivity rash was 
identified as a signal early in development; few events were reported, and these were mild to 
moderate, self-limited, not dose dependent, and resolved with continued dosing without 
recurrence. Increases in ALT/AST were generally transient, asymptomatic, not dose dependent, 
and heavily confounded by prior administration of androgens. The overall benefit-risk balance is 
therefore considered to be acceptable. 
6. 
TRIAL OBJECTIVES 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
• To evaluate the long-term safety and tolerability of daily dosing of oral BCX7353 in 
subjects with HAE  
6.1.2. 
Secondary Objectives 
• To assess the effectiveness (ie, HAE attack frequency, severity, and disease activity 
over time) of BCX7353 during long-term administration  
• To evaluate QoL during long-term administration of BCX7353 
• To evaluate subject’s satisfaction with medication during long-term administration of 
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7. 
OVERALL STUDY DESIGN AND PLAN 
This is a single-arm open-label study designed to evaluate the long-term safety of prophylactic 
treatment with daily oral BCX7353 in subjects with HAE. The study will also evaluate the 
long-term effectiveness and impact on QoL or general well-being of subjects who receive 
BCX7353 prophylactic treatment, and the subject’s satisfaction with the medication. Based on 
the final results from Part 1 of the randomized, double-blind, placebo-controlled efficacy study 
(BCX7353-302), the dose of BCX7353 used in this study is 150 mg QD. 
Subjects may be enrolled once all eligibility criteria and study requirements are met. 
On-treatment study visits will occur at Weeks 4, 12, 24, 48, 72, and 96. An independent DMC 
has been reviewing the safety data from this study in concert with the accumulating safety 
information generated across the BCX7353 clinical development program. The DMC met at a 
frequency of  approximately every 12 weeks until a total of approximately 200 subjects across 
the Phase 3 Study, BCX7353-302, and the current study (BCX7353-204) completed 48 weeks of 
dosing with active drug. Since a total of over 200 subjects have completed 48 weeks across the 
studies, the DMC is now provided with data every 6 months until the last subject completes the 
study or approval is obtained in the first country globally. A formal meeting of the DMC 
members will not be required; however, if the data review identifies any concern, the DMC 
members may elect to hold a formal DMC meeting. In addition, the emergence of a new, 
clinically significant safety signal may prompt an ad hoc DMC review. 
Approximately 475 subjects will be enrolled into the study, with approximately 250 subjects 
planned to be enrolled in the US. Subjects will be eligible to receive BCX7353 for up to 
96 weeks, until the product becomes commercially available, or until the Sponsor discontinues 
development of the product for the prevention of angioedema attacks, whichever comes first.   
A study schema is shown in Figure 1.  
All subjects will be instructed to complete their diaries to document all angioedema attacks that 
occur.  
Acute attacks of angioedema will be treated in accordance with the subject’s normal standard of 
care. Treatment for acute attacks of HAE will not be provided by the Sponsor. 
Subjects will complete the angioedema quality of life questionnaire (AE-QoL) to assess 
health-related QoL and the Treatment Satisfaction Questionnaire for Medication (TSQM) to 
assess their satisfaction with the study medication. Additionally, subjects will be assessed if days 
were lost from school and/or work. 
Safety and tolerability will be evaluated through assessments of AEs, laboratory analyses 
(clinical chemistry, hematology, coagulation and urinalysis), vital signs, ECGs, and physical 
examinations at the study visits indicated in the schedule of assessments (see Table 3).  


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Figure 1. 
Study Schema  
 
Abbreviations: EOT = end of treatment; WK = week. 
  
  
7.1. 
Endpoints 
7.1.1. 
Safety Endpoints 
The primary objective of the study is to obtain long-term safety of BCX7353. The safety 
endpoints will include the following: 
• The proportion of subjects who discontinue BCX7353 due to a TEAE 
• The proportion of subjects with treatment-emergent SAEs 
• The proportion of subjects with TEAEs 
• The proportion of subjects with treatment-emergent Grade 3 or 4 AEs 
• The proportion of subjects with treatment-emergent, treatment-related AE consistent 
with a drug rash  
• The proportion of subjects with treatment-emergent Grade 3 or 4 laboratory 
abnormalities 
7.1.2. 
Effectiveness Endpoints 
Effectiveness endpoints will include the following:  
• Number and rate of HAE attacks  
• Durability of response (attack rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Patient-reported outcomes (HAE disease-specific AE-QoL questionnaire scores and 
TSQM Global Satisfaction scores) 
• Number of attacks requiring attack medication 
• Discontinuations due to lack of efficacy (through Week 48 only) 
• Severity of attacks 


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Additional related details of HAE attacks (eg, symptoms, anatomical location, hospitalizations, 
emergency room visits, attack severity, attack duration) and number of days lost from work 
and/or school due to attacks will be summarized. 
All attacks recorded by the subjects will be reviewed and confirmed or rejected according to a set 
of pre-defined rules prior to inclusion in effectiveness analyses. These rules, which have been 
constructed in concert with HAE-treating physicians, are outlined in the Statistical Analysis Plan 
(SAP). 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Approximately 475 subjects are planned to be enrolled globally in the study, with approximately 
250 subjects planned to be enrolled in the US, which includes any adolescent subjects enrolled in 
the substudy.  
8.2. 
Subject Selection 
8.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1. Males and nonpregnant, nonlactating females ≥ 18 years of age (main study) or ≥ 12 to 
17 years of age (substudy).    
2. Subjects with a clinical diagnosis of HAE Type I or II who, in the opinion of the  
Investigator, are expected to benefit from an oral treatment for the prevention of angioedema 
attacks. A clinical diagnosis of HAE Type I or II is defined as:  
•  A C1 esterase inhibitor (C1-INH) functional level below the assay lower limit of 
normal as assessed during the screening period by chromogenic assay OR 
• Laboratory documentation of historical C1-INH functional level below the assay lower 
limit of normal OR 
• Subjects who currently use plasma derived or recombinant C1-INH based therapies for 
acute attacks or prophylaxis may use one of the following to confirm their diagnosis: 
o SERPING-1 gene mutation known or likely to be associated with HAE Type 1 
or II as assessed during the screening period OR 
o A confirmed family history of C1-INH deficiency 
3. Subject weight ≥ 40 kg. 
4. Access to one or more targeted medications for the treatment of acute HAE attacks. The 
following are acceptable: icatibant, plasma-derived C1-INH (any form), ecallantide, 
recombinant C1-INH. 
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a. Be a woman of childbearing potential (defined as a nonmenopausal adult or 
adolescent female who has not had a hysterectomy, bilateral oophorectomy, or 
documented ovarian failure) who agrees to use at least an acceptable effective 
contraceptive method during the study and for a duration of 30 days after last dose of 
study drug. One or more of the following methods are acceptable:  
 Surgical sterilization (ie, bilateral tubal occlusion or vasectomy of male partner) 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS) (implanted 
any time prior to or during screening) 
 Implantable or injectable progesterone hormonal contraception initiated at least 
7 days prior to the screening visit  
 Combined (estrogen- and progestogen-containing) oral, intravaginal, or 
transdermal or oral progesterone norethindrone-based hormonal contraception 
initiated at least 28 days prior to the screening visit 
 Male or female condom with or without spermicide 
 Use of an occlusive cap (diaphragm, or cervical/vault caps) with spermicide 
(foam/gel/film/cream/suppository) 
Female subjects who report being postmenopausal for ≤ 2 years and have a 
follicle-stimulating hormone (FSH) ≤ 40 mIU/mL must agree to use at least an 
acceptable effective contraceptive method and (as proposed above) during study and 
for 30 days after the last dose of study drug. 
Female subjects of childbearing potential who declare themselves as either sexually 
abstinent or exclusively having female sexual partners do not need to use an 
acceptable method of contraception. This declaration should be reviewed with the 
subject throughout the study to ensure continued accuracy. Abstinence in this study is 
defined as “true abstinence: when this is in line with the preferred and usual lifestyle 
of the subject.”  
b. Be a woman of nonchildbearing potential (defined as postmenopausal for > 2 years or 
having an FSH > 40 mIU/mL if postmenopausal ≤ 2 years or have had a 
hysterectomy, bilateral oophorectomy, or documented ovarian failure). 
6. Able to provide written, informed consent. Subjects aged ≥ 12 to 17 years who are screened 
for the substudy must be able to read, understand, and be willing to sign an assent form in 
addition to a caregiver providing informed consent. 
7. In the opinion of the  Investigator, the subject is able to adequately comply with all required 
study procedures for the duration of the study. The subject must demonstrate adequate 
compliance with all study procedures required including diary recording of HAE attacks.  
8.2.2. 
Exclusion Criteria 
Subjects must meet none of the numbered exclusion criteria below to be eligible for participation 
in this study. Medications prohibited for use during the study are addressed in Section 9.7.1. 
1. Pregnancy or breast feeding or planned pregnancy during the study period. 


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2. Any clinically significant medical condition or medical history that, in the opinion of the  
Investigator or Sponsor, would interfere with the subject’s safety or ability to participate in 
the study. Examples include active malignancy under treatment, uncontrolled cardiovascular 
disease (recent acute myocardial infarction, unstable angina), organ dysfunction such that 
supportive care is required (dialysis, oxygen therapy, cirrhotic care). 
3. Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or participation in the study. 
4. Clinically significant abnormal ECG including but not limited to, a QTcF > 470 msec for 
women, a QTcF > 450 msec for men, or ventricular and/or atrial premature contractions that 
are more frequent than occasional, and/or as couplets or higher in grouping. 
5. Use of daily concomitant medications that are predominantly metabolized by CYP2D6 or 
CYP3A4 and have a narrow therapeutic range, within 7 days of the baseline visit or planned 
initiation during the study, as defined in Section 9.7.1. 
6. Use of oral androgens for treatment of HAE (prophylaxis or acute) within 28 days of the 
baseline visit or planned initiation during the study.  
7. Any laboratory parameter abnormality that, in the opinion of the  Investigator, is clinically 
significant and relevant for this study. 
8. Investigational drug exposure within 30 days prior to the screening visit. 
9. Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ 
anaphylaxis with unclear etiology. 
10. History of alcohol or drug abuse within the previous year, or current evidence of substance 
dependence or abuse (self-reported alcoholic intake > 3 units of alcohol/day). 
11. Current infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV). 
12. Subjects with an immediate family relationship to either Sponsor employees, the  
Investigator or employees of the study site who are named on the delegation log. 
13.  Subjects who are held in an institution by a government or judicial order. 
8.3. 
Subject Discontinuation from the Study and from Study Drug 
8.3.1. 
Subject Discontinuation from the Study 
Participation in the study is strictly voluntary; a subject may withdraw consent to contribute 
additional study information at any point. A subject who withdraws consent or is discontinued 
from study drug (see Section 8.3.2) will be requested to attend an end-of-study visit to complete 
all end-of-study evaluations. Subjects who discontinue the study but will continue to receive 
BCX7353 via another mechanism will have end-of-study assessments performed prior to 


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receiving BCX7353 outside of the study protocol.Although a subject may withdraw from the 
study at any time without specifying a reason for withdrawal, if known, the reason for 
withdrawal will be recorded in the subject’s medical records (source documents) and the CRF. If 
the reason for subject withdrawal is not known, the subject must be contacted to establish 
whether the reason was an AE, and if so, this must be reported in accordance with the procedures 
outlined in Section 12. If at any point in the study, the clinic is unable to contact the subject after 
appropriate attempts have been made, according to local clinic standards, the subject will be 
considered lost to follow-up.  
Once subjects have discontinued the study, the Sponsor will no longer provide treatment through 
the study. Following withdrawal from the study, a subject will be able to receive further 
treatment as recommended by their treating physician and according to the accepted standard of 
care. 
8.3.2. 
Subject Discontinuation from Study Drug 
A subject will be permanently withdrawn from study drug for any of the following bulleted 
reasons, which will be recorded in the source documents and CRF. When medically feasible, the 
Medical Monitor must be consulted prior to subject discontinuation. In all cases, subjects who 
prematurely and permanently discontinue study drug should complete all scheduled procedures 
for the end-of-study visit outlined in Table 3. 
• Emergence of any laboratory abnormality or AE that in the judgment of the  
Investigator compromises the ability of the subject to continue study-specific 
procedures or it is considered not to be in the subject’s best interest due to an altered 
benefit-risk profile 
• Reoccurrence of treatment-emergent AST or ALT elevation > 5 × ULN (confirmed) 
if BCX7353 is restarted after meeting hold criteria as outlined in Section 12.2.2. 
• Treatment-emergent ALT or AST > 3 × ULN combined with either laboratory 
abnormalities indicative of significant hepatic toxicity (ie, meeting Hy’s law, total 
bilirubin> 2 × ULN OR with an INR > 1.5) or with symptomatology of acute 
hepatitis (ie, severe fatigue, nausea, vomiting, right upper quadrant pain and 
tenderness, fever, rash, and/or eosinophilia [> 5%]) 
• Subsequent determination that inclusion/exclusion criteria were not met  
• Intercurrent illness or emergence of a new illness/medical condition that would, in the 
judgment of the  Investigator, affect assessments of clinical status to a significant 
degree 
• Subject noncompliance with study drug or to the protocol 
• Subjects with BCX7353-related Grade 3 or 4 rash as described by the Division of 
Microbiology and Infectious Diseases (DMID) criteria “skin-mucocutaneous” will be 
discontinued from study, if suspected to be due to BCX7353, and treated according to 
best medical practice. All subjects with a suspected drug rash should undergo specific 
rash evaluation as described in Section 11.1.12. A Grade 3 rash is defined as 
vesiculation or moist desquamation or ulceration, and a Grade 4 rash is defined as 
exfoliative dermatitis, mucous membrane involvement or erythema multiforme or 


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suspected SJS or necrosis requiring surgery. Subjects with a Grade 1 or 2 study 
drug-related rash may continue BCX7353 if the  Investigator and subject deem it 
appropriate.  
9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug and Study Drug Product 
BCX7353 is an oral small molecule inhibitor of plasma kallikrein. All subjects will receive up to 
96 weeks of BCX7353 capsules for oral administration at a dose 150 mg QD.  
The study drug consists of BCX7353 capsules. The capsules are comprised of the API 
(BCX7353) blended with the excipients pregelatinized starch, polyplasdone XL, colloidal silicon 
dioxide, and magnesium stearate in a gelatin capsule. 
 Subjects will receive a daily dose of 150 mg supplied as 1 capsule per day. 
Additional details for the chemical and physical characteristics of BCX7353 may be found in 
the IB. 
9.2. 
Description of Study Drug Packaging, Labeling, and Storage 
The study drug will be packaged in bottles. As the pharmaceutical development program for 
BCX7353 progresses, alternate packaging configurations may be introduced. Subjects will be 
dispensed a sufficient number of capsules to cover at least a 1-month dosing period. Additional 
visits for dispensing of study drug supply may occur after Week 24 as needed. 
Each container of study drug will be labeled with the information required per local law and may 
include: Sponsor name, study protocol number, description of the contents including mg 
strength, a statement regarding the investigational (clinical trial) use of the study drug, expiry 
date, and kit treatment number. 
Study drug must be stored between 15°C and 25°C (room temperature). 
Details on the study drug packaging, labeling, shipment, storage and dispensing will be provided 
in the Investigational Medicinal Product (IMP) manual. 
9.3. 
Treatment Allocation and Study Drug Blinding 
This is an open-label study. Subjects will receive BCX7353 150 mg administered orally QD. 
Sites will request a kit allocation for eligible subjects in the interactive (web) response 
system (IXRS), preferably after all baseline assessments to confirm eligibility have been 
completed. If required by site procedures (i.e., dispensing of allocated study drug must occur 
through a pharmacy), the request may be made on the business day prior to the planned baseline 
visit.  
During the conduct of the study, responsibility for kit supply and resupply may be transferred to 
a specialty pharmacy selected by the Sponsor and subjects may receive study drug directly from 
the specialty pharmacy. Detailed instructions will be provided at the time of implementation.  


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9.4. 
Study Drug Administration and Treatment Compliance 
Subjects will be instructed to take 1 BCX7353 capsule orally QD at approximately the same time 
each day, with whichever meal is typically the largest of the day. Subjects will be instructed to 
take study drug with food, or within 30 minutes after consuming food. It is recommended that 
the study drug be administered with food to help minimize GI effects. If GI-related symptoms 
are noted as an AE, the site should query the subject and record whether the drug is being taken 
as instructed (i.e., with food). 
Subjects will be instructed to maintain approximately the same daily dosing interval between 
study drug doses. If a subject forgets to take the study drug at the correct time, the dose may be 
taken later in the day; however, no more than 1 dose of BCX7353 should be taken on any 
calendar day. The subject should resume their regular dosing schedule on the next day.  
Subjects will be instructed to bring all drug kits (including both unused and used kit bottles) and 
diaries with them for each study visit. Accountability and adherence will be reviewed at each 
clinic visit. Subjects do not need to withhold any doses on clinic days or take a dose in the clinic, 
unless the clinic visit falls during the subject’s normal time of dosing. 
If a specialty pharmacy is used, specialty pharmacy staff may contact subjects directly to better 
understand the subject experience with study drug during the subject’s participation in the study.  
9.5. 
Study Drug Dose Modification 
No dose reductions are permitted.  
Study drug interruptions are discussed in Section 12.1.8. 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability 
Accountability of study drug dispensed and returned (as applicable) will be performed at 
Baseline and at each study visit. Returned study drug bottles and/or kits must be retained and 
reviewed during monitoring visits by the clinical research associate (CRA) (Section 14.2).  
The  Investigator/pharmacist/pharmacy must maintain accurate records of the disposition of all 
study drugs received from the Sponsor, issued to the subject (including date), and any drug 
destroyed. The Sponsor will supply a specific drug accountability form. At the end of the study, 
information describing study drug supplies (eg, kit numbers) and disposition of supplies for each 
subject must be provided, signed by the  Investigator or designee, and collected by the CRA. If 
any errors or irregularities in any shipment of study medication to the site are discovered at any 
time, the Sponsor (and or designee) must be contacted immediately. 
At the end of the study or at other times as agreed by all involved parties, all study drug not 
dispensed or administered will either be collected and returned to the Sponsor or destroyed on 
site as dictated by the appropriate Standard Operating Procedure. 
9.7. 
Concomitant Medications 
All subjects in the study must refrain from taking prohibited concomitant medications as outlined 
in Section 9.7.1. 


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Details of all prior medications (taken within 30 days of screening) and all current concomitant 
medication use (including herbal supplements), including all medications administered for the 
treatment of AEs, will be recorded in the source documentation /CRFs.  
Subjects whose illness is being treated with C1-INH, tranexamic acid, or lanadelumab 
prophylaxis regimens are allowed to continue on their regimen; however, the  Investigator is 
encouraged to assess response to BCX7353 therapy and reduce and/or discontinue prophylactic 
C1-INH, tranexamic acid, or lanadelumab use over time if clinically warranted. 
Steady state levels of BCX7353 are reached with daily dosing between 6 and 12 days. Therefore, 
the following strategies are recommended for subjects who are beginning BCX7353 in place of 
another method of prophylaxis: 
Table 2. 
Recommended Strategies for Switching to BCX7353 Prophylaxis from 
Another Therapy 
Current Prophylactic Therapy 
Timing of BCX7353 Initiation 
Androgens (eg, danazol) 
Discontinue androgens. Day 1 of BCX7353 
dosing may occur a minimum of 28 days after 
the last dose of androgens.  
Androgens may be discontinued or tapered in 
accordance with the usual practice of the  
Investigator; however, last dose must occur a 
minimum of 28 days prior to BCX7353 
initiation. 
Tranexamic acid  
Discontinue tranexamic acid dosing 14 days 
after first dose of BCX7353.   
C1-INH (eg, Cinryze, Haegarda) 
Discontinue existing C1-INH dosing schedule 
14 days after first dose of BCX7353. 
Lanadelumab-flyo  
Day 1 of BCX7353 dosing to occur on same 
day as lanadelumab injection. No further 
dosing of lanadelumab is required after 
initiating BCX7353. 
9.7.1. 
Prohibited Medications 
The following medications are excluded during the study (Section 8.2.2): 
• Angiotensin-converting enzyme inhibitors within 7 days of the baseline visit or planned 
initiation during the study (potential for exacerbation of HAE) 
• Investigational drug exposure within 30 days prior to the screening visit or initiation 
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• Use of daily concomitant medication that is predominantly metabolized by CYP2D6 or 
CYP3A4 and has a narrow therapeutic range, within 7 days of the baseline visit or 
planned initiation during the study. For the purposes of this protocol, these are:  
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, thioridazine, haloperidol, methadone, procainamide, and 
amitriptyline. Note: Topical or ophthalmic tacrolimus or sirolimus are allowed.  
• Use of oral androgens within 28 days of the baseline visit or planned initiation during the 
study (i.e., danazol, stanozolol, oxandralone, methyl-testosterone). Note: Testosterone 
replacement therapy is allowed.  
10. 
STUDY CONDUCT 
10.1. 
Overview 
This is an open-label study to evaluate the long-term safety and effectiveness of 150 mg QD of 
orally administered BCX7353.  
Subjects will be eligible to receive study drug (BCX7353) for up to 96 weeks, until the product 
becomes commercially available, or until the Sponsor discontinues development of the product 
for the prevention of angioedema attacks, whichever comes first. Study drug will be discontinued 
for subjects who are deriving no clinical benefit, are intolerant of study drug, or experience an 
unacceptable drug-related AE. The Study will be discontinued if ongoing regulatory or 
Institutional Review Board/Ethics Committee (IRB/EC) approval is withdrawn, or in the event 
that technical or logistical factors prevent the ongoing conduct of the study. Subjects who 
discontinue study drug will return to the clinic for an end-of-study visit 3 weeks after the last 
dose of study drug. Subjects who discontinue the study but will continue to receive BCX7353 via 
another mechanism will have end-of-study assessments performed prior to receiving BCX7353 
outside of the study protocol. 
10.2. 
Schedule of Assessments 
The schedule of assessments for this study is presented in Table 3 and procedures are described 
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Table 3. 
Schedule of Assessments: Study BCX7353-204 
Abbreviations: AE = adverse event; AE-QoL = Angioedema Quality of Life questionnaire; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase; BMI = body mass index; BMI = body mass index; C1-INH = C1 esterase inhibitor; ECG = electrocardiogram; EOS = end of 
Assessment 
Screening 
Period 
Baseline 
Visita 
Treatment Period (Visit schedule) 
End of Study 
Assessment 
Screening 
Visit 
(Up to 
Day -28) 
(Day 1) 
Week 4 
(Day 29 
± 2 days) 
Week 12 
(Day 85 ± 
2 days) 
Week 24  
(Day 169 
± 6 days) 
Week 48  
(Day 337 
± 6 days) 
Week 72 
(Day 505 
± 6 days) 
Week 96 
(Day 673 
± 6 days) 
3 weeks 
(± 3 days) 
after last dose 
of study drug 
Informed consent/assent (as 
applicable)b 
X 
X 
 
 
 
 
 
 
 
Inclusion-exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical and medication history, HAE 
medical and medication historyc  
X 
X 
 
 
 
 
 
 
 
Weight/height/BMId 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHh 
X 
 
 
 
 
 
 
 
 
HIV, HCV, HBV serology 
X 
 
 
 
 
 
 
 
 
Diagnosis of HAE establishedi 
X 
 
 
 
 
 
 
 
Androgen discontinuation (if 
applicable)j 
X 
 
 
 
 
 
 
 
 
Clinical chemistry/ 
hematology/ coagulationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample for HLA analysisl 
 
X 
 
 
 
 
 
 
 
Optional sample for exploratory PGm 
 
X 
 
 
 
 
 
 
 
ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE-QoL, assessment of days lost from 
work and/or school and TSQMo 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK sampleq 
 
X 
X 
X 
 
 
 
 
Xq 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary instruction/ review/set-upr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary completions 
 
Study drug dosing 
 
Study drug accountability/ dispensingr 
 
X 
X 
X 
X 
X 
X 
X 
X 


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study; FSH = follicle stimulating hormone; GGT = gamma glutamyltransferase; HAE = hereditary angioedema ; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen;  IXRS = interactive (voice/web) response system; LDH =lactate 
dehydrogenase; LLN = lower limit of normal; PG = pharmacogenomic; QoL = quality of life; QTcF = QT interval corrected using Fridericia’s method; 
TSQM = Treatment Satisfaction Questionnaire for Medication.  
a  The baseline visit should be within 28 days of the screening visit unless the screening visit is extended for previous androgen use, coming off other 
prophylactic therapies or elevated liver enzymes (with Medical Monitor permission).  
b  Informed consent/assent (as applicable) will be signed at the screening visit. 
c  Medical history and medication history will be completed at screening. 
d  BMI calculation and height at screening; weight is to be recorded at each in-clinic visit. Adolescents should also have height recorded at Week 48. 
e Full physical examinations will be performed at screening; symptom-directed physical examinations will be performed at all post-screening visits. 
f  For women of childbearing potential, regardless of contraception or lifestyle, a serum pregnancy test will be administered at screening, urine pregnancy tests 
will be assessed at all subsequent visits as indicated in the table.  
g  To include blood pressure and pulse rate. Temperature and respiratory rate will be captured at screening and baseline only.  
h  For a woman who declares that she has been post-menopausal ≤ 2 years  
i   Subjects with a clinical diagnosis of HAE Type I or II who, in the opinion of the  Investigator, are expected to benefit from an oral treatment for the prevention 
of angioedema attacks. A clinical diagnosis of HAE Type I or II is defined as: A C1-INH functional level below the assay lower limit of normal as assessed 
during the screening period by chromogenic assay OR laboratory documentation of historical C1-INH functional level below the assay lower limit of normal 
OR subjects who currently use plasma-derived or recombinant C1-INH based therapies for acute attacks or prophylaxis may use one of the following to 
confirm their diagnosis: SERPING-1 gene mutation known or likely to be associated with HAE Type I or II as assessed during the screening period OR a 
confirmed family history of C1-INH deficiency.    
j   Subjects who discontinue androgen prophylaxis at the time of signing informed consent or at the screening visit should have ALT, AST, ALP, LDH, GGT, and 
total and direct bilirubin measured 2 weeks (+7 days) after androgen discontinuation. 
k See Table 4 for analytes to be assessed.  
l The sample for HLA may be drawn at baseline or at any subsequent visit. 
m  A blood sample for possible exploratory pharmacogenomic testing will be drawn for all subjects at the baseline/Day 1 visit; however, the sample will be 
analyzed only if consent/assent is obtained for this optional analysis. If a blood sample is not obtained at baseline, the sample may be drawn at any time during 
the study following consent obtained from the subject. 
n  All ECGs during the study will be single assessments with the exception of baseline which will be obtained in triplicate. An ECG should be repeated for a 
change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. Prior to obtaining an ECG, subjects should rest quietly. ECGs should be obtained 
prior to any blood sampling. 
o  AE-QoL and TSQM will be administered once at baseline and at each visit through the End of Study visit. Additional questions regarding loss of time from 
work/school will be instituted at each visit to more fully characterize QoL. Administration of the AE-QoL and TSQM questionnaires and assessment if time 
was lost from school and/or work should be completed by the subjects prior to the other assessments during the visits to prevent influencing subject 
perceptions, if possible. 
p   Concomitant medications will be reviewed at each visit and on treatment, new concomitant medications will be reviewed to determine whether there are any 
contraindications. 
q For adolescent subjects only (≥12 to 17 years of age). The actual date and time of PK blood draw, and time of last study drug dose (relative to PK blood draw) 
will be captured in the CRF. Samples for PK will be collected through the Week 12 visit.  PK sample is required at the EOS visit only if the EOS visit is 
occurring prior to Week 12. 
 


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r  Site staff will review the diary instructions with the subjects at the first clinic visit (Screening visit). Subjects will be instructed to bring the completed diary 
with them to their visits. Any issues with the entered data in the diary will be discussed with the subject and corrections will be made by the subject as 
required. Subjects will enter HAE attacks and relevant details (screening through follow-up).  
s Sites will request kit assignment in the IXRS for eligible subjects at the Day 1 visit. During the conduct of the study, responsibility for kit   
   allocation/distribution may be transferred to a specialty pharmacy selected by the Sponsor.  


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10.3. 
Study Visits 
Details for all study visits are found in Table 3: Schedule of Assessments. 
10.3.1. 
Screening Visit 
Written informed consent and assent (as applicable) must be obtained from each subject before 
initiation of any screening assessments or procedures. Each subject will receive a copy of the 
signed and dated study-specific informed consent form (ICF). Prospective subjects who have 
signed an ICF who are interested in participating in the study will then undergo assessments at a 
screening visit to determine eligibility (as applicable). Signing of the ICF may occur prior to the 
screening visit, which is defined as the visit where site-conducted screening procedures are 
performed.  
In the case of time limitations for conduct of the screening visit, a site is permitted to perform 
screening assessments over more than one screening visit. 
Subjects who discontinue androgen prophylaxis at the time of signing informed consent or at the 
screening visit will also have ALT, AST, ALP, LDH, GGT and total and direct bilirubin 
measured 2 weeks (+7 days) after androgen discontinuation.  
With Medical Monitor permission, screening may be extended for an additional 42 days (for a 
total of 70 days) for subjects transitioning from other prophylactic therapies, including those that 
have AST or ALT elevations > 3 × the ULN at any pre-dose visit.  
Rescreening of ineligible subjects, where there is a reasonable expectation that the subject will 
become eligible, will be approved or denied on a case-by-case basis by the Sponsor Medical 
Monitor. Retesting of specific assessments without entirely rescreening a subject may be 
permitted.  
Subjects who were screen failures on a BCX7353 study may be screened or rescreened for the 
current study where there is a reasonable expectation that the subject will be eligible.  
A screening failure CRF page will be completed for those subjects who do not proceed with 
study dosing, recording the reason for screen failure. 
10.3.2. 
Baseline Visit (Day 1) 
Subjects who meet all study eligibility criteria, and who agree to participate will be asked to 
return for a scheduled baseline visit (Day 1) within 28 days of the screening visit. Screening may 
be extended with Medical Monitor permission for subjects transitioning from other prophylactic 
therapies as stated above. 
Inclusion/exclusion criteria and HAE medical and medication history will be reviewed to ensure 
continued subject eligibility prior to dosing.  
After completion of all Baseline assessments as listed in Table 3: Schedule of Assessments, 
study drug should be dispensed (see Section 9.4).  
10.3.3. 
Week 4 Visit 
Subjects will return to the clinic during Week 4 (study Day 29 ± 2 days).  


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Subjects do not need to withhold any doses on clinic days or take a dose in the clinic unless the 
clinic visit falls during the subject’s normal time of dosing.  
Subjects will be reminded to continue to fill out any HAE attacks in their diary and to bring their 
diary with them to all visits. 
 
10.3.4. 
Week 12, 24, 48, 72, and 96 Visits  
Subjects will return to the clinic for additional visits for up to 96 weeks, until the product 
becomes commercially available, or until the Sponsor discontinues development of the product 
for the prevention of angioedema attacks, whichever comes first. Study visits are planned to 
occur at Week 12 (Day 85 ± 2 days), Week 24 (Day 169 ± 6 days), Week 48 (Day 337 ± 6 days), 
Week 72 (Day 505 ± 6 days), and Week 96 (Day 673 ± 6 days).  
Subjects will be reminded to continue to fill out any HAE attacks in their diary and to bring their 
diary with them to all visits.  
10.3.5. 
End of Study Visit 
Subjects who discontinue study drug will return to the clinic 3 weeks (21 ± 3 days) after the date 
of their last dose for their end of study or withdrawal assessment. Subjects who discontinue study 
drug must undergo all study-related procedures outlined in Table 3.  Subjects who discontinue 
the study but will continue to receive BCX7353 via another mechanism will have end-of-study 
assessments performed at their last regularly scheduled visit. 
If an AE is ongoing at the end of study visit, additional clinic visit(s) or telephone contact(s) may 
be warranted (see Section 12.1.2). 
11. 
ASSESSMENTS 
The schedule of procedures and assessments to be conducted throughout the study are outlined in 
Table 3, with details on the conduct of the procedures/ assessments provided below.  
Even if not provided by the  Investigator, routine and appropriate preventative care such as 
mammograms, cervical and testicular cancer screenings, etc., should be obtained by the subject 
and results provided to the  Investigator to demonstrate ongoing general health due to the 
longstanding duration of this trial. 
11.1. 
 Investigator-Completed Assessments 
Demographic information, including year of birth, sex, race, and ethnicity will be captured for 
each subject participating in the study at the screening visit. Medical and medication history will 
be captured at the screening visit and updated at baseline.  
Contraceptive methods enabling eligibility will be captured in source documentation at the 
screening visit. Contraceptive methods and/or lifestyle should be reviewed throughout the study 
to ensure they remain appropriate for the subject. 
Additionally, subjects will be queried if time was lost from school and/or work, beginning at 
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11.1.1. 
HAE Medical and Medication History 
An HAE medical history questionnaire provided by the Sponsor will be completed at screening. 
All questions on the medical history/medication questionnaire should be completed by the  
Investigator (or designee) from historical source documentation when available, with subject 
input as necessary to complete the remaining questions. 
11.1.2. 
Physical Examination 
A full physical examination will be conducted at screening. All subsequent physical 
examinations will be abbreviated (i.e., targeted or symptom-directed) to include, at a minimum, 
evaluation of any new signs or symptoms.  
Genitourinary and breast examinations may be omitted when not required by normal site 
practice.  
11.1.3. 
Weight/Body Mass Index 
For determination of height and weight, subjects should be clothed with shoes removed.  
BMI should be calculated using the following formula: 
BMI = weight (kg)/height (m)2 
BMI and height are only to be captured at the screening visit. Adolescents will also have height 
captured at Week 48. 
11.1.4. 
12-lead Electrocardiograms  
A standard bedside or routine 12-lead ECG machine that calculates heart rate and measures the 
PR, QRS, QT, RR, and QTc (QTcF) intervals will be utilized. Prior to obtaining an ECG, 
subjects should rest quietly. 
Qualified site personnel must review the ECGs and automated findings for gross abnormalities 
and to review any interval measurements of concern (absolute readings and for post-baseline 
ECGs, a change from baseline). For all ECGs, the clinical interpretation of the ECG and 
calculated QTcF (if not automated by the ECG machine and including adjudication of any 
automated measurements or diagnoses) should be recorded directly on a hard copy of the ECGs. 
Copies of the ECGs may be requested by the Sponsor. All subject identifiers will be masked 
prior to provision to the Sponsor. 
Baseline (predose) ECGs will be obtained in triplicate (i.e., 3 separate readings taken at 1- to 
5-minute intervals), with baseline values calculated from an average of the 3 readings. All other 
ECGs will be single assessments. ECG readings should be obtained prior to blood sampling. 
 An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval 
> 500 msec. 
11.1.5. 
Vital Signs 
 Blood pressure (systolic and diastolic) and pulse rate should be taken after the subject has 
rested. Blood pressure measurements must be obtained with an appropriate cuff size and with the 
subject’s arm supported at the level of the heart. It is acceptable to obtain a pulse rate from the 


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blood pressure or ECG machine. Temperature and respiratory rate will be captured at screening 
and baseline only. 
11.1.6. 
Clinical Laboratory Evaluations 
 Blood and urine samples will be obtained per the schedule of events. Individual laboratory tests 
to be performed are provided in Table 4.  
All laboratory samples will be collected using kit supplies provided by the central laboratory, 
which will also analyze all samples. If results are obtained from both central and local 
laboratories for the same assessments at a single study time point, only the central laboratory 
results will be used for study purposes. Additionally, urine pregnancy tests will be provided by 
the central laboratory but will be analyzed at the clinical site. A laboratory reference manual will 
be provided to the site detailing kit contents, reordering instructions, sample collection, handling, 
storage and shipment.  
Results from the laboratory values should be reviewed as received by the  Investigator. Evidence 
of this review should be provided in the source records and may include printing of the 
laboratory reports with a signature attesting to a review. For out-of-range lab findings, the 
interpretation of clinically significant or not clinically significant should be denoted in the source 
records. Clinically significant laboratory findings in the opinion of the  Investigator should be 
recorded as an AE and handled as described in Section 12.1.  
 
 
 
 


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Table 4. 
Clinical Laboratory Evaluations 
Hematology  
• 
Basophils 
• 
Eosinophils 
• 
Hematocrit  
• 
Hemoglobin 
• 
Lymphocytes 
• 
Mean cell hemoglobin (MCH) 
• 
Mean cell hemoglobin 
concentration (MCHC) 
• 
Mean cell volume (MCV) 
• 
Monocytes 
• 
Neutrophils 
• 
Platelet count 
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count 
 
 
Urinalysis 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocytes 
• 
Nitrites 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Reflex to microscopy for 
abnormal findings 
Coagulation 
• 
Prothrombin time (PT) 
• 
Activated partial 
thromboplastin time (aPTT) 
• 
International normalized ratio 
(INR) 
Clinical Chemistry 
• Alanine aminotransferase (ALT) 
• Albumin 
• Alkaline phosphatase 
• Amylase 
• Aspartate aminotransferase (AST) 
• Bilirubin (total) 
• Bilirubin (direct; only if total is 
elevated) 
• Blood urea nitrogen (BUN) 
• Calcium 
• Chloride 
• Creatinine 
• Gamma glutamyl transferase 
(GGT) 
• Glucose or glucose  
• Lactate dehydrogenase (LDH) 
• Lipase (reflex if amylase is > 2 × 
ULN) 
• Magnesium 
• Potassium 
• Phosphate (inorganic) 
• Protein (total) 
• Sodium 
• Uric acid 
 
 
Other Tests  
 
Virology (Screening Only) 
• Hepatitis B surface antigen 
• Hepatitis C antibody; reflex 
to hepatitis C virus RNA if 
antibody is positive 
• HIV antibody 
 
Pregnancy tests 
• 
Serum β-HCG (females of 
childbearing potential) 
• 
Urine β-HCG (females of 
childbearing potential) 
• 
Reflex to serum β-HCG for 
a positive urine β-HCG 
 
FSH (postmenopausal females 
≤ 2 years)  
 


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11.1.7. 
Screening for Human Immunodeficiency Virus, Hepatitis B, and Hepatitis 
Serology  
Blood samples will be collected at screening for serologic testing for evidence of HIV, chronic 
hepatitis B, and chronic hepatitis C infection. 
11.1.8. 
Pregnancy Testing and Follicle-Stimulating Hormone 
FSH will be measured at screening in women declaring themselves postmenopausal ≤ 2 years. At 
screening, a serum pregnancy test should also be drawn in the event a woman subject 
postmenopausal ≤ 2 years is found to be of childbearing potential.  
For women and adolescents of childbearing potential, a serum pregnancy test will be 
administered at screening. Urinary pregnancy tests will be assessed at all subsequent visits. A 
serum pregnancy test should immediately be drawn and sent for analysis for any positive urine 
pregnancy test. 
Urine pregnancy tests will be provided by the central laboratory but will be resulted locally.   
11.1.9. 
HAE Diagnostic Criteria 
Subjects with a clinical diagnosis of HAE Type I or II who, in the opinion of the Investigator, are 
expected to benefit from an oral treatment for the prevention of angioedema attacks. A clinical 
diagnosis of HAE Type I or II is defined as:  
• A C1 esterase inhibitor (C1-INH) functional level below the assay lower limit of normal 
as assessed during the screening period by chromogenic assay OR  
• Laboratory documentation of historical C1-INH functional level below the assay lower 
limit of normal OR  
• Subjects who currently use plasma derived or recombinant C1-INH based therapies for 
acute attacks or prophylaxis may use one of the following to confirm their diagnosis:  
o SERPING-1 gene mutation known or likely to be associated with HAE Type 1 or 
II as assessed during the screening period OR  
o A confirmed family history of C1-INH deficiency 
To utilize a family history of C1 INH deficiency to establish an HAE diagnosis for eligibility, the 
Investigator should document this based on either the Investigator’s personal knowledge (ie, if a 
relative of the screening subject is also a patient of the same Investigator/practice) or interaction 
with medical staff of the treatment facility where the relative receives HAE care, who confirms 
the diagnosis. No historical laboratory documentation on the relative should be collected in the 
source documents. 
11.1.10. 
Other Laboratory Assessments 
All subjects will have a blood sample for HLA analysis drawn at baseline/Day 1 (or any other 
time point on study if not obtained at baseline). Samples will be sent to a central laboratory for 
analysis. The results will not be communicated back to the  Investigator or subjects because the 
results are not intended for diagnostic or prognostic purposes and will be used in a research 
related fashion only. 


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11.1.11. 
Pharmacokinetics 
A blood sample for PK analyses will be drawn on adolescent subjects (≥12 to 17 years of age) at 
Baseline and study visits through Week 12. The time of last study drug dose and time of PK 
blood draw will be recorded in the CRF.  
Instructions for collection, processing, storage, and shipment of PK samples will be provided to 
the clinical site in a separate document. 
11.1.12. 
Pharmacogenomic Testing 
For subjects who, are willing to participate and sign separate informed consent, possible 
exploratory pharmacogenomics testing may be performed. Testing may be undertaken in one or 
more locus/loci if desired by the Sponsor to examine whether allelic variations account for 
efficacy or safety findings. Samples will be sent to a central laboratory for analysis and results 
will not be returned to sites.  
11.1.13. 
Rash Assessment 
Because of the potential for a study drug-related rash, all sites should be prepared to report 
details of suspected drug rashes and provide photographs.  
Subjects should be medically evaluated for any diffuse maculopapular rash that could be drug- 
related.  Rashes that resolve rapidly and therefore cannot be medically evaluated will not result 
in a protocol deviation. The site must enter the event into EDC as an AE (flagged as an EOSI) 
and inform the Sponsor Medical Monitor via the EOSI form of all BCX7353-related 
maculopapular rashes (Section 12.1.5.1) after assessment. If the rash is assessed as not 
maculopapular (eg, urticarial) or not related to BCX7353 (i.e., has a clear alternative etiology), 
then the rash is reported as an AE, treated per  Investigator judgement, and no further special 
assessment is required.  
The following assessments must be completed for all subjects with a diffuse maculopapular rash 
assessed as related to BCX7353 as soon as logistically possible:  
• Full dermatological exam to include the scope of the rash (location), vital signs, and 
mucosal examination. The notes documenting the examination should include 
detailed description of the rash; presence or absence of desquamation; presence or 
absence of blistering and if present, its extent; presence or absence of mucosal 
involvement and if present, its extent; and any other associated abnormal physical 
findings.  
• Vital signs including temperature 
• High resolution photographs taken to provide both detail regarding the rash (close-up) 
and details regarding the extent of the rash (whole body or body part). Cameras must 
be able to provide clear images taken in close proximity to the skin. The picture 
should include a ruler (centimeter) for scale. Every attempt to protect subject 
anonymity should be made. 
• All detailed clinical information regarding the rash, examination, treatment and 
interpretation of the event needs to be reported on an SAE/Event of Special Interest 
(EOSI) report form as per Section 12.1.5.1. 


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Most subjects will not need further evaluation for appropriate diagnosis or treatment. However, 
if laboratory evaluations (i.e. blood safety assessment labs) are done, these should be performed 
through the central lab. If they are performed at a local lab, include a redacted copy of the results 
or enter the values on the EOSI report. If it is determined by the  Investigator or another clinician 
that a biopsy would be appropriate, a redacted copy of the pathology report as part of the EOSI 
reporting procedure should be sumbited. If the study site cannot perform a biopsy (if indicated) 
or any of the above mandatory assessments (i.e., photographs), then it is appropriate to refer the 
subject to a physician who can perform the assessments/biopsy (i.e., a dermatologist). If a 
non-study physician performs any of the assessments or biopsy, submit the redacted written 
consultation report. 
Dosing of BCX7353 may continue in subjects experiencing a Grade 1 or 2 drug rash if the 
subject and  Investigator agree. The EOSI form and any additional information should be 
received by the Sponsor in a timely manner for Sponsor review. The  Investigator’s intention 
regarding BCX7353 dosing (i.e., continuation, temporary interruption or discontinuation) should 
be clearly stated on the EOSI form. The Sponsor may discuss the drug rash with the  Investigator 
if there are questions or concerns. 
11.2. 
Subject-Completed Assessments 
11.2.1. 
Patient-Reported Outcomes 
The disease-specific questionnaire, AE-QoL, and TSQM will each be administered once at 
baseline, at each visit through Week 96 (or end of treatment), and at the end-of-study visit.  
An assessment of days lost from work or school during the previous 12 months will be captured 
at the baseline visit. Days lost from work or school since the previous visit will also be captured 
at each study visit through Week 96 (end of treatment) and through the end-of-study visit 
3 weeks after the last dose of study drug.  
Additionally, other patient-reported outcomes may be implemented at any study visit to fully 
characterize QoL. 
Each questionnaire will be translated into the local language as required. For all 
subject-completed forms, clinic staff should ensure the subject reads the instructions and 
completes the questionnaires in full prior to filing in the source documentation.  
Where possible, the questionnaires should be completed by the subject prior to other assessments 
for that visit to prevent influencing subject perceptions. 
11.2.2. 
HAE Attack and Dosing Diary 
The Sponsor will supply diaries to all sites. Sites will dispense diaries to subjects at screening. 
Diaries will be collected at each visit and at follow-up. 
At the Screening visit, subjects will be instructed how to complete the diary for an attack. While 
a subject has a diary in their possession, the subject will fill out the HAE attack diary recalling 
whether symptoms of an HAE attack were experienced. Subjects need only to fill out the diary 
details section when there is presence of HAE symptoms. If the subject does report an attack in 
their diary, additional details about the attack will be required, including location of the 
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Further training on completing the diary should be provided at each clinic visit.  
While study staff are not permitted to make any entries into the diary, subjects may be asked to 
rectify incomplete diary entries made since the last visit based on outstanding questions a subject 
may have or incorrect assumptions/interpretation of diary questions.  
Subjects should bring their diary to each study visit. It is also acceptable for completed diaries to 
be returned to the site on a monthly basis after Week 4. 
12. 
ADVERSE EVENT MANAGEMENT AND REPORTING 
12.1. 
Adverse Events 
AEs will be assessed and recorded from the time of signing of the informed consent through the 
appropriate follow-up period. Full details on recording and reporting AEs are provided in 
Section 12.1.2. 
12.1.1. 
Definitions 
12.1.1.1. Adverse Event  
An AE is any untoward medical occurrence in a clinical study subject. No causal relationship 
with the study drug or with the clinical study itself is implied. An AE may be an unfavorable and 
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical 
study. Clinically relevant abnormal results of diagnostic procedures including abnormal 
laboratory findings (eg, requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be AEs. If the diagnostic procedure 
prompts no additional treatment, visits, or monitoring, it will not meet the definition of an 
adverse event.  
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period (see Section 12.1), including medical triggers resulting in an 
HAE attack. Emotional stress will not be considered an AE unless it results in a 
medical diagnosis or requires medical treatment.  
• Findings from protocol-mandated interventions. This can include laboratory 
assessments performed in the course of the trial. AEs should only be reported if the 
abnormalities are changes from baseline and are clinically significant as described 
above. 
• Pre-existing medical conditions (other than the condition being studied) judged by the  
Investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. When recording such events on an 
AE/SAE eCRF page, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (eg, “more frequent 
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An adverse reaction is defined in Article 2(n) of Directive 2001/20/EC as follows: all untoward 
and unintended responses to a study drug/IMP related to any dose administered. The definition 
covers also medication errors and uses outside what is foreseen in the protocol, including misuse 
and abuse of the product. The definition implies a reasonable possibility of a causal relationship 
between the event and the study drug/IMP. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
For the purposes of this protocol, HAE attacks and their associated symptoms will not be defined 
as AEs, even if the subject requires hospitalization. All HAE attacks and associated symptoms 
are reported in the subject diary and are a reflection of the disease under study. The events that 
may trigger a HAE attack such as an infection or trauma are considered AEs and should be 
reported as such. 
Hospitalization scenarios do not require reporting as an SAE where there is no occurrence of an 
AE. These scenarios include a planned hospitalization or prolonged hospitalization to: 
• Perform a routine control screening for a preexisting illness or to diagnose a suspected 
illness. In the case of the latter, the symptomatology should be reported as an AE and 
amended if a diagnosis is confirmed. 
• Undergo a diagnostic or elective surgical procedure for a preexisting medical condition 
that has not changed (eg, a joint replacement for which the subject was on a waiting list). 
• Undergo medical observation due to HAE (eg, admission after a routine dental procedure 
in an HAE patient). 
• Undergo medical observation without the occurrence of an AE due to standard of care in 
the region or hospital. 
Surgical procedures should not be reported as AEs. The condition for which the surgery is 
required should be reported as the AE, if it occurs or is detected during the study period. Planned 
surgical measures permitted by the clinical study protocol and the conditions(s) leading to these 
measures are not AEs, if the condition(s) was (were) known before the start of study treatment. 
In the latter case the condition should be reported as medical history. 
AEs are designated as “non-serious” or “serious.” 
12.1.1.2. Serious Adverse Event 
A SAE is an AE/reaction that results in any of the following outcomes: 
• Death 
• Is life-threatening (subject is at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe) 
• Requires subject hospitalization (formal admission to a hospital for medical reasons) 
or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (i.e., there is a substantial 
disruption of a person's ability to carry out normal life functions) 
• Is a congenital anomaly/birth defect 


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Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject’s health or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. For this study, examples of such events may include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in subject hospitalization.  
In addition, the Sponsor considers events of abortion (spontaneous or induced), fetal demise, and 
still birth as SAEs for reporting purposes. 
Some hospitalization scenarios, as outlined in Section 12.1.1.1 do not require reporting as SAEs. 
Overdose will be considered an SAE only if any of the seriousness criteria are met. Any clinical 
complication in association with the overdose should be reported as an AE or SAE (as 
applicable) along with the overdose (see Section 12.2.2). Details of signs or symptoms, clinical 
management and outcome should be reported, if available. Overdose without associated signs or 
symptoms should not be recorded as AEs but should be recorded as protocol deviations. 
12.1.1.3. Adverse Events of Special Interest 
For this protocol, non-serious treatment-emergent maculopapular rashes that are deemed related 
to BCX7353 will be considered EOSIs. This does not include other types of rashes such as 
urticaria or eczema. All treatment-emergent skin conditions should be reported as AEs but only 
maculopapular rashes deemed related to BCX7353 should be considered EOSIs.  
An EOSI  event in and of itself will not be considered serious unless it meets the seriousness 
criteria above. Events of maculopapular rash assessed as possibly, probably, or definitely related 
to BCX7353 regardless of severity must be reported to the Sponsor Medical Monitor as 
described in Section 12.1.5.1. Management of BCX7353 drug-related rash is provided in 
Section 11.1.12. 
12.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events 
Reports of all AEs and SAEs, regardless of  Investigator attribution, are to be collected from the 
time of signing of the informed consent through to the last study visit (i.e., through the 
posttreatment end-of-study visit). All AEs and SAEs are to be reported on the AE CRF.  
AEs should be documented on CRFs as  Investigators become aware of them. AEs are to be 
followed until the event resolves. If an event is ongoing at the End of Study visit, Grade 1 and 
2 events do not need to be followed if the event is deemed unlikely to be related or not related to 
study drug (see Section 12.1.3 for AE grading). For all Grade 3 and 4 events or events deemed at 
least possibly related to use of study drug, the event should be followed until the AE is resolved 
or the subject is in a clinically stable condition with regards to the AE. 
The  Investigator shall report all SAEs immediately to the Sponsor by communicating with the 
Medical Monitor (phone or email) and by submission of an SAE report form via email, and 
entering the event onto the AE CRF within 24 hours of their knowledge of the event (see 
Section 12.1.5). The SAE report form is a detailed, written report on the SAE provided by the 
Sponsor or designee. The  Investigator should follow all unresolved SAEs observed during the 


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study until they are resolved, or are judged medically stable, or are otherwise medically 
explained. 
The  Investigator should attempt, if possible, to establish a diagnosis based on the presenting 
signs and symptoms. In such cases, the diagnosis should be documented as the AE and not the 
individual sign/symptom. If a clear diagnosis cannot be established, each sign and symptom must 
be recorded individually. Once a diagnosis is made during evaluation or treatment, the  
Investigator will update the AE record with this diagnosis. The immediate and follow-up reports 
shall identify subjects by the unique subject numbers assigned to them to ensure that the Sponsor 
shall have the necessary information to continuously assess the benefit-risk profile of the study 
drug in clinical trial. 
12.1.3. 
Definition of Severity 
All AEs will be assessed (graded) for severity and classified using the DMID criteria for grading 
AEs (Publish date November 2007, see Section 16.1). Any AEs not covered by the DMID 
criteria will be assessed and classified into 1 of 4 clearly defined categories as follows: 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required. The AE does not interfere with the participant’s normal 
functioning level. It may be an annoyance. 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; no or 
minimal intervention required. The AE produces some impairment of 
functioning, but it is not hazardous to health. It is uncomfortable or an 
embarrassment. 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; medical 
intervention may be required. The AE produces significant impairment of 
functioning or incapacitation. 
Life-
threatening: 
(Grade 4): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required to prevent death, 
hospitalization or hospice care probable. 
Severity refers to the medical perspective of an event while seriousness reflects the outcome of 
the event (i.e., hospitalization). Events of mild severity can lead to hospitalization and therefore 
be serious while severe events such as a headache may not meet seriousness criteria.  
12.1.4. 
Definition of Relationship to Study Drug 
The  Investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug using the following guidelines: 
Not Related: 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident, and no 
temporal relationship exists between the study drug and the event. 


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Unlikely: 
The event does not follow a reasonable temporal sequence from drug 
administration and is readily explained by the subject’s clinical state or by 
other modes of therapy administered to the subject. 
Possibly 
Related: 
There is some temporal relationship between the event and the administration 
of the study drug and the event is unlikely to be explained by the subject’s 
medical condition, other therapies, or accident. 
Probably 
Related: 
The event follows a reasonable temporal sequence from drug administration, 
abates upon discontinuation of the drug, and cannot be reasonably explained 
by the known characteristics of the subject’s clinical state. 
Definitely 
Related: 
The event follows a reasonable temporal sequence from study drug 
administration, follows a known or suspected response pattern to the study 
drug, is confirmed by improvement upon stopping the study drug 
(dechallenge), and reappears upon repeated exposure (rechallenge, if 
rechallenge is medically appropriate). 
The Sponsor may upgrade causality if deemed appropriate. 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions 
Any SAE must be reported by phone or email to the Sponsor Medical Monitor and in writing via 
email using the SAE report form within 24 hours of the  Investigator’s awareness of the SAE. In 
addition, all SAEs must be recorded on the AE CRF in real time. All additional follow-up 
evaluations of the SAE must be reported to BioCryst or its designee as soon as they are available. 
The SAE report forms should be sent to the following email address: 
Phone (24 hours) +1 919-859-7905 
Email: mm@biocryst.com 
Immediate reporting should allow BioCryst to take the appropriate measures to address potential 
new risks in a clinical trial. Therefore, the initial report should be submitted by the  Investigator 
within a very short period of time and under no circumstances should this period exceed 24 hours 
following awareness of the SAE. 
The follow-up report should allow BioCryst to determine whether the SAE requires a 
reassessment of the benefit-risk profile of the study drug in clinical trial, if the relevant 
information was not already available and provided in the initial report. 
US-based  Investigators or designees at each site are responsible for submitting any 
investigational new drug (IND) safety report (initial and follow-up) (i.e., suspected unexpected 
serious adverse reactions [SUSARs]) or other safety information (eg, revised IB) to the IRB and 
for retaining a copy in their files, unless otherwise instructed. 
European-based  Investigators or designees at each site are responsible for retaining copies of all 
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BioCryst or its designee will submit all SUSAR reports (initial and follow-up) or other safety 
information (eg, revised IB) to the required authorities. 
BioCryst shall ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the competent authorities in all 
European Member States concerned, the US, and other countries as warranted as well as to the 
independent ethics committees (IECs), and in any case no later than seven (7) days after 
knowledge by BioCryst of such a case, and that relevant follow-up information is subsequently 
communicated within an additional eight (8) days. All other SUSARs shall be reported to the 
competent authorities concerned and to the IECs concerned as soon as possible but within a 
maximum of 15 days of first knowledge by BioCryst. BioCryst or designee shall also inform all  
Investigators. 
12.1.5.1. Reporting Events of Special Interest 
Although not an SAE, all events of diffuse maculopapular rash assessed as related to BCX7353 
regardless of severity, must be reported to the Sponsor Medical Monitor in writing via email 
using the SAE/EOSI report form after the  Investigator’s assessment of the event. High 
resolution photographs must also be submitted as described in Section 11.1.12. In addition, the 
event must be recorded on the AE CRF in real time. All additional follow-up evaluations of the 
event must be reported to BioCryst or its designee as soon as they are available. The SAE/EOSI 
report form should be sent to the following email address:  
Phone (24 hours) +1 919-859-7905 
Email: mm@biocryst.com 
This method of reporting will allow BioCryst to obtain more information than can be captured in 
the eCRF for this event. The report form will allow a full clinical description and information 
regarding the evaluation that cannot be documented in the EDC due to free text limitations to be 
shared with BioCryst. Therefore, the initial report and photographs should be submitted by the  
Investigator within a very short period of time.  
The follow-up report should contain new information about the clinical course, medical 
evaluation, additional photographs (if relevant), biopsy (if done), and laboratory results (if done). 
12.1.6. 
Pregnancy 
Any female subject who becomes pregnant during the course of the study should have study drug 
discontinued immediately and must be followed through the end of the pregnancy. Male subjects 
whose partners become pregnant do not need to discontinue study drug. While pregnancy is not 
considered an AE, all cases of fetal drug exposure via the parent as a study participant (including 
partners of study participants) are to be reported immediately to BioCryst or its designee. 
Consent from pregnant partners of study participants will be obtained prior to reporting any 
details of the pregnancy. Information related to the pregnancy must be given on a “Pregnancy 
Confirmation and Outcome” form that will be provided by the Sponsor or its designee so that the 
pregnancy may be followed and an outcome determined. Any AEs or SAEs experienced by a 
pregnant subject are to be reported as directed above in Section 12.1.2 and Section 12.1.5. Any 
complications reported in a subject’s pregnant partner should be reported on the Pregnancy 
Confirmation and Outcome form. All pregnancies must be followed to outcome which occurs 


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when an infant is delivered (live or still born), there is fetal demise, or there is an abortion 
(spontaneous or induced). Abortion (spontaneous or induced), fetal demise, and still birth along 
with congenital abnormalities in the newborn, should be reported as separate SAEs. 
12.1.7. 
Serious Breaches of Good Clinical Practice 
It is the responsibility of the Sponsor to notify the licensing authority of any serious breach of 
Good Clinical Practice (GCP) which is likely to effect, to a significant degree, the safety or 
mental integrity of the subjects of the study or the scientific value of the study. All serious 
breaches will be notified to the relevant competent authority within 7 days. The reporting to the 
Sponsor will be performed by the party who suspects the serious breach. 
12.1.8. 
Treatment Interruptions 
Treatment interruptions as a result of  Investigator management of AEs potentially related to 
study drug are permissible. Resumption of study drug administration is also permissible upon 
resolution of the event, as assessed by the  Investigator, with a plan for stringent monitoring of 
the subject for recurrence of the AE as appropriate. In addition, other extenuating circumstances 
may lead to treatment interruptions such as vomiting during an abdominal HAE attack or 
required fasting for medical procedures; in these cases, study drug should be resumed once the 
extenuating circumstance is resolved.  
The Sponsor Medical Monitor should be notified in the event of a treatment interruption due to 
an AE. Any treatment interruption will be recorded in the CRF and source documents, including 
the reason for the interruption. 
12.2. 
Toxicity Management 
The  Investigator (or qualified designee) will grade clinically significant events and laboratory 
abnormalities according to that detailed in Section 12.1.3. Grade 3 and 4 clinically significant 
laboratory abnormalities should be confirmed by repeat testing and before any contemplated 
study drug discontinuation, unless such a delay is not consistent with good medical practice. 
In the event that a new safety signal emerges, a meeting of the DMC may be convened by the 
Sponsor to evaluate risk to subjects and recommend appropriate actions. Based on the data 
presented, a decision will be made as to whether to halt the study, to continue dosing, or to 
continue dosing with provisions introduced into the protocol via substantial amendment. 
12.2.1. 
Rash 
Special evaluation of BCX7353 related maculopapular drug rash is required as per 
Section 11.1.12 and special reporting is described in Section 12.1.5.1.  
Management of rash should be based on best medical practice and address the subject’s 
presentation. If a subject experiences a Grade 3 or 4 rash suspected to be due to BCX7353, the 
subject should have BCX7353 dosing stopped immediately as per Section 8.3.2. Grade 3 rashes 
would include rashes with vesiculation, moist desquamation, or ulceration and Grade 4 rashes 
would encompass rashes with mucous membrane involvement or significant exfoliation, 
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12.2.1.1. Study Drug Administration for Grade 1 or 2 Rashes Considered Related to 
Study Drug 
Investigators and subjects may elect to continue dosing if the subject experiences a Grade 1 or 2 
rash that is deemed related to BCX7353 but the subject is considered to be deriving benefit. By 
DMID criteria, this reaction would be described as pruritus and/or erythema (Grade 1) or a 
diffuse maculopapular rash and/or dry desquamation (Grade 2). In addition, subjects would have 
to be constitutionally well (no fever, no change in appetite, no malaise, etc.), have no mucosal 
involvement, no vesicles and have no evidence of any hypersensitivity involving the liver or 
kidney. If laboratory assessment is performed mild or moderate eosinophilia may be present but 
should not prevent continuation of study drug if all other criteria are met. Rash treatment should 
primarily address symptoms (i.e., antihistamines, topical antipruritics and/or topical 
corticosteroids). Oral corticosteroids should be avoided, as there is no evidence that oral 
corticosteroids benefit patients with bland drug-related cutaneous reactions.  
If the subject’s rash does not improve, or worsens to include vesicles, wet desquamation or 
ulceration (Grade 3), then BCX7353 should be immediately discontinued. Subjects who remain 
on study drug should be followed closely until the rash resolves.  
12.2.2. 
Aminotransferase (ALT or AST) Elevation  
All baseline or treatment-emergent ALT or AST elevations > 3 × ULN (ie, Grade 3 and above) 
should be confirmed within 72 hours with repeat assessment of ALT and AST as well as total 
bilirubin, ALP, prothrombin time /INR, and complete blood count for eosinophil levels. If 
subjects are asymptomatic with no other pertinent laboratory abnormality, study drug may be 
continued under close observation with every 2 week assessment of transaminase levels, total 
bilirubin, and ALP. These may be done at a local laboratory as long as results are reported to the  
Investigator as soon as they are available and the investigative site contacts the subject to 
ascertain any symptoms. If either ALT or AST continue to increase and the subject remains 
asymptomatic, study drug dosing must be held if: 
• Either ALT or AST is > 5 × ULN for more than 2 weeks  
• The ALT or AST reaches > 8 × ULN  
The subject should continue regular assessments as deemed appropriate by the  Investigator of 
ALT, AST, total bilirubin, ALP, prothrombin time/INR, and complete blood count for eosinophil 
levels until ALT and/or AST are < 3 × ULN. 
Provided specific criteria are met, the  Investigator and subject may elect to resume BCX7353 
dosing. All of the following criteria must be met for dosing to resume: 
• The subject is considered to have been deriving benefit from BCX7353 prior to holding 
study drug.  
• Transaminases return to ≤ 2 × ULN for subjects whose baseline transaminase levels were 
above the ULN, and ≤ ULN for those whose baseline transaminase levels were ≤ ULN. 
• Subjects have not initiated or restarted androgens during the period BCX7353 was held. 
• The subject agrees to continue every 2 week monitoring of ALT, AST, total bilirubin, 
ALP, CBC (eosinophil levels) and prothrombin/INR until levels appear stable and 


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transaminase levels remain < 3 × ULN for at least 1 month after restarting BCX7353 
dosing. 
If at any time, the criteria as outlined in Section 8.3.2 is met, the study drug must be permanently 
discontinued. 
12.2.3. 
Overdose 
To date there is no experience with overdose of oral BCX7353. Single doses of up to 1000 mg, 
7 days of dosing up to 500 mg/day, and 14 days of dosing with 350 mg/day revealed no 
clinically significant safety concerns in healthy subjects in Study BCX7353-101. In 
Study BCX7353-102, multiple dosing with 350 mg BCX7353 for up to 9 days either following 
or current with single doses of CYP probe substrate drugs in healthy subjects overall did not 
reveal any new safety concerns. Safety data generated in Study BCX7353-203, 28-day dosing 
with up to 350 mg/day, revealed no clinically significant safety concerns in subjects with HAE. 
Subsequently, subjects enrolled in BCX7353-106 were exposed to BCX7353 450 mg QD for 
14 days without any unexpected AEs or increased AE severity. 
In the event that study personnel become aware of an overdose of study drug/IMP (≥ 150 mg per 
calendar day) that is associated with an AE, both the overdose and the resultant event should be 
reported as AEs. Overdose without any symptoms (i.e., AEs) does not need to be reported as an 
AE. If overdose occurs with or without associated AEs, subjects should undergo clinical and 
laboratory monitoring as appropriate for their clinical condition and, if indicated, should receive 
clinically-indicated supportive therapy.  
Additional information about overdose as an AE or SAE is discussed in Section 12.1.1.2. 
12.3. 
Data Monitoring Committee 
Data from ongoing studies BCX7353-302 (Phase 3 study), BCX7353-301 (Phase 3 study) and 
the current study, BCX7353-204, are reviewed by the BCX7353 data monitoring committee 
(DMC). Since a total of over 200 subjects have completed 48 weeks across the studies, the DMC 
will be provided with data for review every 6 months until the last subject completes the study or 
the product is approved in the first country globally. A formal meeting of the DMC members 
will not be required; however, if the data review identifies any concern, the DMC members may 
elect to hold a formal DMC meeting. Where possible, scheduled DMC meetings for this protocol 
may be aligned with those of other protocol(s). The DMC may also be convened if a new 
clinically significant safety signal emerges or at other times as requested. 
The latest data review was conducted on 23 October 2019.   
The recommendation of the DMC was that all 3 studies proceed per protocol. 
A separate DMC Charter will describe membership, roles, timing of DMC review, and 
responsibilities of the DMC members. 


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13. 
STATISTICS 
13.1. 
Sample Size Considerations 
No sample size calculations were conducted for this open-label, long-term safety study. 
Approximately 475 subjects may be enrolled in this study, with approximately 250 subjects 
planned to be enrolled in the US, to provide access to BCX7353 for additional subjects who, in 
the opinion of the  Investigator, are expected to benefit from treatment with an oral treatment for 
the prevention of angioedema attacks.  
13.2. 
Stratification 
Not applicable. 
13.3. 
Statistical Methods 
A detailed SAP will be developed to describe the methods of analyses and summaries, including 
all endpoints, time points, populations, missing data, etc. Deviations from the analyses outlined 
in the SAP will be described in the CSR.  
13.3.1. 
Analysis Populations 
The analysis populations are defined below. 
13.3.1.1. Screen Failures 
Subjects who give written informed consent but are not assigned to study treatment and are noted 
as screen failures in the CRF are considered screen failures. 
13.3.1.2. Safety Population 
The safety population will include all subjects who received at least 1 capsule of study drug. This 
population will be used for all analyses of accountability, demographics, BCX7353 drug 
concentrations, and safety. 
13.3.1.3. Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who are allocated to study drug. The 
ITT population will be used as the primary population for effectiveness analyses. Subjects will 
be analyzed based on the treatment to which they were allocated. 
13.3.2. 
General Considerations for Data Analysis 
In general, descriptive summaries will include n, mean, standard deviation, median, minimum, 
and maximum for continuous variables and n and percent for categorical variables. Summaries 
will be presented by treatment group and by study visit. 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA). 


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13.3.3. 
Missing Data 
For subjects who prematurely discontinue the study, all available data will be included for the 
key safety and effectiveness analyses.  
13.3.4. 
Subject Demographic and Disposition Data 
Demographic data and baseline characteristics including age, gender, race or ethnicity, height, 
weight, BMI, and HAE history will be summarized by treatment group.  
Subject disposition will be presented for all subjects. The number of subjects who completed 
through each study visit and those that discontinued from the study will be provided. The reasons 
for early discontinuation also will be presented. A tabulation of the number of subjects exposed 
to study drug and duration of exposure will also be presented. Treatment adherence, dose 
interruptions and reason for dose interruptions will be provided as summaries or listed as 
appropriate. 
13.3.5. 
Analysis of Safety Variables 
Safety endpoints that will be summarized, at a minimum by treatment group, include the 
proportion of subjects 1) with TEAEs; 2) who discontinue BCX7353 due to TEAEs; 3) with 
treatment-emergent SAEs; 4) with treatment-emergent Grade 3 or 4 AEs; 5) with 
treatment-emergent treatment-related AEs consistent with a drug rash as identified by the  
Investigator (eg, maculopapular rash, papular rash identified as an EOSI), and 6) with 
treatment-emergent Grade 3 or 4 laboratory abnormalities.  
Time to discontinuation due to a TEAE, and time to development of drug-related rash will be 
estimated using the Kaplan-Meier method. For those with a drug-related rash, clinical and 
laboratory findings will be summarized and the proportion of subjects who successfully 
continued therapy following onset of rash. 
AEs will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) PT and SOC. 
The occurrence of TEAEs will be summarized using MedDRA PT, SOC, and severity. Separate 
summaries of TEAEs, treatment-emergent SAEs, AEs considered to be related to study drug, and 
AEs leading to study drug interruption will be generated. All AEs will be listed for individual 
subjects showing both verbatim and preferred terms.  
Descriptive summaries for vital signs, weight, bedside ECG parameters, and clinical laboratory 
results will be presented. Laboratory abnormalities will be graded according to the DMID Adult 
Toxicity Table (Publish Date: Draft, November 2007; Appendix 16.1).  
Any graded abnormality that occurs following the initiation of study drug and represents at least 
1-grade increase from the baseline assessment is defined as treatment-emergent. The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized. 
Laboratory toxicity shifts from baseline to worst postbaseline assessments will be summarized.  
The number and percentage of subjects having elevations in liver enzyme abnormalities (ALT, 
AST, or bilirubin) in relation to fold above ULN will be summarized according to the FDA’s 
Premarketing Clinical Evaluation on Drug-Induced Liver Injury Guidance for Industry (FDA 
2009). 
Clinically significant abnormal morphological ECG findings will be summarized.  


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The change from baseline in QTcF will be determined by routine ECGs. At each time point 
ECGs are analyzed, an individual subject’s change from baseline will be calculated as: 
∆ik= (QTcF for subject at time point k – Baseline QTcF) 
Where QTcF measurements will be the average of triplicate ECGs at baseline and single values 
at each time point.  
For routine ECGs, the number and proportion of subjects with QTcF ≤ 450, > 450 to ≤ 480, 
> 480 to ≤ 500, and > 500 msec; or changes of ≤ 30, > 30 to ≤ 60, or > 60 msec will be 
summarized.  
Physical examination findings will be listed.  
Concomitant medications and those discontinued during the study will be coded using the World 
Health Organization drug dictionary and summarized.  Subjects with medications changes prior 
to baseline may also be summarized.  
13.3.6. 
Analysis of Effectiveness Variables 
The following effectiveness endpoints will be summarized and listed by treatment group: 
• Number and rate of HAE attacks 
• Durability of response  
• Number and proportion of days with angioedema symptoms days 
• Patient-reported outcomes: HAE disease-specific AE-QoL questionnaire scores and 
TSQM Global Satisfaction scores 
• Number of attacks requiring attack medication 
• Discontinuations due to lack of efficacy (through 48 weeks only) 
• Disease severity  
All attacks recorded by the subjects will be reviewed and confirmed or rejected according to a set 
of pre-defined rules prior to inclusion in effectiveness analyses. These rules, which will be 
constructed in concert with HAE-treating physicians, will be outlined in the SAP. 
The attack rate will be calculated as the number of attacks per month (28 days) by treatment for 
each subject, adjusted for the total duration of treatment. The attack rate will be listed and 
summarized using all available data. The durability of response assessment will be based on 
attack rate trend over time. Alternatively, the attack rate change may also be assessed relative to 
recent HAE attack documentation. Summaries and/or comparisons of effectiveness endpoints 
may be performed for those who received concomitant C1-INH and those who did not.  
Additional related details of HAE attacks (e.g., hospitalizations and emergency room visits) and 
number of days lost from work and/or school due to attacks will be summarized and listed. 
Summaries may be produced separately for pre-96 week attacks and post-96 week attacks as 
fewer details are collected in the diary post 96 weeks. 
Details of these analyses will be provided in the SAP. 


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13.3.7. 
Interim and Final Analyses 
Interim analyses may be performed during the course of the study as needed to support 
regulatory filings and safety updates. The final analysis will be performed when the last subject 
has completed the final study visit, the data are cleaned, and the database has been authorized for 
analysis. 
13.3.8. 
Quality of Life Analyses 
Scores at each visit and change from baseline in the domain scores of the AE-QoL (function, 
fatigue, nutrition, and fear/shame) as well as the composite score will be summarized by 
treatment group.  
The change from baseline in TSQM Global Satisfaction scores as well as effectiveness, side 
effects, and convenience subscales will be summarized. 
13.3.9. 
Pharmacokinetic Analyses 
Plasma samples for determination of BCX7353 concentrations are planned to be collected at 
Baseline and Weeks 4 and 12  for adolescent subjects only (≥12 to 17 years of age). The 
resulting PK data may be pooled in a meta analysis to facilitate population PK analyses. 
14. 
STUDY ADMINISTRATION 
14.1. 
Regulatory and Ethical Considerations 
14.1.1. 
Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; GCPs, including ICH of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Guidelines (ICH E6); 
FDA/European Medicines Agency regulatory requirements and other national laws as applicable; 
and in accordance with the ethical principles of the Declaration of Helsinki. In addition, the 
study will be conducted in compliance with all applicable local laws and regulatory requirements 
relevant to the use of new therapeutic agents. 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals 
Before initiation of the study at an investigational site, the protocol, the ICF, the subject 
information sheet (if applicable), and any other relevant study documentation will be submitted 
to the appropriate IRB/IEC. Written approval of the study must be obtained before the study 
center can be initiated or the IMP can be released to the  Investigator. Any necessary extensions 
or renewals of IRB/IEC approval must be obtained, in particular, for changes to the study such as 
modification of the protocol, the ICF, the written information provided to subjects, and/or other 
procedures. 
The IRB/IEC will be promptly provided any new information that may adversely affect the 
safety of the subjects or the conduct of the study. On completion of the study, the IRB/IEC will 
be provided with a report of the outcome of the study. 


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Written reports of clinical study status will be submitted to the IRB/IEC annually or more 
frequently if requested by the IRB/IEC. A final study notification will also be forwarded to the 
IRB/IEC after the study is completed or in the event of premature termination of the study in 
accordance with the applicable regulations. The study will be considered to be completed once 
the last subject completes their last study visit. Copies of all contact with the IRB/IEC should be 
maintained in the study file. Copies of clinical study status reports (including termination) should 
be provided to BioCryst. 
14.1.3. 
Subject Informed Consent: Adults 
A signed ICF must be obtained from each subject prior to performing any study-related 
procedures. Each subject should be given both verbal and written information describing the 
nature and duration of the clinical study. The informed consent process should take place under 
conditions where the subject has adequate time to consider the risks and benefits associated with 
his/her participation in the study. Subjects will not be screened or treated until the subject has 
signed an approved ICF written in a language in which the subject is fluent.  
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/IEC. The ICF 
should be in accordance with the current revision of the Declaration of Helsinki, current ICH and 
GCP guidelines, and BioCryst policy. 
The  Investigator must explain to potential subjects the aims, methods, reasonably anticipated 
benefits, and potential hazards of the trial and any discomfort it may entail. Subjects will be 
informed that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time. They will be told that refusal to participate in the study will not prejudice 
future treatment. They will also be told that their records may be examined by competent 
authorities and authorized persons but that personal information will be treated as strictly 
confidential and will not be publicly available. Subjects must be given the opportunity to ask 
questions. After this explanation and before entry into the trial, consent should be appropriately 
recorded by means of the subject’s dated signature. The subject should receive a signed and 
dated copy of the ICF. The original signed ICF should be retained in the study files. The  
Investigator shall maintain a log of all subjects who sign the ICF and indicate if the subject was 
enrolled into the study or reason for non-enrollment. 
In the event the subject is requested to undergo a skin biopsy due to rash, a separate informed 
consent will be required. Subjects with a Grade 1 or 2 rash remaining on study drug may undergo 
a biopsy, for which a separate informed consent will be obtained. 
14.1.4. 
Subjects Informed Consent: Adolescents 
Subject informed consent must be obtained from each parent/caregiver prior to performing any 
study-related procedures. Similarly, assent will be obtained from subjects ≥ 12 years to 17 years 
of age prior to performing any study-related procedures. If the local requirements limit the age of 
assent, then assent will be obtained based on those requirements. Each parent/caregiver and 
subject should be given both verbal and written information describing the nature and duration of 
the clinical study. The informed consent and assent process should take place under conditions 
where the parent/caregiver has adequate time to consider the risks and benefits associated with 
his/her child’s participation in the study. Subjects will not be screened or treated until the 
parent/caregiver and subjects has signed an approved ICF and assent form written in a language 
in which the subject is fluent. The ICF and assent forms that are used must be approved both by 


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BioCryst and by the reviewing IRB/IEC. The ICF and assent forms should be in accordance with 
the current revision of the Declaration of Helsinki, current ICH and GCP guidelines, and 
BioCryst policy.  
  
The  Investigator must explain to potential subjects and their parent/ caregiver the aims, methods, 
reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may 
entail. Each parent/caregiver will be informed that they are free for their child not to participate 
in the trial and that they may withdraw consent for their child to participate at any time. They 
will be told that refusal for their child to participate in the study will not prejudice future 
treatment. They will also be told that their child’s records may be examined by competent 
authorities and authorized persons but that personal information will be treated as strictly 
confidential and will not be publicly available.  
Parents/caregivers and subjects must be given the opportunity to ask questions. After this 
explanation and before entry into the trial, consent and assent should be appropriately recorded 
by means of the parent’s/caregiver’s and subject’s dated signature. The parent/ caregiver should 
receive a signed and dated copy of the ICF, and, if applicable, the assent. The original signed 
informed consent and assent, if applicable, should be retained in the study files. The  Investigator 
shall maintain a log of all subjects for whom consent was signed and indicate if the subject was 
enrolled into the study or reason for non-enrollment. 
In the event the subject is requested to undergo a skin biopsy due to rash, a separate informed 
consent and assent form will be required. Subjects with a Grade 1 or 2 rash remaining on study 
drug may undergo a biopsy, for which a separate informed consent and assent will be obtained. 
14.1.5. 
 Investigator Reporting Requirements 
The  Investigator will provide timely reports regarding safety to his/her IRB/IEC as required. 
14.2. 
Study Monitoring 
During trial conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed. The monitors will review source documents to 
confirm that the data recorded on CRFs is accurate. The  Investigator and institution will allow 
BioCryst representatives, monitors, or its designees direct access to source documents to perform 
this verification. 
It is important that the Principal  Investigator(s) and their relevant personnel are available during 
the monitoring visits and that sufficient time is devoted to the process. 
14.3. 
Quality Assurance 
The Principal  Investigator may be subject to visits by the IRB/IEC, and/or by a quality 
assurance group for audits performed by BioCryst, or its designee, and/or to inspection by 
appropriate regulatory authorities. 
It is important that the  Investigator(s) and their relevant personnel are available during the 
possible audits or inspections and that sufficient time is devoted to the process. 


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14.4. 
Study Termination and Site Closure 
Overall, the Sponsor may suspend enrollment into the study, suspend treatment of ongoing 
subjects, or terminate the study to ensure that subjects’ safety and welfare are protected. The 
entire study, or individual sites, may be terminated for any of the following reasons: 
• changes in scientific knowledge that lead to a negative impact on the risk/benefit profile 
for subjects 
• request of BioCryst or competent public authorities / IRB / EC 
• if recruitment cannot be completed in specified time frame 
• if the permit to manufacture or import IMP is revoked 
• if the study drug becomes commercially available 
BioCryst reserves the right to discontinue the trial prior to inclusion of the intended number of 
subjects but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the  Investigator must contact all participating subjects immediately after 
notification. As directed by BioCryst, all study materials must be collected and all CRFs 
completed to the greatest extent possible. 
An individual trial center that is determined to be unsuitable by Sponsor, competent public 
authorities or EC may be terminated, without affecting the other trial sites.  
Except for those situations outlined in Section 8.3, no other formal stopping rules for individual 
subjects, parts of the trial or the entire trial, will be defined. Individual subjects will be 
discontinued from the study following the emergence of any laboratory abnormality or AE that 
in the judgment of the  Investigator compromises the ability to continue study-specific 
procedures or is considered not to be in the subject’s best interest. 
14.5. 
Records Retention 
To enable evaluations and/or audits from regulatory authorities or BioCryst, the  Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, CRFs, and medical/hospital records), all original signed ICFs, all CRFs, and 
detailed records of study drug accountability and treatment disposition. The records should be 
retained by the  Investigator according to local regulations or as specified in the Clinical Trial 
Agreement, whichever is longer. 
If the  Investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another  Investigator, another 
institution, or to BioCryst. The  Investigator must obtain BioCryst’s written permission before 
disposing of any records and must notify BioCryst before transferring any records to another 
facility. 
All correspondence related to records retention, destruction or transfer of study documents 
should be sent directly to BioCryst study personnel, copying the email archives@biocryst.com. 


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14.6. 
Confidentiality of Information and Data 
BioCryst affirms the subject’s right to protection against invasion of privacy and secure 
maintenance of the confidential nature of their personal data. Only a subject identification 
number and subject identifiers permitted by local regulation will identify subject data retrieved 
by BioCryst. However, in compliance with federal regulations, BioCryst requires the  
Investigator to permit BioCryst’s representatives and, when necessary, representatives of the 
FDA or other regulatory authorities to review and/or copy any medical records relevant to the 
study, maintaining pseudo-anonymity. 
All parties will abide by all applicable laws and regulations regarding subject privacy and 
confidentiality, including, the Health Insurance Portability and Accountability Act (HIPAA), 
where this rule is applicable and the requirements of the Data Protection Regulation in the 
European Union, where applicable. A valid authorization and consent must meet the 
specifications of the applicable laws and regulations relating to such personal data and health 
information. It is the responsibility of the  Investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are 
required for US sites only. 
14.7. 
Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict 
confidence along with all information furnished by BioCryst. Except as provided through written 
agreement between BioCryst, independent analysis and/or publication of these data by the  
Investigator or any member of his/her staff is not permitted without prior written consent of 
BioCryst. Such consent will not be withheld unreasonably. BioCryst is in agreement with the 
principle of full disclosure of clinical trial results. 


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15. 
REFERENCES 
Aygoren-Pursun, E., A. Bygum, V. Grivcheva-Panovska, M. Magerl, J. Graff, U. C. Steiner, 
O. Fain, A. Huissoon, T. Kinaciyan, H. Farkas, R. Lleonart, H. J. Longhurst, W. Rae, M. 
Triggiani, W. Aberer, M. Cancian, A. Zanichelli, W. B. Smith, M. L. Baeza, A. Du-Thanh, 
M. Gompels, T. Gonzalez-Quevedo, J. Greve, M. Guilarte, C. Katelaris, S. Dobo, M. 
Cornpropst, D. Clemons, L. Fang, P. Collis, W. Sheridan, M. Maurer and M. Cicardi (2018). 
"Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema." N Engl J Med 
379(4): 352-362. 
Bork, K., J. Hardt and G. Witzke (2012). "Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency." J Allergy Clin Immunol 130(3): 692-697. 
Bork, K., G. Meng, P. Staubach and J. Hardt (2006). "Hereditary angioedema: new findings 
concerning symptoms, affected organs, and course." Am J Med 119(3): 267-274. 
Bouillet, L., H. Longhurst, I. Boccon-Gibod, K. Bork, C. Bucher, A. Bygum, T. Caballero, C. 
Drouet, H. Farkas, C. Massot, E. W. Nielsen, D. Ponard and M. Cicardi (2008). "Disease 
expression in women with hereditary angioedema." Am J Obstet Gynecol 199(5): 484 e481-
484. 
Caballero, T., H. Farkas, L. Bouillet, T. Bowen, A. Gompel, C. Fagerberg, J. Bjokander, K. 
Bork, A. Bygum, M. Cicardi, C. de Carolis, M. Frank, J. H. Gooi, H. Longhurst, I. Martinez-
Saguer, E. W. Nielsen, K. Obtulowitz, R. Perricone, N. Prior and C. I. D. W. Group (2012). 
"International consensus and practical guidelines on the gynecologic and obstetric 
management of female patients with hereditary angioedema caused by C1 inhibitor 
deficiency." J Allergy Clin Immunol 129(2): 308-320. 
Cicardi, M., K. Bork, T. Caballero, T. Craig, H. H. Li, H. Longhurst, A. Reshef, B. Zuraw 
and Hawk (2012). "Evidence-based recommendations for the therapeutic management of 
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International 
Working Group." Allergy 67(2): 147-157. 
Cornpropst, M., S. Dobo, J. Collier, A. Rose, R. Wilson, Y. S. Babu, P. Collis and W. 
Sheridan (2016). "BCX7353, a Potent Inhibitor of Plasma Kallikrein, Shows Sustained 
Maximal Enzyme Inhibition When Dosed Orally Once Daily: Results from a Phase I Trial in 
Healthy Subjects." Elsevier(AAAAI, Los Angeles). 
FDA (2009). "Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation." US DHHS, FDA, 
CDER(https://www.fda.gov/downloads/guidances/UCM174090.pdf). 
Kaplan, A. P. (2010). "Enzymatic pathways in the pathogenesis of hereditary angioedema: 
the role of C1 inhibitor therapy." J Allergy Clin Immunol 126(5): 918-925. 
Kaplan, A. P. and B. Ghebrehiwet (2010). "The plasma bradykinin-forming pathways and its 
interrelationships with complement." Mol Immunol 47(13): 2161-2169. 
Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-
481. 


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Lumry, W. R., A. J. Castaldo, M. K. Vernon, M. B. Blaustein, D. A. Wilson and P. T. Horn 
(2010). "The humanistic burden of hereditary angioedema: Impact on health-related quality 
of life, productivity, and depression." Allergy Asthma Proc 31(5): 407-414. 
Saxena, P., P. Thompson, Y. d'Udekem and I. E. Konstantinov (2011). "Kallikrein-kinin 
system: a surgical perspective in post-aprotinin era." J Surg Res 167(1): 70-77. 
Shire (2018). "Takhyzyro (lanadelumab-flyo) injection, for subcutaneous use US Prescribing 
Information." 9. 
Weller, K., M. Magerl, A. Peveling-Oberhag, P. Martus, P. Staubach and M. Maurer (2016). 
"The Angioedema Quality of Life Questionnaire (AE-QoL) - assessment of sensitivity to 
change and minimal clinically important difference." Allergy 71(8): 1203-1209. 
Zuraw, B. L., A. Banerji, J. A. Bernstein, P. J. Busse, S. C. Christiansen, M. Davis-Lorton, 
M. M. Frank, H. H. Li, W. R. Lumry and M. Riedl (2013). "US Hereditary Angioedema 
Association Medical Advisory Board 2013 Recommendations for the Management of 
Hereditary Angioedema Due to C1 Inhibitor Deficiency." J Allergy Clin Immunol Pract 1(5): 
458-467. 
Zuraw, B. L. and S. C. Christiansen (2011). "Pathophysiology of hereditary angioedema." 
Am J Rhinol Allergy 25(6): 373-378. 
 
 


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16. 
APPENDICES 
16.1. 
DMID Adult Toxicity Table (DRAFT, Publish Date: November 2007) 
https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf 
Copies of the DMID Toxicity Table will be available to the medical staff throughout the project. 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to 
moderate 
limitation 
in 
activity - some assistance may be needed; no or minimal 
medical intervention/therapy required 
GRADE 3 
Severe  
 
Marked limitation in activity, some 
assistance usually required; medical intervention/therapy 
required, hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme 
limitation 
in 
activity, 
significant 
assistance 
required; 
significant 
medical 
intervention/therapy required, hospitalization or hospice 
care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
HEMATOLOGY 
 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hemoglobin 
 
9.5 - 10.5 gm/dL 
 
8.0  - 9.4gm/dL 
 
 6.5 - 7.9 gm/dL 
 
< 6.5 gm/dL 
 
Absolute Neutrophil Count 
 
1000-1500/mm3 
 
750-999/mm3 
 
500-749/mm3 
 
<500/mm3 
 
Platelets 
 
75,000-
99,999/mm3 
 
50,000-
74,999/mm3 
 
20,000-49,999/mm3 
 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
 
 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL  
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL  
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
 
Fibrin Split Product 
 
20-40 mcg/ml 
 
41-50 mcg/ml 
 
51-60 mcg/ml 
 
> 60 mcg/ml 
 
Prothrombin  
Time (PT) 
 
1.01 - 1.25 x ULN 
 
1.26-1.5 x ULN 
 
1.51 -3.0 x ULN 
 
>3 x ULN 
 
Activated Partial 
Thromboplastin (APPT) 
 
1.01 -1.66 x ULN 
 
1.67 - 2.33 x 
ULN 
 
2.34 - 3 x ULN 
 
> 3 x ULN 
 
Methemoglobin 
 
5.0 - 9.9 % 
 
10.0 - 14.9 % 
 
15.0 - 19.9% 
 
> 20.0 % 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
CHEMISTRIES (continued) 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
 
1.0 -1.4 mg/dL  
intensive therapy  
or 
hospitalization 
required 
 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x 
ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
 
BUN 
 
1.25 - 2.5 x ULN 
 
2.6 - 5 x ULN 
 
5.1 - 10 x ULN 
 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
 
 
 
Creatinine 
 
1.1 - 1.5 x ULN  
 
1.6 - 3.0 x ULN 
 
3.1 - 6 x ULN 
 
> 6 x ULN or 
dialysis required 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ENZYMES 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Alkaline Phosphatase 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Amylase 
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
Lipase  
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
 
 
URINALYSIS 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Proteinuria 
 
1+ 
 or  
200 mg - 1 gm 
loss/day 
 
2-3+  
or  
1- 2 gm 
loss/day 
 
4+ 
 or  
2-3.5 gm loss/day 
 
nephrotic 
syndrome  
or 
> 3.5 gm loss/day 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
 
gross, with or 
without clots, OR 
red blood cell casts 
 
obstructive or 
required 
transfusion 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
SKIN 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
 
 
 
 
SYSTEMIC 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Allergic Reaction 
 
pruritus without 
rash 
 
localized 
urticaria 
 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
 
Fever: oral 
 
37.7 - 38.5 C or  
100.0 - 101.5 F 
 
38.6 - 39.5 C or 
101.6 - 102.9 F 
 
39.6 - 40.5 C or 
103 - 105 F 
 
> 40 C or 
> 105 F 
 
Fatigue 
 
normal activity 
reduced < 48 hours 
 
 normal activity 
decreased 25- 
50% > 48 hours 
 
normal activity 
decreased > 50% 
can’t work 
 
unable to care for 
self 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
1 
 
JTITLE PAGE 
STATISTICAL ANALYSIS PLAN 
PHASE II-III 
 
VERSION: 1.0 
DATE OF PLAN: 26 February 2019 
BASED ON: 
 Protocol Version 5.0 (US only): 7 February 2019 
Protocol Version 4.0: 5 October 2018 
Protocol Version 3.0: 6 December 2017 
Protocol Version 2.0: 5 December 2017 
Protocol Version 1.0: 20 September 2017 
STUDY TITLE: 
An open-label study to evaluate the long-term safety of daily oral BCX7353 in subjects with 
Type I and II hereditary angioedema 
STUDY DRUG: 
BCX7353 
PROTOCOL NUMBER: 
BCX7353-204 
SPONSOR: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703 
(919) 859-1302 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents.  
The information in this document contains proprietary and confidential information belonging to 
BioCryst Pharmaceuticals, Inc. As a result, no part of this document should be copied, referred 
to, released, published or otherwise disclosed in any manner or media without prior written 
approval from BioCryst Pharmaceuticals, Inc. 
 
CONFIDENTIAL 




Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
3 
 
TECHNICAL SUMMARY REPORT (TSR) 
 
 
Name of Sponsor/Company 
BioCryst Pharmaceuticals, Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
BCX7353 
Page: 
 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-
(5-((3-
cyanophenyl)(cyclopropylmethyla
mino)methyl)-2-fluorophenyl)-3-
(trifluoromethyl)-1H-pyrazole-5-
carboxamide dihydrochloride  
 
 
Title of Study: 
An open-label study to evaluate the long-term safety of daily oral BCX7353 in subjects with Type I and II 
hereditary angioedema  
Investigators: 
Study Centers: Global, multiple study centers 
Studied period (years):  
2 
Phase of development:  
2 
Objectives: 
Primary:  
• 
To evaluate the long-term safety and tolerability of daily dosing of oral BCX7353 in subjects with 
hereditary angioedema (HAE) 
Secondary:  
• 
To assess the effectiveness (ie, HAE attack frequency, severity, and disease activity over time) of 
BCX7353 during long-term administration 
• 
To evaluate quality of life (QoL) during long-term administration of BCX7353 
• 
To evaluate subject’s satisfaction with medication during long-term administration of BCX7353 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
4 
 
Methodology: 
This is a 2-arm, open-label study to evaluate the long-term safety and effectiveness of 2 dose levels of orally 
administered BCX7353 in subjects with HAE who either have participated in a previous study of BCX7353 or 
who are expected to derive benefit from an oral treatment to prevent angioedema attacks. 
Subjects who meet the inclusion and exclusion criteria will be enrolled into the study. Subjects will be allocated 
to 1 of 2 treatment groups: 
• 
Group 1: BCX7353 110 mg administered orally 
• 
Group 2: BCX7353 150 mg administered orally 
Subjects will receive 96 weeks of daily BCX7353. Study visits will occur at Screening, Baseline/Day 1, and at 
Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. Telephone contact will occur at Weeks 16, 20, 28, 32, 40, 44, 
52, 56, 64, 68, 76, 80, 88, and 92. An independent Data Monitoring Committee (DMC) will review the safety 
data from this study in concert with accumulating safety information generated across the BCX7353 clinical 
development program. For this study, the DMC will convene and review safety data once the first 10 subjects 
enrolled complete 12 weeks of dosing and approximately every 12 weeks thereafter until the last enrolled subject 
completes Week 48. After the last subject completes Week 48, the DMC will be provided with data every 
6 months until the last subject completes Week 96, although a formal meeting of DMC members may not be 
required.  
Subjects who have previously been treated with BCX7353 are not required to undergo a screening visit if the last 
dose of study drug was < 84 days ago. If the subject is directly rolling over from another BCX7353 study either 
without treatment interruption or with < 14 days of study drug interruption, the final study visit assessments in 
the prior BCX7353 study will serve as the baseline values for this study; however, relevant baseline assessments 
for this study will be performed at the final on-treatment visit for the prior study visit. Enrollment without 
treatment interruption into the current study will obviate the requirement for a follow-up visit in the previous 
BCX7353 study. 
Subjects will be eligible to receive study drug (BCX7353) for 96 weeks or until the Sponsor discontinues 
development of the product, whichever comes first. Study drug will be discontinued for subjects who are deriving 
no clinical benefit, are intolerant of study drug, or experience an unacceptable drug-related adverse event (AE). 
The study will be discontinued if ongoing regulatory or institutional review board/ethics committee approval is 
withdrawn, or in the event that technical or logistical factors prevent the ongoing conduct of the study. Safety and 
tolerability will be evaluated through assessments of AEs, laboratory analyses (clinical chemistry, hematology 
and urinalysis), vital signs, electrocardiograms (ECGs), and physical examinations. The main study will be 
comprised of adult subjects (≥ 18 years of age); a substudy in participating regions will be included that allows 
adolescent subjects ≥ 12 to 17 years of age to screen and enroll. Subjects will document all angioedema attacks 
that occur while on study drug. Angioedema attacks will be treated in accordance with the subject’s normal 
standard of care. Treatments for angioedema attacks will not be provided by the Sponsor. 
Subject-reported outcomes will be completed by subjects for the disease-specific Angioedema Quality of Life 
(AE-QoL) questionnaire and Treatment Satisfaction Questionnaire for Medication (TSQM), where validated 
translations are available. Additionally, subjects will be asked about time away from work or school. 
Number of Subjects (planned and analyzed):  
Approximately 225 subjects 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
5 
 
Diagnosis and main criteria for inclusion (see protocol section 8.2): 
Inclusion Criteria: 
1) Males and non-pregnant, non-lactating females ≥ 18 years of age (main study) or ≥ 12 to 17 years of age 
(substudy) 
2) Subjects with Type I or Type II HAE who either have: 
a) Participated in a BCX7353 study OR 
b) In countries open to recruitment of treatment-naïve subjects under a prior version of 
Protocol BCX7353-204:  
In the opinion of the Investigator, subjects are expected to benefit from an oral treatment for the prevention of 
angioedema attacks and have a clinical diagnosis of HAE Type I or II, defined as having a C1 esterase 
inhibitor (C1-INH) functional level below 50% and a complement 4 (C4) level below the lower limit of the 
normal (LLN) reference range, as assessed during the screening period. 
In the absence of a low C4 value drawn during the intercritical period (ie, subject is not having an HAE 
attack), 1 of the following is acceptable to confirm the diagnosis of HAE: 1) a SERPING-1 gene mutation 
known or likely to be associated with HAE Type I or II assessed during the screening period; 2) a confirmed 
family history of C1-INH deficiency; 3) a C4 redrawn and retested during an attack with the results below the 
LLN reference range measured during the screening period 
For subjects with a C1-INH function ≥ 50% but less than the assay LLN, a SERPING-1 gene mutation known 
or likely to be associated with HAE Type I or II, assessed during the screening period OR a repeat C1-INH 
functional test < 50% will be considered acceptable for enrollment. 
3) Subject weight ≥ 40 kg 
4) Access to appropriate medication for the treatment of acute HAE attacks 
5) Agreement to use acceptable effective contraception 
6) Able to provide written, informed consent. Subjects aged ≥ 12 to 17 years who are screening for the substudy 
must be able to read, understand, and be willing to sign an assent form in addition to a caregiver providing 
informed consent 
7) In the opinion of the Investigator, the subject is able to adequately comply with all required study procedures 
for the duration of the study. The subject must demonstrate adequate compliance with all study procedures 
required including diary recording of HAE attacks 
Exclusion Criteria: 
1) Pregnancy or breast feeding or planned pregnancy during the study period. 
2) Any clinically significant medical condition or medical history that, in the opinion of the Investigator or 
Sponsor, would interfere with the subject’s safety or ability to participate in the study. 
3) Discontinuation of study drug due to hypersensitivity reaction to BCX7353 in a prior study. This includes 
subjects who had a rash of any severity identified as possibly, probably, or definitely related to active BCX7353 
in the previous study. 
4) Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or 
rendering of informed consent or participation in the study. 
5) Clinically significant abnormal ECG including but not limited to, a corrected QT interval using Fridericia's 
method (QTcF) > 470 msec for women, a QTcF > 450 msec for men, a PR interval > 220 msec (both sexes), or 
ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or 
higher in grouping. 
6) Unacceptable noncompliance in a previous BCX7353 study as assessed by the Sponsor or Investigator. 
7) Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac 
arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other cardiovascular disease. 
8) Known family history of sudden cardiac death. Family history of sudden death from HAE is not exclusionary. 
9) History of or current implanted defibrillator or pacemaker. 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
6 
 
10) Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, or CYP3A4 and that 
have a narrow therapeutic range, including those known to prolong the QT interval within 7 days of the baseline 
visit or planned initiation during the study. 
11) Use of a medication that is transported by P-glycoprotein and has a narrow therapeutic range, within 7 days 
of the baseline visit or planned initiation during the study. 
12) Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and 
relevant for this study. 
13) Calculated creatinine clearance ≤ 30 mL/min or aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) value ≥ 3 times the upper limit of the normal (ULN) reference range value at screening 
or last available visit prior to enrollment. 
14) Investigational drug exposure, other than BCX7353, within 30 days prior to the screening visit (or baseline if 
no screening visit). 
15) Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear 
etiology. 
16) History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or 
abuse (self-reported alcoholic intake > 3 units of alcohol/day). 
17) For subjects undergoing a screening visit, a positive drugs of abuse screen (unless used as a medical treatment 
[eg, with a prescription]). 
18) For subjects undergoing a screening visit, current infection with hepatitis B virus, hepatitis C virus, or human 
immunodeficiency virus. 
19) Subjects with an immediate family relationship to either Sponsor employees, the Investigator or employees of 
the study site who are named on the delegation log. 
20) Subjects who are held in an institution by a government or judicial order. 
Test product, dose and mode of administration:  
BCX7353 capsules, to be administered orally. Subjects will receive a dose of 110 mg or 150 mg once per day. 
Duration of treatment:  
Subjects will be eligible to receive BCX7353 for 96 weeks or until the Sponsor discontinues development of the 
product; whichever comes first. Study drug will be discontinued for subjects who are deriving no clinical benefit, 
are intolerant of study drug, or experience an unacceptable drug-related AE. 
Reference therapy, dose and mode of administration: 
Not applicable. 
Criteria for evaluation (see protocol section 13.3.5 and 13.3.6): 
Effectiveness: 
Effectiveness will be evaluated by the number of angioedema attacks and related details (timing, duration of 
symptoms, anatomical location, treatment), number of days with angioedema symptoms, assessment of attack 
severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits. 
Safety: 
Safety will be evaluated by AEs, laboratory analyses (clinical chemistry, hematology, coagulation, urinalysis, 
creatine kinase-MB, troponin I and T, neutrophil gelatinase-associated lipocalin), vital signs, ECGs, and physical 
examinations. An independent DMC will review safety data in accordance with a separate DMC Charter. 
Subject Reported Outcomes/Quality of Life: 
QoL will be assessed using the AE-QoL questionnaire and subject’s satisfaction with their medication using the 
TSQM. The number of days lost from school and/or work will also be assessed. 


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Statistical methods: 
Analysis of Safety: Safety endpoints will be summarized by treatment group and will include the proportion of 
subjects with treatment-emergent AEs (TEAEs); who discontinue due to a TEAE; who experience a 
treatment-emergent serious adverse event (SAE); who experience a Grade 3 or 4 TEAE; who experience a 
treatment-emergent, treatment-related AE consistent with a drug rash as identified by investigator as an event of 
special interest; who experience treatment-emergent, abdominal-related gastrointestinal AEs; and who experience 
Grade 3 or 4 laboratory abnormalities. 
AEs will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) and 
system organ classification (SOC). The occurrence of TEAEs will be summarized using MedDRA PT, SOC, and 
severity. In addition to severity, AEs and SAEs will also be summarized based on Investigator assessment of 
relationship to study drug. 
Time to discontinuation due to a TEAE, and time to development of drug-related rash will be estimated using the 
Kaplan-Meier method. For those with a drug-related rash, clinical and lab findings will be summarized and the 
proportion of subjects who successfully continued therapy following onset of rash. 
Descriptive statistics for vital signs, weight, and clinical laboratory results will be presented by study visit. 
Laboratory abnormalities will be graded and flagged automatically with a reference range scale. The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized. Laboratory 
toxicity shifts from baseline to the worst post-baseline value as well as the last visit will be summarized. The 
number and percentage of subjects having elevations in ALT, AST, or bilirubin abnormalities in relation to fold 
above the ULN will be summarized according to the Food and Drug Administration’s Premarketing Clinical 
Evaluation on Drug-Induced Liver Injury Guidance for Industry. 
Clinically significant abnormal ECG findings will be summarized by study visit. Changes from baseline in ECG 
parameters will also be summarized by study visit. The number and proportion of subjects with clinically 
important absolute and change from baseline thresholds in QTcF will be summarized. 
Analysis of Effectiveness: Effectiveness endpoints will be analyzed by treatment group and will include 
angioedema attack rate, durability of response, number and proportion of days with angioedema symptoms, 
angioedema attack medication administrations, discontinuations due to lack of efficacy, and disease severity. The 
durability of response assessment will be based on attack rate trend over time, and the attack rate change from 
observed values for each subject in their respective previous efficacy study (where applicable) over time. 
Additional related details of HAE attacks (eg, symptoms, anatomical location, hospitalizations, emergency room 
visits, attack severity, attack duration) and number of days lost from work and/or school due to attacks will be 
listed and summarized using descriptive statistics. 
No formal tests of hypotheses will be conducted. 
Quality of Life Analyses: The baseline, follow-up and change from baseline in the domain scores of the AE-QoL 
as well as the composite score of each instrument will be calculated and summarized by treatment group. 
Individual items will be analyzed to understand their contribution to the domain sub-scores. A TSQM global 
satisfaction score will be calculated as validated. Data on the global score as well as relevant subscales will be 
listed and summarized. 
 


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TABLE OF CONTENTS 
JTITLE PAGE .................................................................................................................................1 
1. 
LIST OF ABBREVIATIONS.....................................................................................13 
2. 
INTRODUCTION ......................................................................................................15 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................15 
3.1. 
Study Objectives .........................................................................................................15 
3.1.1. 
Primary Objective .......................................................................................................15 
3.1.2. 
Secondary Objective ...................................................................................................16 
3.2. 
Study Endpoints ..........................................................................................................16 
3.2.1. 
Safety Endpoints .........................................................................................................16 
3.2.2. 
Effectiveness Endpoints ..............................................................................................16 
4. 
STUDY DESIGN .......................................................................................................17 
4.1. 
Summary of Study Design ..........................................................................................17 
4.2. 
Definition of Study Drugs ..........................................................................................18 
4.3. 
Sample Size Considerations .......................................................................................18 
4.3.1. 
Sample Size Justifications ..........................................................................................18 
4.4. 
Allocation to Treatment Group ...................................................................................18 
4.5. 
Assessments ................................................................................................................18 
5. 
PLANNED ANALYSES ............................................................................................22 
5.1. 
Interim Analyses .........................................................................................................22 
5.2. 
Final Analyses ............................................................................................................22 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................23 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........23 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................24 
6.3. 
Data Management .......................................................................................................24 
6.4. 
Data Presentation Conventions ...................................................................................24 
6.5. 
Analysis Populations ..................................................................................................25 
6.5.1. 
Screen Failures ............................................................................................................25 
6.5.2. 
Safety Population ........................................................................................................25 
6.6. 
Baseline Definition .....................................................................................................25 
6.6.1. 
Baseline Attack Rate ...................................................................................................25 


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6.7. 
Derived and Transformed Data ..................................................................................25 
6.7.1. 
Baseline Age ...............................................................................................................25 
6.7.2. 
Study Day ...................................................................................................................26 
6.7.3. 
Change from Baseline .................................................................................................26 
6.7.4. 
Prior Androgen Use ....................................................................................................26 
6.7.5. 
Subjects Entering the Study on Prophylactic HAE Medications ................................26 
6.7.6. 
Visit Windows ............................................................................................................26 
6.7.7. 
Multiple Assessments .................................................................................................27 
6.7.8. 
Derived Efficacy Endpoints ........................................................................................28 
6.7.8.1. 
Subject-Reported Attack .............................................................................................28 
6.7.8.2. 
Adjusted Attack ..........................................................................................................28 
6.7.8.3. 
Attack Rate .................................................................................................................28 
6.7.8.4. 
Number and Proportion of Days with Angioedema Symptoms .................................29 
6.7.8.5. 
Durability of Response ...............................................................................................30 
6.7.8.6. 
Subjects Who Are Attack Free ...................................................................................30 
6.7.8.7. 
Attack Duration ..........................................................................................................30 
6.7.8.8. 
Attack Onset Relative to Initial Dose of Study Drug .................................................30 
6.7.8.9. 
Medications to Treat HAE Attacks.............................................................................30 
6.7.8.10. 
Time to First Use of HAE Rescue Targeted Medication for an Adjusted 
Attack ..........................................................................................................................30 
6.7.8.11. 
Attack Symptoms ........................................................................................................31 
6.7.8.12. 
Attack Location ..........................................................................................................31 
6.7.8.13. 
Attack Triggers ...........................................................................................................31 
6.7.8.14. 
AE-QoL ......................................................................................................................32 
6.7.8.15. 
TSQM .........................................................................................................................33 
6.8. 
Handling of Missing Data ...........................................................................................34 
6.8.1. 
Missing Effectiveness Endpoints ................................................................................34 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................34 
6.8.3. 
Missing Start and Stop Dates for Adverse Events ......................................................35 
6.8.4. 
Missing Time of First and Last Dose .........................................................................35 
6.8.5. 
Incomplete Date and Time for a Subject-Reported Attack ........................................35 
7. 
STUDY POPULATION .............................................................................................36 
7.1. 
Subjects Disposition ...................................................................................................36 


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7.2. 
Screen Failures ............................................................................................................37 
7.3. 
Protocol Deviations ....................................................................................................37 
7.4. 
Demographic and Baseline Characteristics ................................................................37 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................37 
7.6. 
HAE Medical and Medication History .......................................................................37 
7.7. 
Prior and Concomitant Non-HAE and HAE Medications ..........................................38 
7.8. 
Baseline Physical Examination ...................................................................................38 
7.9. 
Baseline Primary and Secondary Effectiveness Evaluations ......................................38 
8. 
EFFECTIVENESS .....................................................................................................39 
8.1. 
General Considerations ...............................................................................................39 
8.2. 
Subgroup Analyses .....................................................................................................39 
8.3. 
Analysis of the Effectiveness Endpoints ....................................................................39 
8.3.1. 
Effectiveness Analysis ................................................................................................39 
8.3.1.1. 
HAE Attack Rate ........................................................................................................39 
8.3.1.2. 
Number and Proportion of Days with Angioedema Symptoms .................................39 
8.3.1.3. 
Number and Proportion of Subjects Attack Free ........................................................39 
8.3.1.4. 
Discontinuations Due to Lack of Efficacy ..................................................................39 
8.3.1.5. 
Attack Characteristics .................................................................................................39 
8.3.1.6. 
Use of HAE Attack Medications ................................................................................40 
8.3.1.7. 
AE-QoL ......................................................................................................................40 
8.3.1.8. 
TSQM .........................................................................................................................40 
9. 
SAFETY AND TOLERABILITY ..............................................................................40 
9.1. 
Overall Summary of Tolerability ................................................................................40 
9.2. 
Subgroup Analyses .....................................................................................................40 
9.3. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............41 
9.3.1. 
Summaries of Adverse Event Incidence Rates for All Subjects and Adverse 
Incidence Rates for Serious Adverse Events, Adverse Event Dropouts, and 
Death ...........................................................................................................................41 
9.3.2. 
Investigator-Identified Rash Events of Special Interest .............................................42 
9.3.3. 
Gastrointestinal Abdominal-Related AEs ...................................................................43 
9.3.4. 
Missing and Partial AE Onset Dates ..........................................................................44 
9.3.5. 
Summaries of Adverse Incidence Rates per 100 Person-Years of Exposure to 
Study Treatment ..........................................................................................................44 


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9.4. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................45 
9.5. 
Concomitant and Other Medications ..........................................................................45 
9.5.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........46 
9.6. 
Laboratory Data ..........................................................................................................46 
9.6.1. 
Complement Factors and HAE Diagnosis ..................................................................47 
9.6.2. 
Laboratory Assessments for Rash ..............................................................................47 
9.7. 
Pregnancy ...................................................................................................................48 
9.8. 
Vital Signs ..................................................................................................................48 
9.9. 
12-lead Electrocardiograms ........................................................................................48 
9.10. 
Physical Examination .................................................................................................49 
9.11. 
Study Termination Status ...........................................................................................49 
11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ....................................49 
12. 
REFERENCES ...........................................................................................................50 
13. 
APPENDIX.................................................................................................................51 
13.1. 
Table of Contents for Data Display Specifications ....................................................51 
13.2. 
Data Display Specifications ........................................................................................68 
13.3. 
List of Preferred Terms, High Level Terms, and High Level Group Terms 
for GI Abdominal-Related AEs ..................................................................................69 
 
 
 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ..................................................................................................13 
Table 2: 
Protocol Revision Chronology ...................................................................................15 
Table 3: 
 Schedule of Clinical Assessments .............................................................................19 
Table 4: 
Treatment Descriptors for Displays ............................................................................23 
Table 5: 
Visit Windows (Days) ................................................................................................27 
Table 6: 
Determination of Attack Location Using Symptoms Collected in the Diary .............31 
Table 7: 
Dimensions of the AE-QoL ........................................................................................32 
Table 8: 
List of Questions from TSQM ....................................................................................33 
Table 9: 
Definition of Compliance Categories .........................................................................45 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AE-QoL 
Angioedema Quality of Life 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ALT 
Alanine Aminotransferase 
BCX7353 
Study Drug 
BMI 
Body Mass Index 
C1-INH 
C1 Esterase Inhibitor 
C1-INHf 
Functional C1 Esterase Inhibitor 
C3 
Complement Component 3 
C4 
Complement Component 4 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases 
EC50 
Half Maximal Effective Concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOSI 
Event of Special Interest 
GI 
Gastrointestinal 
HAE 
Hereditary Angioedema 
HLGT 
High Level Group Term 
ICH 
International Council for Harmonisation 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
N 
Total Sample Size 
PBMC 
Peripheral Blood Mononuclear Cells 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QD 
Daily, Every Day 
QTcF 
Fridericia’s Corrected QT Interval 
SAE 
Serious Adverse Event 


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Abbreviation 
Term 
SAP 
Statistical Analysis Plan  
SAS 
Statistical Analysis System  
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TESAE 
Treatment-emergent Serious Adverse Event 
TSQM 
Treatment Satisfaction Questionnaire for Medications 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization  
WHODD 
World Health Organization Drug Dictionary 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol BCX7353-204. A 
summary of protocol revisions is provided in Table 2.  
Table 2: 
Protocol Revision Chronology 
Protocol 
Date 
Key Information 
Protocol Version 1.0 
20 September 2017 
Original 
Protocol Version 2.0 
5 December 2017 
Made administrative clarifications, changed design 
to include 2 dose groups, increased sample size, 
removed option to reduce dose, AECT assessment 
removed, updated prohibited medications  
Protocol Version 3.0 
6 December 2017 
Made administrative clarifications, expanded 
inclusion criteria to include subjects naïve to 
BCX7353 in selected countries 
Protocol Version 4.0 
5 October 2018 
Made administrative clarifications, expanded subject 
numbers, expanded inclusion criteria, extended 
study duration to 96 weeks, added study data, and 
clarified discontinuation criteria 
Protocol Version 5.0 
7 February 2019 
Expanded subject numbers, added US sites, added 
subjects with recent androgen use. 
Abbreviations: AECT = Angioedema Control Test; US = United States. 
 
This SAP was developed in accordance with International Council for Harmonisation (ICH) E9 
guideline. The purpose of this document is to provide details on the statistical methodology used 
to analyze the safety and effectiveness for Study BCX7353-204. Study population definitions, 
derivations of variables, handling of missing data, and other information necessary for analysis 
of study data are provided. Planned tables, figures, and listings are specified. All decisions 
regarding final analysis, as defined in this SAP document, will be made prior to database lock of 
the study data. Further information can be found in the protocol and electronic Case Report 
Forms (eCRFs). 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of daily 
dosing of oral BCX7353 in subjects with hereditary angioedema (HAE). 


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3.1.2. 
Secondary Objective 
The secondary objectives are as follows:  
• To assess the effectiveness (ie, HAE attack frequency, severity and disease activity 
over time) of BCX7353 during long-term administration  
• To evaluate quality of life during long-term administration of BCX7353  
• To evaluate subject’s satisfaction with medication during long-term administration of 
BCX7353 
3.2. 
Study Endpoints 
3.2.1. 
Safety Endpoints 
The safety endpoints will include the following: 
• The proportion of subjects with treatment-emergent adverse events (TEAEs) 
• The proportion of subject with treatment-emergent, treatment-related adverse events 
(AEs) consistent with a drug rash 
• The proportion of subjects who discontinue BCX7353 due to a TEAE 
• The proportion of subjects with treatment-emergent serious adverse events (TESAEs) 
• The proportion of subjects Grade 3 or 4 TEAEs 
• The proportion of subjects with treatment-emergent Grade 3 or 4 laboratory 
abnormalities. 
3.2.2. 
Effectiveness Endpoints 
Effectiveness endpoints will include the following: 
• Number and rate of HAE attacks 
• Durability of response (attack rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Subject-reported outcomes (HAE disease-specific Angioedema Quality of Life 
[AE-QoL] questionnaire scores and Treatment Satisfaction Questionnaire for 
Medication [TSQM]) global satisfaction scores 
• Number of attacks requiring attack medication 
• Discontinuations due to lack of efficacy 
• Severity of attacks 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a 2-arm, open-label study to evaluate the long-term safety and effectiveness of 2 dose 
levels of orally administered BCX7353 in subjects with HAE who either have participated in a 
previous study of BCX7353, or who are expected to derive benefit from an oral treatment to 
prevent angioedema attacks. 
Subjects who meet the inclusion and exclusion criteria will be enrolled into the study. Subjects 
will be allocated to 1 of 2 treatment groups: 
Group 1: 
BCX7353 110 mg administered orally 
Group 2: 
BCX7353 150 mg administered orally 
Subjects will receive 96 weeks of daily BCX7353. Study visits will occur at Screening, 
Baseline/Day 1, and at Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. Telephone contact will 
occur at Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, and 92. An independent data 
monitoring committee (DMC) will review the safety data from this study in concert with 
accumulating safety information generated across the BCX7353 clinical development program. 
For this study, the DMC will convene and review safety data once the first 10 subjects enrolled 
complete 12 weeks of dosing and approximately every 12 weeks thereafter until the last enrolled 
subject completes the study. After the last subject completes Week 48, the DMC will be 
provided with data every 6 months until the last subject completes Week 96, although formal 
meeting of the DMC members will not be required.  
Subjects who have previously been treated with BCX7353 are not required to undergo a 
screening visit if the last dose of study drug was < 84 days ago; however, these subjects are 
required to have a baseline visit. If the subject is directly rolling over from another BCX7353 
study either without treatment interruption or with < 14 days of study drug interruption, the final 
study visit assessments in the prior BCX7353 study will serve as the baseline values for this 
study; however, relevant baseline assessments for this study will be performed at the final on-
treatment visit for the prior study visit. Enrollment without treatment interruption into the current 
study will obviate the requirement for a follow-up visit in the previous BCX7353 study. 
Subjects will be eligible to receive BCX7353 for 96 weeks or until the Sponsor discontinues 
development of the product; whichever comes first. Study drug will be discontinued for subjects 
who are deriving no clinical benefit, are intolerant of study drug, or experience an unacceptable 
drug-related AE. The study will be discontinued if ongoing regulatory or institutional review 
board/ethics committee approval is withdrawn, or in the event that technical or logistical factors 
prevent the ongoing conduct of the study. Safety and tolerability will be evaluated through 
assessments of AEs, laboratory analyses (clinical chemistry, hematology and urinalysis), vital 
signs, electrocardiograms (ECGs), and physical examinations.  
The main study will be comprised of adult subjects (≥ 18 years of age); a substudy in 
participating regions will be included that allows adolescent subjects ≥ 12 to 17 years of age to 
screen and enroll. Subjects will document all angioedema attacks that occur while on study drug. 
Angioedema attacks will be treated in accordance with the subject’s normal standard of care. 
Treatments for angioedema attacks will not be provided by the Sponsor. 


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Subject-reported outcomes will be completed by subjects for the disease-specific AE-QoL 
questionnaire and TSQM, where validated translations are available. Additionally, subjects will 
be asked about time away from work or school. 
4.2. 
Definition of Study Drugs 
Only the investigational product BCX7353 will be used as a study drug in this trial. Two dose 
levels will be examined. 
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
No sample size calculations were conducted for this open-label, long-term safety study. The 
purpose of the study is to characterize the safety profile of 110 and 150 mg daily doses of 
BCX7353. 
Approximately 225 subjects (approximately 110 subjects at each dose level) may be enrolled in 
this study, to allow continued access to BCX7353 following a subject’s participation in a prior 
BCX7353 study, or to provide access to BCX7353 for additional subjects who, in the opinion of 
the Investigator, are expected to benefit from treatment with an oral treatment for the prevention 
of angioedema attacks. 
4.4. 
Allocation to Treatment Group 
This is an open-label study. Subjects will be centrally allocated to 1 of 2 treatment groups:  
• Group 1: BCX7353 110 mg administered orally once daily (QD) 
• Group 2: BCX7353 150 mg administered orally QD 
Sites will request a treatment allocation for eligible subjects in the Interactive Response System, 
preferably after all baseline assessments to reconfirm eligibility have completed. If required by 
site procedures (ie, dispensing of allocated study drug must occur through a pharmacy), the 
treatment allocation request may be made on the business day prior to the planned baseline visit.  
Version 1 of the protocol included only the BCX7353 150 mg dose for those in previous 
BCX7353 clinical trials. As Version 1 of the protocol only utilized the 150 mg dose, sites 
initiated under protocol Version 1 have all subjects allocated to the 150 mg dose. Protocol 
Version 2 allowed for subjects to be treated with either the 110 or 150 mg dose. Protocol 
Version 3 broadened the inclusion criteria to allow for inclusion of subjects who had not 
previously participated in clinical trials of BCX7353. Sites initiated under Protocol Versions 2 or 
3, or who were initially included under Protocol Version 1 and later changed versions, may have 
subjects allocated to 150 or 110 mg. 
No changes to the allocation scheme were made in Protocol Versions 4 and 5. 
4.5. 
Assessments 
The schedule of assessments is provided in Table 3. 


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Table 3: 
 Schedule of Clinical Assessments 
Assessment 
Screening 
Period 
Baseline 
Visita 
Treatment Period (Visit schedule) 
End of Study 
Assessment 
Screening 
Visit 
(Up to 
Day -28) 
(Day 1) 
Week 2  
(Day 15 ± 
2 days)b 
Week 4 
(Day 29 ± 
2 days) 
Week 8 
(Day 57 
± 2 days) 
Week 12 
(Day 85 
± 2 days) 
Visits every 
12 weeks until 
96 weeks 
(± 6 days) 
3 weeks (± 3 
days) after last 
dose of study 
drug 
Informed consentc 
X 
X 
 
 
 
 
 
 
Clinic staff phone call/ communication 
 
 
 
 
 
 
Xd 
 
Inclusion-exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical and medication history, HAE 
medical and medication historye  
X 
X 
 
 
 
 
 
 
Weight/height/BMIf 
X 
X 
 
X 
X 
X 
X 
X 
Drugs of abuse screeng 
X 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
 
X 
X 
X 
X 
X 
Pregnancy testi 
X 
X 
 
X 
X 
X 
X 
X 
Vital signsj 
X 
X 
 
X 
X 
X 
X 
X 
FSHk 
X 
X 
 
 
 
 
 
 
HIV, HCV, HBV serology 
X 
 
 
 
 
 
 
 
Diagnosis of HAE establishedl 
X 
 
 
 
 
 
 
Clinical chemistry/ 
hematology/coagulationg 
X 
X 
Xb 
X 
X 
X 
X 
X 
Troponin I and Troponin T, CK-MB 
 
X 
 
X 
X 
X 
X 
X 
NGAL and ACR 
 
X 
 
 
 
X 
X 
X 
Urinalysisg 
X 
X 
Xb 
X 
X 
X 
X 
X 


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Abbreviations: ACR = spot urine microalbumin to creatinine ratio; AE = adverse event; AE-QoL = Angioedema Quality of Life; ALP = alkaline phosphatase; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; C1-INH = C1 esterase inhibitor; C3 = complement 3; 
C4 = complement 4; CK-MB = creatine kinase MB isoenzyme; CRF = case report form; ECG = electrocardiogram; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HLA = human leukocyte antigen; IXRS = interactive response system; LLN = lower limit of normal; NGAL = neutrophil gelatinase-associated lipocalin; 
PG = pharmacogenomic; PK = pharmacokinetic; QoL = quality of life; QTcF = QT interval corrected using Fridericia’s method; TSQM = Treatment Satisfaction 
Questionnaire for Medication.  
a The baseline visit should be within 28 days of the screening visit. Subjects who have interrupted study drug from a previous BCX7353 study for < 84 days are 
not required to undergo a screening visit. For subjects directly rolling over from another BCX7353 study without treatment interruption or subjects who interrupt 
study drug for < 14 days, the final on-treatment visit in the prior BCX7353 study will be considered the baseline visit for this study.  
Sample for HLA analysis and C3m 
 
X 
 
 
 
 
 
 
Assessment 
Screening 
Period 
Baseline 
Visita 
Treatment Period (Visit schedule) 
End of Study 
Assessment 
Screening 
Visit 
(Up to 
Day -28) 
(Day 1) 
Week 2  
(Day 15 ± 
2 days)b 
Week 4 
(Day 29 ± 
2 days) 
Week 8 
(Day 57 
± 2 days) 
Week 12 
(Day 85 
± 2 days) 
Visits every 
12 weeks until 
96 weeks 
(± 6 days) 
3 weeks (± 3 
days) after last 
dose of study 
drug 
Optional sample for exploratory PGn 
 
X 
 
 
 
 
 
 
ECGo 
X 
X 
 
X 
X 
X 
X 
X 
AE-QoL, assessment of days lost from 
work and/or school and TSQMp 
 
X 
 
X 
X 
X 
X 
X 
Concomitant medicationsq 
X 
X 
X 
X 
X 
X 
X 
X 
PK plasma sampler 
 
X 
 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Diary instruction/ review/set-ups 
X 
X 
 
X 
X 
X 
X 
X 
Allocation to study drugt 
 
X 
 
 
 
 
 
 
Diary completionu 
 
 
Study drug dosing 
 
 
 
Study drug accountability/ dispensing 
 
X 
 
X 
X 
X 
X 
X 


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b The Week 2 visit will consist of monitoring liver function tests only [ALT, AST, GGT, total and direct bilirubin, ALP]; urine and additional tubes of blood may 
be required to accommodate reflex testing for abnormal GGT (see protocol Table 7). If preferred by the subject and clinical site, laboratory values may be drawn 
and resulted locally, with results entered into the CRF.  
c Informed consent will be signed at the screening visit for subjects requiring a screening visit and will be signed for all other subjects at the baseline visit or final 
on treatment visit in the parent study (which serves as the subject’s baseline visit in this study).  
d After the Week 12 visit, clinic staff must contact the subjects at least once every 4 weeks between clinic visits to assess the subject’s overall wellbeing and any 
issues with regards to study drug tolerability. During all calls, sites will also discuss study drug compliance and any issues with the diary or study drug.  
e Medical history and medication history will be completed at screening (for subjects requiring a screening visit) and at baseline. At the Screening visit (or 
baseline for those with no screening visit), the HAE Medical and Medication history form will be updated from the previous HAE study, as applicable, with 
additional questions to be answered if provided.  
f BMI calculation and height at screening; weight is to be recorded at each in-clinic visit.  
g Please see protocol Table 7 for analytes to be assessed. The lipid panel as part of clinical chemistry will only be measured at baseline, Week 12 and then every 
12 weeks.  
h Full physical examinations will be performed at screening and baseline; symptom-directed physical examinations will be performed at all post-baseline visits.  
i For women of childbearing potential, a serum pregnancy test will be administered at screening, urine pregnancy tests will be assessed at all subsequent visits as 
indicated in the table. Demonstration of a negative urine pregnancy test will be required prior to dispensing study drug.  
j To include blood pressure and pulse rate. Temperature and respiratory rate will be captured at screening and baseline only. Prior to obtaining vital signs, subjects 
should rest in a supine position for at least 5 minutes.  
k For a woman who declares that they have been post-menopausal ≤ 2 years or was considered a woman of childbearing potential in the previous study. The 
sample may be drawn at baseline for those who those who do not undergo a screening visit; however, the subject must have a negative urine pregnancy test at 
baseline prior to receiving study drug.  
l For subjects that have not participated in a previous BCX7353 study, a clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a 
C1-INH functional level below 50% and a C4 level below the lower LLN reference range, as assessed during the Screening period. In the absence of a low C4 
value drawn during the inter-critical period, one of the following is acceptable to confirm the diagnosis of HAE assessed during the Screening period: 1) a 
SERPING-1 gene mutation known or likely to be associated with HAE Type I or II; 2) a confirmed family history of C1-INH deficiency; 3) a C4 redrawn and 
retested during an attack with the results below the LLN reference range.  
m A sample for HLA analysis will be drawn on subjects who have not donated one in a previous study. The sample may be drawn at baseline or at any subsequent 
visit.  
n All ECGs during the study will be single assessments with the exception of baseline which will be obtained in triplicate. An ECG should be repeated for a 
change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. Prior to obtaining an ECG, subjects should rest quietly in a supine position for at least 
10 minutes.  
o AE-QoL and TSQM will be administered once at baseline and at Weeks 4, 8, 12, and every 12 weeks thereafter. Additional questions regarding loss of time 
from work/school will be instituted at each visit to more fully characterize QoL.  
p Concomitant medications will be reviewed at each visit and on treatment, new concomitant medications will be reviewed to determine whether there are any 
contraindications or dosage adjustments required.  
q The actual date and time of PK blood draw, and time of last study drug dose (relative to PK sample draw) will be captured in the CRF.  
r Site staff will review the diary instructions with the subjects at the first clinic visit. Subjects will be instructed to bring the completed diary with them to their 
visits. Any issues with the entered data in the diary will be discussed with the subject and corrections will be made by the subject as required.  
s Sites will request a treatment allocation in the IXRS for eligible subjects at the Day 1 visit  
t At any time the diary is in a subject’s possession, they will enter HAE attacks and relevant details and dosing information (as applicable) once per day. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
DMC meetings will occur after the first 10 subjects have completed 12 weeks of treatment and 
every 12 weeks thereafter until the last enrolled subject completes 48 weeks, or as DMC 
meetings are conducted in concert for related BCX7353 studies. 
Before each scheduled DMC meeting, a packet of summary materials will be prepared and 
distributed for the Committee’s review. The packet will include study disposition, demographic, 
and safety information by treatment group. Study disposition will consist of the number of 
subjects screened, the number of subjects allocated to treatment, the number of subjects who 
received treatment, the number of subjects who completed the study, the number of subjects who 
were withdrawn from the study and the primary reasons for withdrawal, the number of subjects 
ongoing in the study, the number of subjects who completed dosing in the entire study, the 
number of subjects withdrawn from the study medication, and the primary reasons for 
withdrawal, and the number of subjects ongoing on study medication. Demographic information 
will consist of age, gender, race, ethnicity, weight, height, and body mass index (BMI). 
Safety summaries will include an overall summary of TEAEs (overall numbers of subjects with 
TESAEs, TEAEs, drug-related TEAEs, TEAEs leading to discontinuation of study drug, Grade 3 
or 4 TEAEs, and drug-related TEAEs of Grade 3 or 4), summaries of TEAEs by system organ 
class (SOC) and preferred term (PT), which include TESAEs, TEAEs, Grade 3 or 4 TEAEs, 
TEAEs leading to discontinuation of study drug, and summaries of subjects with 
treatment-emergent laboratory abnormalities overall and for each laboratory panel by parameter 
and grade. Relevant review materials will normally be sent to DMC members and open session 
participants 5 business days before each scheduled meeting. 
All summary materials will be distributed via email. 
An internal analysis will be conducted at the time of the BCX7353-302, Part 1 analysis. This 
analysis will be used to write the draft report for the BCX7353-204 study. 
An interim analysis will be performed when approximately 100 subjects at either the 110 or 
150 mg dose from a combination of studies BCX7353-204 and BCX7353-302 complete 
48 weeks. Additionally, an integrated analysis of safety and effectiveness involving data from 
both studies will be performed. This analysis will be used for regulatory submissions. 
Other interim analyses may be performed as needed during the course of the study to support 
regulatory filings and safety updates at the request of the Sponsor. 
5.2. 
Final Analyses 
The final analysis will be completed after the last subject completes the final study visit or 
discontinues the study and the resulting clinical database has been cleaned, quality checked, 
locked, and authorized for analysis. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Tables and listings will be prepared in accordance with the current ICH Guidelines (ICH E3 
Structure and Content of Clinical Study Reports 1996). The information and explanatory notes in 
the “footer” or bottom of each table and listing will include the following information: 
• Date of data extraction 
• Date of output generation 
• Statistical Analysis Software (SAS®) program name, including the path where the 
program is stored 
• Any other output specific details that require further elaboration 
In general, tables will be formatted with columns displaying findings for all subjects by 
treatment group and all subjects across treatment groups. 
Version 9.4 or higher of the SAS system will be used to analyze the data and to generate tables, 
figures, and listings. All SAS programs prepared to analyze the data will be properly annotated 
so as to permit uninvolved outside statistical experts to replicate all the analyses specified in this 
SAP. 
These listings will generally be sorted by treatment group, subject identifier, and visit, if 
applicable.  
Summary displays will be presented by treatment. A column that combines both active 
treatments will also be included. Table 4 shows treatment descriptors for displays. 
Table 4: 
Treatment Descriptors for Displays 
Sort Order 
Treatment 
Notes 
1 
BCX7353 110 mg 
110 mg 
2 
BCX7353 150 mg 
150 mg 
3 
Total 
Combined 110 mg and 150 mg groups 
 
Summary tables for medications and free-text fields for HAE medication history are coded 
according to the World Health Organization Drug Dictionary (WHODD) from March 2017. AE 
PTs and body/organ systems are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.1.  


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6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Tables, listings, and figures will be numbered using a decimal system to indicate the main levels 
of unique displays and sub-levels of replicate displays. The first level represents the appendix 
within which the tables, figures, and listings will appear. This will be 14 for tables and figures 
and 16 for listings. For tables, the second level of the numbering represents the type of data; 1 for 
Study Population, 2 for Effectiveness, 3 for Safety, 4 for Health Outcomes, and 5 for 
pharmacokinetics (PK). The third level of numbering represents the type of endpoint within the 
data type, the fourth represents a count of displays for the endpoint, and the fifth level is used for 
repeated tables. For example, tables may be repeated using a different population or for a subset 
of subjects. 
Secondary titles will be used to identify the analysis population used for the displays. 
Listings will be numbered starting with 16.2.1 and with sequential numbering in the third level in 
accordance with ICH guidelines. Listings will be sorted and presented by dose, subject number, 
and visit, if applicable.  
6.3. 
Data Management 
A data management plan will be developed and approved prior to data entry. Data will be 
captured using the Medidata electronic data capture system. Electronic validation steps (edit 
checks) will be utilized, and data cleaning will occur in conjunction with each site. Prior to 
transfer of data provided by vendors (eg, laboratory data), a data transfer agreement including 
specifications for the type of file, definitions of variables, and contact information for the 
sending and receiving parties will be developed and finalized. PharPoint standard operating 
procedures (SOPs) will be used. 
Data will be mapped to Study Data Tabulation Model (SDTM)-compliant datasets prior to 
creation of Analysis Data Model (ADaM)-compliant derived datasets for use in the creation of 
summary tables. All analyses will be generated using SAS version 9.4 or above and in 
accordance with PharPoint SOPs. 
6.4. 
Data Presentation Conventions 
Continuous variables (eg, age) are summarized using descriptive statistics (the number of 
subjects with available data, the mean, standard deviation (SD), median and minimum and 
maximum). Categorical variables (eg, race) are summarized using counts and percentages. 
Percentages are calculated using the total subjects per treatment group. 
The following conventions are applied to all data presentations and summaries. 
• For continuous variables, all mean and median values are formatted to 1 more 
decimal place than the measured value. SD values are formatted to 2 more decimal 
places than the measured value. Minimum and maximum values are presented with 
the same number of decimal places as the measured value. 
• For categorical variables, the number and percentage of responses are presented in the 
form XX (XX.X%) where the percentage is in the parentheses. 


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• Date variables are formatted as DDMMMYYYY for presentation. Time is formatted 
in military time as HH:MM for presentation. 
• Wherever possible, data will be decimal aligned. 
The table of contents as part of this SAP along with the table and listing shells provided in 
separate documents provide the expected layout and titles of the tables, listings and figures. Any 
changes to format, layout, titles, numbering, or any other minor deviation will not necessitate a 
revision to the SAP, nor will they be considered as deviations from planned analyses. Only true 
differences in the analysis methods or data handling will necessitate such documentation. The 
appropriate listings supporting the tables will be included and are not necessarily specified in the 
individual sections throughout the document. 
6.5. 
Analysis Populations  
6.5.1. 
Screen Failures 
Subjects who give informed written consent, but are not allocated to study treatment, and are 
noted as screen failures in eCRF are considered screen failures. These subjects will not be treated 
with study drug and will not be summarized other than on the disposition table. Data collected 
from screen failures may be presented on corresponding data listings. 
6.5.2. 
Safety Population 
The safety population will include all subjects who receive at least 1 dose of study drug. This 
population will be used in the assessment and reporting of demographic information, baseline 
disease characteristics, safety data, and PK concentrations. Data will be analyzed according to 
the actual treatment received on Day 1 of the study. 
6.6. 
Baseline Definition 
Baseline is the last available assessment prior to the time of first dose unless otherwise specified.  
6.6.1. 
Baseline Attack Rate 
No baseline attack rate is calculated for the following reasons: 
• Not all subjects entering the study have baseline measures collected as some subjects 
are rolling over from previous studies. 
• Some subjects are on other prophylactic HAE medications 
• Some subjects are discontinuing androgens that were used as HAE prophylaxis 
6.7. 
Derived and Transformed Data 
6.7.1. 
Baseline Age  
Age in years will be reported as recorded on the demographics form. 


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6.7.2. 
Study Day 
Study Day 1 is defined as the date of first dose. 
If the date of interest occurs on or after the first dose date, study day will be calculated as (date 
of interest – date of first dose + 1). If the date of interest occurs prior to the first dose date, study 
day will be calculated as (date of interest – date of first dose). There is no study day 0.  
6.7.3. 
Change from Baseline 
Change from baseline is calculated as (post-baseline result – baseline result).  
Percent change from baseline is calculated as ((change from baseline/baseline result) × 100). 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percent change from baseline will be set to missing as well. 
6.7.4. 
Prior Androgen Use 
Subgroup analyses for prior androgen use (latency and duration) are described in Section 9.2. 
Details of calculations for latency and duration are described in this section. 
Any medications classified as androgens or androgen derivatives (based on WHODD, 
March 2017) used prior to the study treatment start date will be considered “prior androgens”. 
These medications will include androgens (unspecified), oxandrolone, danazol (brand 
name = Danocrine), and stanozolol. 
Total duration of prior androgen use includes days from beginning of first date of each androgen 
used to last dosing date of each androgen. Any days of overlapping multiple androgen use will 
be counted once for total duration.  
Total duration of prior androgen use within the 12 months prior to treatment start date will be 
calculated similarly to total duration of prior androgen use. The prior 12-month window will 
include days from treatment start date minus 365 up to treatment start date. For androgens started 
prior to treatment start date minus 365, start date of androgen will be considered treatment start 
date minus 365 for this analysis. Duration will be calculated as stop date – start date + 1. If 
androgen was started and stopped on the same day, duration will be 1 day. 
Days since stopping last androgen use (latency) are calculated as date of last androgen use - 
treatment start date. 
6.7.5. 
Subjects Entering the Study on Prophylactic HAE Medications 
Any subject who took Berinert, Ruconest, Haegarda, or Cinryze (all C1-inhibitors or C1-esterase 
inhibitors [C1-INH]) on Study Day 1 with regular frequency of administration (eg, once weekly, 
twice weekly, etc.) or tranexamic acid taken daily and not flagged on the concomitant 
medications eCRF as ‘PRN’ are considered to be on current prophylactic medication. 
6.7.6. 
Visit Windows 
For summary purposes in general, records will be assigned to the scheduled visit collected on the 
eCRF. Unscheduled and early termination visits will be assigned to an analysis window 


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according to the study day of the actual visit date using the visit windows displayed in Table 5. 
All information collected at an unscheduled visit will be identified as such in the listings. 
Table 5: 
Visit Windows (Days) 
Visit 
Relative Target Day 
Protocol-Specified Visit 
Window 
Analysis Visit Window 
Screening visit 
 
-28 to -1 
-28 to -1 
Baseline visit 
1 
1 
1 
Week 2 (Day 15) 
15 
12 – 18 
2 – 22 
Week 4 (Day 29) 
29 
27 – 31 
23 – 43 
Week 8 (Day 57) 
57 
55 – 59 
44 – 71 
Week 12 (Day 85) 
85 
83 – 87 
72 – 127 
Week 24 (Day 169) 
169 
163 – 175 
128 – 211 
Week 36 (Day 253) 
253 
247 – 259 
212 – 295 
Week 48 (Day 337) 
337 
331 – 343 
296 – 379 
Week 60 (Day 421) 
421 
415 – 427 
380 – 463 
Week 72 (Day 505) 
505 
499 – 511 
464 – 547 
Week 84 (Day 589) 
589 
583 – 595 
548 – 631 
Week 96 (Day 673) 
673 
667 – 679 
≥ 632 
 
In certain presentation, the HAE attack rates are analyzed by month. The HAE attack will be 
assigned to an analysis month according to the study day of the actual HAE attack using the 
following conventions: 
Attack Day 
Analysis Month for Display 
1 – 28 
Month 1 (Day 1 – 28)  
29 – 56 
Month 2 (Day 29 – 56) 
57 – 84a 
 Month 3 (Day 57 – 84)  
a Continues for additional months (28-day blocks) through the end of the study. 
 
6.7.7. 
Multiple Assessments 
Where multiple scheduled measurements are recorded for a given time point (ie, triplicate ECGs 
or repeated blood pressure assessments), the mean of the measurements will be calculated and 
used in any derivation of summary statistics. All available data will be listed. 
When multiple visits occur within the same window, the scheduled visit will be used in the 
analysis if available. If no scheduled visit occurs within the window and unscheduled visit(s) 
and/or an early termination visit occur within the window, the analysis visit closest to the target 
day will be selected for use in analysis. If deemed appropriate by the sponsor (eg, in the case of a 


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retest), unscheduled visits may be chosen for analysis given documentation of the desired visit 
from the sponsor.  
Results from unscheduled visits will be eligible for inclusion in analyses of worst post-baseline 
results regardless of their use for ‘by visit’ displays.  
Listings will display all visits as recorded on the eCRF, including the date and study day. All 
available data including any totals, domains, or subscales of scale assessments summarized will 
be listed. 
6.7.8. 
 Derived Efficacy Endpoints 
6.7.8.1. 
Subject-Reported Attack  
A subject-reported attack is any attack reported on the HAE Attack Details eCRF page. Each 
reported attack will count as a separate attack, even if the time periods for the attacks are 
overlapping. 
6.7.8.2. 
Adjusted Attack  
Subject-reported attacks reported must meet the following criteria (applied in order) for inclusion 
in effectiveness analyses: 
• Attack must include at least 1 symptom of swelling  
• Subject response to diary question, “In retrospect, could there be an alternative 
explanation for your symptoms other than an HAE attack (ie, allergic reaction, viral 
cold etc.)?” must be “no”. 
• Attack must be unique (attack began > 24 hours from the end of the prior attack). 
• Any attack that begins within 24 hours from the end of a prior attack will be 
combined with the prior attack. 
• If the entire adjusted attack is untreated, it must have a duration > 24 hours  
Using the above criteria, adjusted attacks will be determined programmatically. For adjusted 
attacks that span 2 or more subject-reported attacks, attack triggers, locations, symptoms, 
duration, and other characteristics will be based on the information from each component 
subject-reported attack. Additionally, the start date/time of the adjusted attack will be the start 
date/time from the first attack and then end date/time of the adjusted attack will be the end 
date/time from the last attack being collapsed programmatically.  
6.7.8.3. 
Attack Rate 
The observed attack rate will be computed as the number of attacks per month, where 1 month is 
defined as a 4-week period (28 days). 
In general, the formula for computing an attack rate is the number of attacks meeting the attack 
criteria divided by the duration of the reporting period of interest.  
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 (𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ) =
 Number of Attacks ∗28
 Duration of Treatment Period of Interest 


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For subjects who complete the reporting period of interest, duration of reporting period of 
interest is defined as the last day in the reporting period – first day in reporting period + 1. For 
subjects who discontinue treatment prematurely in the reporting period of interest, the duration 
of reporting period of interest is defined as (last day of treatment +1) – first day in reporting 
period + 1. For example, if a subject receives the last treatment on Day 13 of Month 3 with 
2 attacks between Day 1 and Day 14, that subject will be considered to have had a rate of 
4 attacks/month (2 × 28/14 = 4) for Month 3. Both the reporting period and the treatment period 
have been adjusted to include an additional day as the subject prematurely discontinued dosing in 
Month 3. 
Subject-Reported Attack Rate 
Subject-reported attack rates will be computed for the entire dosing period. 
Adjusted Attack Rate 
Adjusted attack rates will be computed for the following reporting periods of interest and 
expressed in units of attacks/month where 1 month = 28 days: 
• By month 
• Entire dosing period 
For adjusted attack rates by month, months will be defined in blocks of 28 days, beginning on 
Day 1, the day of first dose. Should a subject prematurely discontinue treatment at the end of the 
monthly reporting period (ie, Day 28), any attacks any attacks that occur within 24 hours after 
last dose will be counted in the calculation of attack rate of the prior month and the additional 
24-hour period will be included in the duration of the reporting period. For example, if a subject 
has 1 attack from Day 1 to 28, discontinues drug on Day 28, and has an attack on Day 29, the 
Month 1 (Day 1 to Day 28) attack rate will be 0.55 attacks/month (2 × 28/29 = 0.55).  
No imputation will be performed for missing data.  
Adjusted Attack Rate by Location 
Adjusted Abdominal-only, Peripheral, and Mixed attack rates will be computed using the 
location definitions provided in Section 6.7.8.12. 
6.7.8.4. 
Number and Proportion of Days with Angioedema Symptoms 
The number of days with angioedema symptoms is the sum of the days during the reporting 
period for which at least one symptom is reported during an adjusted HAE attack. The definition 
of the reporting period will be defined for subjects who discontinue in the same manner as for 
the attack rate calculation (see Section 6.7.8.3). 
The percentage of days with angioedema symptoms is derived as the number of days with 
angioedema symptoms divided by the duration of the reporting period of interest. The calculation 
will be performed similarly to the calculation of the attack rate (see Section 6.7.8.3). 


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6.7.8.5. 
Durability of Response 
The durability of response is defined as the adjusted attack rate trend over time. Adjusted attack 
rates by month (28-day blocks of time, starting with Day 1) will be calculated and summarized. 
6.7.8.6. 
Subjects Who Are Attack Free 
A subject who completes dosing in the reporting period of interest and has no adjusted attacks 
during this same period is considered attack free. Subjects with no adjusted attacks in the 
reporting period but who discontinue before the end of the period or who experience adjusted 
attacks in the period are not considered attack-free. For the purposes of this analysis, the 
reporting period is zero to 24 weeks zero to 48 weeks, and for the entire study. 
6.7.8.7. 
Attack Duration 
The duration of each subject-reported attack will be calculated in hours, based on the start and 
stop date and time of the subject-reported attack (time the attack finished). For an adjusted attack 
that includes more than one subject-reported attack, the duration is calculated from the start of 
the first subject-reported attack to the end of the last subject-reported attack that has been 
combined into one adjusted attack. Similarly, the duration of the attack from start of the attack to 
time that the worst was over will also be calculated. 
All subject-reported attack durations will be included in listings and those included in adjusted 
attacks will be denoted. Adjusted attack duration will be summarized. 
6.7.8.8. 
Attack Onset Relative to Initial Dose of Study Drug 
The time to onset of each subject-reported attack from the time of the initial dose of study drug 
reported in the subject eCRF page will be calculated and displayed in the listing of attack 
information. If there is no dosing time reported for the dose taken prior to the attack, the attack 
onset time relative to prior dose will be missing. The attack onset time relative to prior dose of 
study drug is information used in the listing of attack data only. 
6.7.8.9. 
Medications to Treat HAE Attacks 
The following medications reported taken as acute treatment in the subject diary will be 
classified in the analyses as targeted medications to treat subject-reported HAE attacks: Berinert, 
Cinryze, Kalbitor, Firazyr, Ruconest, and fresh frozen plasma. 
The following medications, also recorded in the subject diary as HAE treatments, will be 
classified as non-targeted medications: pain medication, nausea medication, intravenous fluids, 
other. 
6.7.8.10. Time to First Use of HAE Rescue Targeted Medication for an Adjusted Attack 
For each subject, the time to first use of HAE targeted rescue medication to treat an adjusted 
attack will be calculated as the number of days from the first dose of study drug to the first use of 
rescue medication. 


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6.7.8.11. Attack Symptoms 
Symptoms reported for adjusted attacks will be included in summaries of attack characteristics. 
In addition, listings of diary data will show symptoms for all subject reported attacks. 
6.7.8.12. Attack Location 
The anatomical location of each subject-reported and adjusted attack will be determined based 
on the symptoms indicated in the diary as shown in Table 6. 
Table 6: 
Determination of Attack Location Using Symptoms Collected in the Diary 
Abdominal-Only Attack 
Mixed Attack 
Peripheral Attack  
(Inclusive of Skin and Airway Swelling) 
Symptoms checked must only come from 
this box: 
Internal swelling or symptoms of internal 
swelling in the abdomen: 
Nausea 
Abdominal discomfort 
Cramps (colicky pain) 
Vomiting 
Abdominal pain 
Diarrhea 
Must have at least 
1 symptom from left and 
right box (from abdominal 
and peripheral attack 
characterization) 
Symptoms checked must only come from this 
box: 
Visible swelling:  
face/head 
neck (outer swelling) 
legs, buttocks/genitals 
eyes 
arms 
feet 
stomach (outside)  
mouth/tongue/lips  
hands 
chest/back 
joints 
Internal swelling or symptoms of internal 
swelling of the airways: 
lump in throat/tightness 
change in voice 
difficulty swallowing 
difficulty breathing 
Pink rings (erythema marginatum) 
Note: Symptoms of headache and substantial fatigue may be checked by the subject but play no role in the 
characterization of the location of a subject-reported attack.  
 
6.7.8.13. Attack Triggers 
Attack triggers for adjusted attacks will be summarized with the attack characteristics for 
adjusted attacks. In addition, attack triggers for each subject-reported attack will be included in 
the listings. 


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6.7.8.14. AE-QoL 
The AE-QoL (Weller, Groffik et al. 2012) consists of 4 domains and a total score. Each item 
answered by the subject scores between 0 and 4 points depending on the answer option chosen 
by the subject. The first answer option gets 0 points, the second option 1 point, the third option 
2 points, etc. Dimensions of the AE-QoL are shown in Table 7. 
Table 7: 
Dimensions of the AE-QoL 
Dimensions  
Item 
Functioning 
1. Impairment of work 
2. Impairment of physical activity 
3. Impairment of spare time activities 
Fatigue/Mood 
4. Impairment of social relations 
6. Difficulties of falling asleep 
7. Waking up during the night 
8. Feeling tired during the day 
9. Difficulties in concentrating 
10. Feeling downhearted 
Fears/Shame 
12. Feeling burdened at having swellings 
13. Fear of new suddenly appearing swellings 
14. Fear of increased frequency of swellings 
15. Ashamed to visit public places 
16. Embarrassed by the appearance of swellings 
17. Fear of long-term negative drug effects 
Nutrition 
5. General limitations in foods and eating 
11. Limitations in the selection of food and beverages 
Total Score  
Items 1 to 17 
Abbreviations: AE-QoL = angioedema quality of life questionnaire. 
 
The AE-QoL domain scores and the AE-QoL total score are calculated using the following 
formula: 
AE-QoL Domain Score = 
∑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
max (∑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) ∗100 
where 
∑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 = Sum of reported item scores per case report form  
max (∑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) = Sum of the Maximum possible score for each domain 
The calculated AE-QoL domain scores range from 0 (best) to 100 (worst). 


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The calculated AE-QoL ranges from 0 (best) to 100 (worst).  
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 scores will not be calculated 
if more than one item is left unanswered in that domain. The AE-QoL total score will not be 
calculated if more than 25% of items (ie, > 4 items) are left unanswered. Note that subjects who 
do not work were instructed to leave question 1 blank. As long as that is the only question in the 
functioning domain that is missing, the functioning domain can still be calculated.  
6.7.8.15. TSQM 
The TSQM consists of 14 items of which 13 items are made up of 3 specific scales 
(Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global 
Satisfaction). In addition, 1 item (Item 4) questions whether as a result of taking this medication, 
the subject experienced any side effects at all, which can be answered by yes and no. Table 8, 
reproduced from (Atkinson, Sinha et al. 2004), details the individual items in the TSQM.  
Table 8: 
List of Questions from TSQM 
Item # 
TSQM Item 
1 a 
How satisfied or dissatisfied are you with the ability of the medication to prevent or treat 
your condition?  
2 a 
How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
3 a 
How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working? 
4 b 
As a result of taking this medication, do you currently experience any side effects at all? 
5 
How bothersome are the side effects of the medication you take to treat your condition? 
6 
To what extent do the side effects interfere with your physical health and ability to function 
(ie, strength, energy levels, etc.)? 
7 
To what extent do the side effects interfere with your mental function (ie, ability to think 
clearly, stay awake, etc.)? 
8 
To what degree have medication side effects affected your overall satisfaction with the 
medication?  
9 
How easy or difficult is it to use the medication in its current form? 
10 
How easy or difficult is it to plan when you will use the medication each time?  
11 
How convenient or inconvenient is it to take the medication as instructed? 
12 
Overall, how confident are you that taking this medication is a good thing for you? 
13 
How certain are you that the good things about your medication outweigh the bad things?  
14 a 
Taking all things into account, how satisfied or dissatisfied are you with this medication?  
Abbreviations: TSQM = Treatment Satisfaction Questionnaire for Medication. 
 


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At baseline, TSQM questionnaires were presented to subjects with instructions that they 
complete the questionnaire based on their usual medications. At all other time points for 
collection of TSQM, subjects are asked to think about their level of satisfaction or dissatisfaction 
with the medication they are taking in this clinical trial. 
Scale scores are calculated for each scale and are transformed into scores ranging from 0 to 
100 (Quintiles IMS 2017). Of note, a score can be computed for a domain only if no more than 
1 item is missing from that domain. The calculations specific to each domain are presented in 
detail below.  
•Global Satisfaction  
([(Sum(Item 12 to Item 14)) – 3] divided by 14) * 100  
o If Item 12 or 13 is missing  
([(Sum(the 2 completed items)) – 2] divided by 10) * 100  
o If Item 14 is missing  
([(Sum(Item 12 and Item 13)) – 2] divided by 8) * 100  
 
•Effectiveness  
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100  
o If 1 item is missing  
([Sum(the 2 completed items)) – 2] divided by 12) * 100  
 
•Side Effects  
If Question 4 is answered ‘No’ then score = 100 
Else…  
([Sum(Item 5 to Item 8) – 4] divided by 16) * 100  
o If 1 item is missing  
([(Sum(the 3 completed items)) – 3] divided by 12) * 100  
 
•Convenience  
([Sum(Item 9 to Item 11) – 3] divided by 18) * 100  
o If 1 item is missing  
([(Sum(the 2 completed items)) – 2] divided by 12) * 100 
 
6.8. 
Handling of Missing Data 
6.8.1. 
Missing Effectiveness Endpoints 
For subjects who prematurely discontinue the study, all available data will be included for the 
key safety and effectiveness analyses. No imputation for missing data will occur. 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
For analysis of medications, a complete date should be established in order to identify whether a 
medication was taken during the study treatment period or not. For the purpose of handling 
partially reported start and stop dates for medication the following algorithm will be applied: 


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• Missing start day, but month and year present: 
If trial medication had been taken in the same month and year as the occurrence of the 
medication, then the start day of the event/medication will be assigned to the day of 
first dose of trial medication. 
Otherwise the start day will be set to the first day of the month. 
• Missing start day and month, but year present: 
If trial medication had been taken in the same year as the occurrence of the 
medication, then the start date of the medication will be assigned to the date of first 
application of trial medication. 
Otherwise the start day and month will be set to 01 January. 
• Missing end day, but month and year present: 
The day will be set to the last day of the month. 
• Missing end day and month, but year present: 
The end day and month will be set to the date of trial termination. 
However, if trial termination year is greater than the year of the event/medication, 
then the day and month will be set to 31 December. 
• Completely missing start date: 
For HAE medications collected on subject diaries, the date will be set to the 
corresponding HAE attack date. For all other concomitant medications, a completely 
missing start date will be set to the treatment start date (if prior to the medication end 
date) or otherwise will be set to the medication end date. 
In subject data listings, start and stop date of medication will be displayed as reported on the 
eCRF. 
6.8.3. 
Missing Start and Stop Dates for Adverse Events 
The same conventions for addressing incomplete dates for prior and concomitant medications 
will also be used for AEs. 
6.8.4. 
Missing Time of First and Last Dose  
In case of missing time for first dose, it will be assumed that baseline pre-dose measures that 
were to be taken prior to first dose according to the protocol were in fact taken prior to dosing. 
In case the time of the last dose is not reported on the diary, time of dose will be assigned as the 
median dosing time from all prior doses for the subject, as subjects are to dose once per day at 
approximately the same time each day. 
6.8.5. 
Incomplete Date and Time for a Subject-Reported Attack 
For HAE attacks reported with a missing stop date and or time, the following algorithm will be 
applied: 


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• Missing start time but start date present: 
The start time will be set to 12:00PM. 
• Missing start date and time: 
The start date will be set to the diary date for which the question was answered “Yes”. 
The start time will be set to 12:00PM 
• Missing stop time, but stop date present: 
The stop time will be set to 11:59PM 
• Missing stop date and time:  
The stop date will be set to the attack start date, the stop time will be set to 11:59PM 
7. 
STUDY POPULATION 
7.1. 
Subjects Disposition 
Subject disposition will be presented for all subjects. The number of subjects who completed 
through each study visit and those that discontinued from the study will be provided. The 
primary reasons for early discontinuation will also be presented by dose. Reasons for exclusion 
from the safety population will be tabulated. Days on study will be summarized by treatment 
group. 
Subject status at the end of the study will be listed and summarized based on the safety 
population, showing the number and percentage of subjects with early discontinuation of study 
treatment and early withdrawal from the study along with reasons for each item. The listings will 
include whether subjects discontinued from the study drug, whether they withdrew from the 
study and the reasons for the discontinuation of study drug, along with the date of first and last 
dose and the date of completion or discontinuation from the study drug and date of study 
withdrawal. Duration on study treatment and on the study will also be provided. 
A consolidated standards of reporting trials (CONSORT) diagram will be created based on the 
summary tables for the study report. This will include summary tables assessed for eligibility, 
subjects excluded (not meeting entrance criteria, declining to participate, and other reasons for 
exclusion), subjects enrolled, subjects allocated to either treatment group, including subjects who 
did and did not receive intended treatment (with reasons given for not receiving intended 
treatment), subjects lost to follow-up or discontinuing treatment (with reasons given), and 
subjects analyzed vs. not analyzed (with reasons given for subjects who are not included in an 
analysis). 
A summary of enrollment by country and investigator site will be provided. Early 
discontinuation will be summarized by country and investigator site. 
Summaries of prior androgen use will be provided by overall duration of prior use, duration of 
use within 12 months prior to treatment start date, and time since stopping androgen use to 
treatment start date (latency). 


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7.2. 
Screen Failures 
The number of screen failures and percent of screened subjects who are screen failures will be 
summarized along with reasons for screen failure on the disposition table. A listing of 
demographic information for screen failures will be provided. 
7.3. 
Protocol Deviations 
Protocol deviations will be included in listings and summaries for the CSR. A separate document 
will detail decision-making guidelines for determining whether a protocol deviation is major or 
minor. It will also detail a list of categories of protocol deviations. 
7.4. 
Demographic and Baseline Characteristics 
Demographics, including age, gender, race, ethnicity, childbearing potential, weight, height, and 
BMI will be summarized using descriptive statistics by treatment group. Time from last 
BCX7353 dose to baseline will be summarized and listed for subjects who were enrolled in 
previous clinical trials of BCX7353. 
Age (in years) will be reported as the age at consent or assent, as collected in the eCRF. 
Body mass index (kg/m2) will be calculated using the standard formula: 
BMI (kg/m2) = 
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡 (𝑚𝑚)2 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be listed for each subject. 
7.6. 
HAE Medical and Medication History 
HAE and HAE medication history will be summarized for the following where possible: 
• HAE history 
• Past on-demand treatments of HAE 
• Current on-demand treatments of HAE 
• Past prophylactic treatments of HAE  
Past on-demand treatments will include those medications that were taken as needed and 
discontinued prior to the initiation of study treatment as recorded on the HAE Medication 
History Page. Past prophylactic treatments will include those medications that were taken as 
prophylaxis and discontinued prior to the initiation of study treatment as recorded on the HAE 
Medication History Page. Current on-demand medications will include those that are noted at 
screening as currently used for on-demand treatment as recorded on the HAE Medication History 
Page. Summaries will include a grouping of any C1-INH medication as well as displays of 
individual medications. The C1-INH grouping will include plasma-derived C1-INH replacement 
(brand names = Cinryze, Berinert, Haegarda), recombinant C1-INH replacement (brand 
name = Ruconest), icatibant (brand name = Firazyr), Ecallentide (brand name = Kalbitor), fresh 
frozen plasma, and lanadelumab (brand name = Takhzyro). The summary of androgens will 


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include androgens (unspecified), oxandrolone, danazol (brand name = Danocrine), and 
stanozolol. 
For subjects who are not rolling over from a previous BCX7353 study, a summary of screening 
complement 4 (C4) and functional C1 esterase inhibitor (C1-INHf) will be provided in categories 
showing how subjects met the inclusion criteria confirming diagnosis of Type I or II HAE. 
Confirmation by SERPING, if required, will be included in the summary. Categories for C4 will 
be C4 < lower limit of normal (LLN) and C4 ≥ LLN and for C1-INHf will be < 50%, 50% to 
< 74%, and ≥ 74%. Where the C4 test has been repeated, the test result for the repeat will be 
used in this summary.  
In addition, detailed SERPING data will be listed. 
7.7. 
Prior and Concomitant Non-HAE and HAE Medications  
Medication use is collected for the period from 30 days prior to Screening to study completion, 
with the exception of contraceptives, which are collected from 60 days prior to Screening. 
Medications received and stopped prior to the date of first dose will be considered prior 
medications. 
Medications will be considered as concomitant if the start date of the medication is on or after 
the date of first intake of study drug or if the start date is prior to the first date of study drug but 
the medication is ongoing during the treatment period in the study. Medications started more 
than 30 days post discontinuation of study drug will not be considered concomitant medications. 
Medication verbatim text will be coded using the WHODD, March 2017. The number and 
percentages of subjects taking each medication will be summarized by World Health 
Organizaton (WHO) preferred name. Multiple uses of the same medication (by preferred name) 
will be counted once only per subject per study treatment. No inferential statistics will be 
provided. 
HAE-related medications listed in subject diaries as taken for subject-reported attacks will be 
listed and summarized separately from HAE-related medications identified as concomitant 
medications. An attack-level summary will also be provided showing the number of attacks for 
which the various HAE-related medications were taken based on the subject diary and the 
concomitant medication form (androgens) in the eCRF. 
Subjects who enter the study on prophylactic HAE medications will be summarized by treatment 
group. The time to discontinuation of prophylactic HAE medications will be estimated by the 
Kaplan-Meier method. Subjects who enter on prophylactic HAE medications and do not 
discontinue prophylactic medication will be censored at their last assessment. 
All medication data will be listed. 
7.8. 
Baseline Physical Examination 
Physical examination findings, including baseline, will be listed. 
7.9. 
Baseline Primary and Secondary Effectiveness Evaluations 
All attacks (subject-reported and adjusted) will be listed. 


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Similarly, a summary of baseline AE-QoL total and domain scores will be presented in an 
appropriate summary table.  
8. 
EFFECTIVENESS  
8.1. 
General Considerations 
As the primary nature of this study is to evaluate the safety of BCX7353, effectiveness is 
considered of secondary importance. No formal testing will be conducted. 
8.2. 
Subgroup Analyses 
Subgroup analyses for effectiveness endpoints will not be performed. 
8.3. 
Analysis of the Effectiveness Endpoints 
8.3.1. 
Effectiveness Analysis 
The effectiveness analysis is comprised of multiple endpoints (Section 3.2.2) and will be 
conducted on the safety population.  
8.3.1.1. 
HAE Attack Rate 
The number of subject-reported and adjusted HAE attacks will be analyzed by treatment group 
using appropriate descriptive statistics. The adjusted attack rate (expressed as attacks/month) will 
be presented by month as well as for the entire study dosing period.  
8.3.1.2. 
Number and Proportion of Days with Angioedema Symptoms 
The number and proportion of days with angioedema symptoms reported from adjusted attacks 
will be summarized by month as well as for the entire study dosing period using descriptive 
statistics by treatment group. 
8.3.1.3. 
Number and Proportion of Subjects Attack Free  
The number and proportion of subjects adjusted attack free will be summarized using descriptive 
statistics by treatment group. 
8.3.1.4. 
Discontinuations Due to Lack of Efficacy 
The number of subjects who discontinue due to lack of efficacy will be provided with subject 
disposition and will be summarized by treatment group.  
8.3.1.5. 
Attack Characteristics 
Characteristics of adjusted attacks, including location of attack, duration of attacks from start to 
finish and from start to the time the worst symptoms of the attack were over, triggers, swelling, 
other symptoms, whether the attack was treated, severity as assessed by the subject’s ability to 
do daily activities, appearance affected, professional care sought, and location of professional 
care will be summarized and listed. 


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The time to first adjusted attack will be estimated using Kaplan-Meier. Subjects who do not 
experience an adjusted attack will be censored at the time of study treatment discontinuation. 
A summary of duration of attack for abdominal, peripheral, and mixed attacks will also be 
provided for subject-reported and adjusted HAE attacks. 
8.3.1.6. 
Use of HAE Attack Medications 
Use of HAE medications as noted in the diary will be summarized separately from concomitant 
medications as noted in Section 7.7 . In addition, summaries of the number of subject-reported 
HAE attacks requiring treatment will be provided.  
The time to first use of HAE targeted rescue medication for an adjusted attack will be estimated 
using Kaplan-Meier estimates. Subjects who do not use HAE rescue medication will be censored 
at the time of study treatment discontinuation. 
8.3.1.7. 
AE-QoL 
Subject-reported outcomes including the AE-QoL questionnaire domain scores (total, 
functioning, fatigue/mood, fears/shame, and nutrition) will be calculated as discussed in 
Section 6.7.8.14. The AE-QoL will be summarized by domain/subscale, visit and treatment 
group using descriptive statistics.  
8.3.1.8. 
TSQM 
TSQM is measured at baseline and represents satisfaction with their usual medication. The 
baseline scores may be reflective of satisfaction with the subject’s previous treatment or with no 
treatment. 
TSQM scores for Effectiveness, Side Effects, Convenience, and Global Satisfaction and 
corresponding change from baseline values will be calculated for each visit as discussed in 
Section 6.7.8.15. The TSQM scores will be summarized by score, treatment and visit. 
9. 
SAFETY AND TOLERABILITY 
9.1. 
Overall Summary of Tolerability 
The summaries of tolerability will be presented in the tables described in Section 9.3 and 
Section 9.4. 
9.2. 
Subgroup Analyses 
The following subgroup analyses for selected safety endpoints will be performed: 
• Prior androgen use (latency: time between stopping androgen and starting BCX7353: 
< 2 weeks, 2 weeks to < 1 month, 1 month to < 2 months, and ≥ 2 months) 
• Duration of prior androgen use (never used, < 6 month, 6 months to < 1 year, 1 year 
to < 5 years, 5 years to < 10 years, ≥ 10 years). 


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9.3. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
The following are safety endpoints: 
• Proportion of subjects with TEAEs  
• Proportion of subjects with TESAEs 
• Proportion of subjects who discontinue BCX7353 due to a TEAE 
• Proportion of subjects with treatment-emergent Grade 3 or 4 AEs 
• Proportion of subjects with treatment-emergent, treatment-related AE consistent with 
a drug rash 
• Proportion of subjects with treatment-emergent Grade 3 or 4 laboratory abnormalities 
AEs will be mapped to a MedDRA version 19.1 SOC and PT. If a subject experiences multiple 
events that map to a single preferred term, the greatest severity grade according to the Division 
of Microbiology and Infectious Diseases (DMID) November 2007 criteria and strongest 
investigator assessment of relation to study medication will be assigned to the preferred term for 
the appropriate summaries. Should an event have a missing severity or relationship, it will be 
classified as having the highest severity and/or strongest relationship to study medication. All 
AEs will be listed for individual subjects showing both verbatim and preferred terms. 
TEAEs are defined as AEs that occurred on or after first dose of study treatment through 30 days 
post-discontinuation of study treatment. All AEs that occurred prior to the initiation of study 
treatment or those recorded after 30 days after the last dose of study treatment will be excluded 
from the tables but will be included in the listings. 
Drug-related events are defined as those AEs that the Investigator believes were possibly, 
probably, or definitely related to the study drug. 
9.3.1. 
Summaries of Adverse Event Incidence Rates for All Subjects and Adverse 
Incidence Rates for Serious Adverse Events, Adverse Event Dropouts, and Death 
A brief summary of AEs will show, by treatment group, the number and percentage of subjects 
who 1) had any AE, 2) had any drug-related event, 3) permanently discontinued from study drug 
due to an AE, 4) had any serious adverse event (SAE), 5) had any Grade 3 or higher AE, 6) had 
any Grade 3 or higher drug-related AE, 7), had any AE leading to interruption of study drug, 
8) had a drug-related SAE, or 9) had a fatal SAE. 
AEs will be summarized by treatment group. For each SOC and PT, the number and percentage 
of subjects reporting an event will be calculated. In summary tables, SOCs and events within a 
SOC will be presented by decreasing frequency count based on the total number of events. 
Multiple events (by subject or SOC as appropriate) will be counted only once per subject per 
dose in each summary. For summaries that use severity grade, the most severe event will be 
selected. 


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The following summary tables (number and percentage of subjects) of TEAEs (by SOC and PT) 
will be provided by treatment group: 
• Overall summary of TEAEs 
• Summary of TEAEs 
• Summary of drug-related TEAEs 
• Summary of treatment-emergent adverse events by severity 
• Summary of Grade 3 or Grade 4 TEAEs 
• Summary of drug-related, Grade 3 or Grade 4 TEAEs 
• Summary of TESAEs  
• Summary of TEAEs leading to permanent discontinuation of study treatment 
• Summary of TEAEs leading to interruption of study treatment 
• Summary of drug-related, TESAEs 
In addition, summaries of frequent TEAEs and drug-related TEAEs will be provided by 
preferred term (not by SOC and PT), in decreasing order of frequency. Frequent TEAEs will be 
defined as TEAEs that occur in at least 5% of the total number of subjects in the clinical trial. 
The number of events will be displayed on all summary tables except the overall summary of 
TEAEs. All TEAE analyses will be repeated using subgroups. 
A single presentation of the summary of TEAEs for subjects entering on prophylactic 
medications will be presented. For this presentation, only TEAEs occurring while the subject 
was simultaneously taking BCX7353 and prophylactic medication will be summarized. 
Data listings will be provided for all AE data. In addition to listing all AEs, distinct data listings 
will also be provided for the following: 
• Grade 3 or Grade 4 AEs  
• AEs leading to permanent study discontinuation 
• SAEs (fatal and non-fatal) 
9.3.2. 
Investigator-Identified Rash Events of Special Interest 
All rashes, regardless of assess causality or severity are reported as events of special (EOSI) 
interest by investigators in a protocol defined manner. However, the endpoint of interest is the 
proportion of subjects with a treatment-emergent, treatment-related AE consistent with drug 
rash. These events are marked as EOSI on the AE eCRF page and will be referred to as 
investigator-identified drug rash. 
For the investigator-identified rashes, separate listings will be provided. In addition, for 
investigator-identified rashes there will be a summary that shows, by treatment group, the 
number and percentage of subjects with: 
• A TEAE  


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• A drug-related TEAE  
• Permanent discontinuation from study drug due to the TEAE  
• An AE that was considered an TESAE  
• Any Grade 3 or higher TEAE  
• Any Grade 3 or higher drug-related TEAE  
• Any TEAE leading to interruption of study drug  
• An TEAE that was considered a drug-related TESAE 
• A TEAE that required use of concomitant medication 
For treatment-emergent investigator-identified rashes, time to development of the AE will be 
estimated using the Kaplan-Meier method. The results will be displayed in summary tables as 
well as in a Kaplan-Meier plot. Subjects who do not experience the event of interest will be 
censored at the date of the last dose. Summary displays for the investigator-identified rashes will 
include a count of the number of AEs as well as the number of subjects who experience each AE. 
A Kaplan-Meier plot and summary of duration of event will be provided for the 
investigator-identified rashes. The summary display will provide the median duration of event by 
treatment group, with the event as the unit of interest rather than the subject. 
9.3.3. 
Gastrointestinal Abdominal-Related AEs 
Gastrointestinal (GI) abdominal-related AEs are also of interest, although these are not AEs of 
special interest for investigator reporting purposes. There are no appropriate standard MedDRA 
queries (SMQs) to evaluate abdominal-related AEs that are appropriate to assess potential 
adverse events associated with BCX7353 use. In order to create a list of PTs that are pertinent, 
the events to be analyzed have been prospectively defined as all PTs within the MedDRA 19.1 
hierarchy under the High Level Group Terms (HLGTs) of 1) gastrointestinal signs and 
symptoms and 2) gastrointestinal motility and defaecation conditions (See Section 13.3 for a 
detailed list of PTs High Level Terms, and HLGTs). This selection is broad enough so that GI 
events are appropriately identified and analyzed but excludes terms that, although in the GI SOC, 
are not representative of the events of concern such as oral or esophageal events.  
For the GI abdominal-related events, separate listings will be provided. In addition, for GI 
abdominal-related events there will be a summary that shows, by treatment group, the number 
and percentage of subjects with: 
• A TEAE 
• A drug-related TEAE  
• Permanent discontinuation from study drug due to the TEAE  
• An AE that was considered an TESAE  
• Any Grade 3 or higher TEAE  
• Any Grade 3 or higher drug-related TEAE  


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• Any TEAE leading to interruption of study drug  
• An TEAE that was considered a drug-related TESAE 
• A TEAE that required use of concomitant medication 
For treatment-emergent GI abdominal-related AEs, time to development of the AE will be 
estimated using the Kaplan-Meier method. The results will be displayed in summary tables as 
well as in a Kaplan-Meier plot. Subjects who do not experience the event of interest will be 
censored at the date of the last dose. Summary displays for the GI abdominal-related TEAEs will 
include a count of the number of AEs as well as the number of subjects who experience each AE. 
A Kaplan-Meier plot and summary of duration of event will be provided for GI 
abdominal-related TEAEs. The summary display will provide the median duration of event by 
treatment group, with the event as the unit of interest rather than the subject. 
A separate analysis will be conducted in which the number and proportion of subjects with either 
a GI abdominal-related TEAE or subject-reported abdominal-only attack is presented. The 
number of events will also be included in the summary. 
9.3.4. 
Missing and Partial AE Onset Dates 
See Section 6.8.3. 
9.3.5. 
Summaries of Adverse Incidence Rates per 100 Person-Years of Exposure to 
Study Treatment 
For this study, the duration of exposure to study treatment may vary due to differential 
follow-up. Because of this, certain AE tables will be repeated using the number of AEs per 
100 person-years of exposure instead of as a count, where 1 year = 365.25 days. 
To determine 100 person-years of exposure, the duration of treatment exposure will be computed 
for each subject and then summed across subjects to obtain the 100 person-years exposure per 
treatment group. The table will then display the rate per 100 person-years of exposure (count of 
AEs reported/total exposure for the treatment group in 100 person-years) values for each 
treatment group and for each AE. 
The following summary tables of rate of TEAEs per 100 person-years of exposure will be 
provided by treatment group (by SOC and PT): 
• Summary of TEAE rate per 100 person-years of exposure 
• Summary of drug-related, TEAE rate per 100 person-years exposure 
• Summary of TESAEs 
A listing of 100 person-years of exposure to study treatment will be provided. 


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9.4. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
The number of subjects exposed to study drug will be presented on the disposition table, and the 
duration of exposure will be presented on the exposure table. Treatment adherence, dose 
interruptions, and reasons for dose interruptions will be provided as summaries and listed. 
A summary and listing of dose reductions will be produced. The listing will include information 
of study day of dose reduction. 
The number of subjects exposed to study treatment and number of subjects who discontinue 
treatment early will be presented on the disposition table. A summary of exposure to study 
treatment will be also be presented and will include a summary of 100 person-years of exposure 
to study treatment as described in Section 9.3.5. Listings of exposure to study treatment and of 
drug accountability will be provided by subject and treatment. Kaplan-Meier plots of duration of 
study treatment will be provided. 
Treatment compliance, based on drug accountability information as collected in the eCRF, will 
be calculated for each study treatment that the subject received as follows: 
Treatment compliance (dispensing)= 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝐸𝐸𝑥𝑥𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∗100 
The number of capsules taken is derived from the number of capsules dispensed (30 per bottle 
dispensed) – the number of capsules returned as reported in the eCRF. For those on the 150 mg 
dose level, the expected number of capsules taken is defined relative to the lot of drug received 
as the number of pills taken × the duration of study treatment (eg, date of the last dose – date of 
the first dose + 1). The number of pills taken is either 3 or 1 depending on lot number. If a 
subject receives drug from different lots, the expected number of capsules taken is calculated 
relative to the dispense and return dates for a given lot and then summed across lots. On a date of 
return, the dose is assumed to be taken from the newly dispensed bottle. For subjects on the 
110-mg dose level, the expected number is defined as 1 × the duration of study treatment. 
A categorical summary of treatment compliance will be produced with the following categories 
shown in Table 9. 
Table 9: 
Definition of Compliance Categories 
Compliance 
Range of Compliance (%) 
Under-dosing 
< 80% 
Acceptable compliance 
80 to < 90% 
Good compliance 
90% to 110% 
Over-dosing 
> 110% 
 
9.5. 
Concomitant and Other Medications 
Medications received and discontinued prior to the date of first dose are considered as prior 
medications. Medications will be considered as concomitant if the start date of the medication is 


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on or after the date of first intake of study drug for the treatment period of interest or if the start 
date is prior to the first date of study drug but the medication is ongoing during the treatment 
period in the study. 
Medication verbatim text will be coded using the WHODD, DDE B2 March 2017 version. 
Concomitant medications will be summarized by treatment and WHO preferred name. Multiple 
medication use (by preferred name) will be counted once only per subject. Concomitant 
medications started more than 30 days post last dose will not be included in summary displays 
but will be listed. 
Concomitant medications that were used for HAE-related indications will also be summarized 
separately.  
9.5.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
See Section 6.8.2. 
9.6. 
Laboratory Data 
The following is a safety endpoint: 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
A listing of clinical laboratory evaluations is provided in protocol Section 11.1.6. 
Clinical laboratory assessments and corresponding changes from baseline will be summarized 
for each laboratory panel by treatment group and visit. Laboratory abnormalities will be graded 
according to the DMID Adult Toxicity Table (publish date: November 2007; see Protocol 
Appendix 16.1). Any graded abnormality that occurs following the initiation of study drug and 
represents at least one-grade increase from the baseline assessment is defined as treatment 
emergent.  
Urinalysis results will be summarized by treatment and visit and listed by subject and treatment. 
The number and percentage of subjects experiencing treatment-emergent graded toxicities will 
be summarized. Treatment-emergent Grade 3 or 4 laboratory abnormalities will be summarized 
separately. Laboratory toxicity shifts from baseline to worst post-baseline assessments will be 
summarized.  
The number and percentage of subjects having elevations in liver enzyme abnormalities (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], or bilirubin) in relation to fold above 
the upper limit of normal (ULN) will be summarized by treatment group. 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments (where “and” indicates elevations occurring at 
the same visit). Within each treatment group and laboratory parameter grouping, a subject may 
be counted once per elevation criteria using the worst-case result. That is, a subject with a 
worst-case ALT elevation >3 × the ULN for a given treatment group would be counted once in 
the ALT > 1.5 × ULN category and once in the ALT > 3 × ULN category, regardless of how 
many ALT elevations the subject had that met the > 3 × ULN and > 1.5 × ULN elevation criteria. 


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• ALT and/or AST > 3 × ULN and total bilirubin > 1.5 or 2 × ULN 
• AST > 1.5, 3, 5, 10, and 20 × ULN 
• ALT > 1.5, 3, 5, 10, and 20 × ULN  
• Total bilirubin > 1, 1.5, or 2 × ULN  
• Alkaline phosphatase (ALP) > 1.5 × ULN 
The summary display of abnormal hepatic laboratory values will be repeated for prior androgen 
use subgroups as defined in Section 9.2. Detailed listings of prior androgen use will be provided 
for subjects with any elevation in the indicated categories. 
Profiles of liver enzymes and bilirubin over time will be graphically displayed for subjects with 
any Grade 3 or 4 abnormality in these analytes. In addition, a listing of all liver function test 
(ALT, AST, bilirubin, ALP, gamma-glutamyl transferase) results for subjects experiencing a 
treatment-emergent Grade 3 or 4 liver function test will be provided. 
In addition, a Hy’s law plot, a shift plot showing liver safety panel tests over time (baseline vs. 
on-study), and distribution plots of ALT, AST, ALP, bilirubin, cholesterol, and triglycerides over 
time will be produced using the format recommended by the FDA/Industry/Academia Safety 
Graphics working group (https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The 
plots to be included are the scatter plot of maximum transaminase versus maximum bilirubin, the 
liver test safety panel over time and the distribution of ALT by time and treatment. The 
distribution plots for AST, ALP, bilirubin, cholesterol and triglycerides will use the same format 
as is used for ALT. 
Separate Kaplan-Meier plots of time to event for a Grade 3 or higher ALT, AST, or total 
bilirubin will be produced. The results will also be displayed in a summary table. Subjects who 
do not experience the event of interest will be censored at the date of the last dose. 
In addition, a listing of all liver function test results for subjects experiencing a 
treatment-emergent Grade 3 or 4 liver function test will be provided. 
A listing of AEs of nausea, vomiting, anorexia, abdominal pain, or fatigue occurring within 
24 hours of an elevation of > 3 × ULN for AST or ALT will be produced. 
9.6.1. 
Complement Factors and HAE Diagnosis 
Laboratory results related to HAE diagnosis, including complement factors C1-INHAg, 
C1-INHf, complement 3 (C3), and C4 will be included in summaries of laboratory data. Criteria 
used to confirm diagnosis of HAE Type I or II will be summarized and listed as described in 
Section 7.6. 
9.6.2. 
Laboratory Assessments for Rash 
For subjects with rash marked as possibly, probably, or definitely related to study drug, 
peripheral blood mononuclear cells (PBMCs) may be collected for analysis of possible 
drug-specific immune responses and possible drug-responsive T-cells. The data from PBMC 
analysis, if collected, may be listed. 


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Other laboratory assessments taken at the time of baseline and at onset of rash, including clinical 
chemistry, hematology with differential, C3 level, and urine eosinophils will be included in 
laboratory listings. 
9.7. 
Pregnancy 
A listing of positive pregnancy test results, if applicable, will be provided. 
9.8. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and respiratory rate) 
and body weight and corresponding changes from baseline will be summarized by treatment 
group and visit using descriptive statistics. These data will be listed by subject, treatment, and 
visit. 
Distribution plots of systolic and diastolic blood pressure over time will be produced using the 
format recommended by the FDA/Industry/Academia Safety Graphics working group 
(https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The graph format to be used is 
the same as the graph provided for the distribution of ALT by time and treatment. 
9.9. 
12-lead Electrocardiograms  
Baseline (predose) ECGs will be obtained in triplicate (ie, 3 separate readings) at 1- to 5-minute 
intervals, with baseline values calculated from an average of the 3 readings. All other ECGs will 
be single assessments. For subjects who are directly rolling over from a previous study or those 
with a treatment interruption of < 14 days from a previous study, the pretreatment ECG values 
obtained in the previous study will serve as the baseline ECG values. 
An ECG should be repeated for a change from baseline in corrected QT interval using Fridercia's 
method (QTcF) > 60 msec or a QTcF interval > 500 msec. 
ECGs and corresponding changes from baseline will be summarized by treatment group and visit 
using descriptive statistics.  
ECG findings will be summarized. 
The change from baseline in QTcF will be summarized at each time point where ECGs are 
analyzed. An individual subject’s change from baseline will be calculated as: 
∆ik= (QTcF for subject i at time point k – Baseline QTcF)  
QTcF measurements will be the average of triplicate ECGs at baseline and single values at all 
other time points.  
For routine ECGs, the number and proportion of subjects with QTcF ≤ 450, > 450 to ≤ 480, 
> 480 to ≤ 500, and > 500 msec; or changes of ≤ 30, > 30 to ≤ 60, or > 60 msec will be 
summarized. Unscheduled ECG results will be included in this summary table. 
All ECG values and findings will be listed by subject, dose, and visit. 
Additionally, a distribution plot of QTcF over time will be produced using the format 
recommended by the FDA/Industry/Academia Safety Graphics working group 


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(https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The graph format to be used is 
the same as the graph provided for the distribution of ALT by time and treatment.  
9.10. 
Physical Examination 
A full physical examination is conducted at screening (if applicable) and baseline, with 
symptom-directed examinations at all post-baseline assessments. Physical examination data will 
be listed by subject and dose. 
9.11. 
Study Termination Status 
Study termination status will be presented on the subject disposition table. 
10. 
PHARMACOKINETICS 
Analyses of PK concentration data will be based on the safety population. PK concentration data 
will be listed by subject, treatment, day, and time. Note that PK concentration data collected at 
each visit will not be summarized by visit as the timing of PK sampling with respect to previous 
dose was not pre-specified. 
The value of half-maximal effective concentration (EC50) is 9 ng/mL. 
The following summary displays will be produced: 
• Summary of number and percentage of collected samples > 4 × EC50, > 6 × EC50, and 
> 8 × EC50 at each visit and overall  
• Summary of number and percentage of samples within a subject > 4 × EC50, 
> 6 × EC50, and > 8 × EC50 
PK concentration data will be combined with data from other studies as part of a population PK 
analysis. A separate SAP will be written for that analysis. 
11. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
Changes from protocol-specified analyses include: removal of the intent-to-treat population, 
removal of analysis of disease severity, removal of comparison of effectiveness endpoints 
between subjects who received the indicated dose and a reduced dose, removal of comparison of 
effectiveness endpoints for those that received concomitant C1-INH and those who did not. 


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12. 
REFERENCES 
Atkinson, M. J., A. Sinha, S. L. Hass, S. S. Colman, R. N. Kumar, M. Brod and C. R. Rowland 
(2004). "Validation of a general measure of treatment satisfaction, the Treatment Satisfaction 
Questionnaire for Medication (TSQM), using a national panel study of chronic disease." Health 
Qual Life Outcomes 2: 12. 
Quintiles IMS (2017). "User Manual for the Treatment Satisfaction Questionnaire for 
Medication (TSQM) Version 1.0." 
Weller, K., A. Groffik, M. Magerl, N. Tohme, P. Martus, K. Krause, M. Metz, P. Staubach and 
M. Maurer (2012). "Development and construct validation of the angioedema quality of life 
questionnaire." Allergy 67(10): 1289-1298. 
 
 


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13.
APPENDIX
13.1. 
Table of Contents for Data Display Specifications 
Title 
Population 
Study Population Section 
Figures 
14.1.1.2 
CONSORT Diagram 
All Subjects 
14.1.6.2 
Kaplan-Meier: Time to Discontinuation of Study Drug 
Safety 
Tables 
14.1.1.1 
Summary of Subject Disposition 
All Subjects 
14.1.1.3 
Summary of Subject Disposition by Country and Site 
All Subjects 
14.1.1.4 
Analysis Populations 
Safety Population 
14.1.1.5 
Confirmation of Clinical Diagnosis 
All Subjects 
14.1.1.6.1 
Summary of Inclusion/Exclusion Criteria Not Met 
Safety Population 
14.1.1.6.2 
Summary of Inclusion/Exclusion Criteria Not Met 
Screen Failures 
14.1.1.7 
Summary of Protocol Deviations 
Safety Population 
14.1.2.1 
Summary of Demographic Characteristics 
Safety 
14.1.2.2 
Summary of Demographic Characteristics 
Safety 
14.1.3.1 
Summary of Medications Taken within 30 Days of 
Screening and Discontinued Prior to Dosing 
Safety 
14.1.3.2 
Summary of Concomitant Medications 
Safety 
14.1.3.3 
Summary of Concomitant Medications for HAE 
Safety 
14.1.3.4 
Summary of Concomitant Medications for HAE – 
Attack Level 
Safety 
14.1.3.5 
Summary of Medications Discontinued During the 
Study 
Safety 
14.1.4.1 
Summary of Baseline HAE Characteristics - HAE 
History 
Safety 
14.1.4.2.1 
Past Prophylactic Medications for HAE 
Safety 
14.1.4.2.2 
Current Prophylactic Medications for HAE 
Safety 
14.1.4.3 
Summary of Current On-Demand Treatments of HAE 
Safety 
14.1.4.4 
Summary of Subjects Entering on Prophylactic 
Medications for HAE 
Safety 
14.1.4.5 
Summary of Subject-Reported Baseline HAE 
Characteristics – Primary Acute Attack Treatment 
Information 
Safety 


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Title 
Population 
 
14.1.5.1 
Summary of Treatment Exposure and Treatment 
Compliance 
Safety 
Effectiveness Section  
 
Figures 
 
14.2.1.2 
Plot of Individual Adjusted Attack Rate 
Safety 
14.2.1.3 
Plot of Individual Subject-Reported Attack Rate 
Safety 
14.2.1.4 
Cumulative Distribution Plot of Adjusted Attack Rate 
Safety 
14.2.1.5 
Cumulative Distribution Plot of Subject-Reported 
Attack Rate 
Safety 
14.2.1.6 
Histogram of Adjusted Attack Rate 
Safety 
14.2.1.7 
Histogram of Subject-Reported Attack Rate 
Safety 
14.2.1.10 
Plot of Mean Adjusted Attack Rate by Month 
Safety 
14.2.1.11 
Plot of On Study Adjusted Attack Rate by Baseline 
Adjusted Attack Rate 
Safety 
14.2.1.17 
Kaplan-Meier Plot of Time (Days) to First Adjusted 
Attack after First Dose of Study Treatment  
Safety 
14.2.1.19 
Kaplan-Meier Plot of Time (Days) to First Use of 
Targeted Rescue Medication for an Adjusted Attack 
Safety 
14.2.4.2 
Plot of Mean AE-QoL Over Time 
Safety 
14.2.4.3 
Plot of Mean Change from Baseline in AE-QoL Over 
Time 
Safety 
14.2.5.2 
Plot of Mean TSQM Over Time 
Safety 
14.2.5.3 
Plot of Mean Change from Baseline in TSQM Over 
Time 
Safety 
Tables 
 
14.2.1.1 
Summary of HAE Attacks 
Safety 
14.2.1.8.1 
Summary of Durability of Response – Adjusted 
Attacks 
Safety 
14.2.1.8.2 
Summary of Durability of Response – Adjusted 
Attacks for Abdominal-Only Attacks 
Safety 
14.2.1.8.3 
Summary of Durability of Response – Adjusted 
Attacks for Peripheral-Only Attacks 
Safety 
14.2.1.8.4 
Summary of Durability of Response – Adjusted 
Attacks for Mixed Location Attacks 
Safety 
14.2.1.9 
Summary of Durability of Response – Subject-
Reported Attacks 
Safety 
14.2.1.12 
Summary of Duration of Adjusted Attacks (hours) 
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Title 
Population 
 
14.2.1.13 
Summary of Duration of Subject-Reported Attacks 
(hours) 
Safety 
14.2.1.14 
Summary of Attack Characteristics for Adjusted 
Attacks 
Safety 
14.2.1.15 
Summary of Attack Locations for Adjusted Attacks 
Safety 
14.2.1.16 
Time to First Adjusted Attack (KM Estimates) 
Safety 
14.2.1.18 
Time to First Use of Targeted Rescue Medication for 
an Adjusted Attack (KM Estimates) 
Safety 
14.2.2 
Summary of Number and Proportion of Subjects 
Adjusted Attack Free 
Safety 
14.2.3 
Summary of Days with Angioedema Symptoms from 
Adjusted Attacks 
Safety 
14.2.4.1 
Summary of AE-QoL Scores 
Safety 
14.2.4.4 
Summary of Number of Days Missed from School or 
Work 
Safety 
14.2.5.1 
Summary of TSQM Global Satisfaction Scores 
Safety 
Safety Section 
Figures 
14.3.1.11.1 
Kaplan-Meier: Time to Discontinuation Due to an AE 
Safety 
14.3.1.11.2 
Kaplan-Meier: Time to Discontinuation Due to an AE 
by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.11.3 
Kaplan-Meier: Time to Discontinuation Due to an AE 
by Duration of Prior Androgen Use 
Safety 
14.3.1.26.1 
Kaplan-Meier: Time to Development of Investigator-
Identified Rash 
Safety 
14.3.1.26.2 
Kaplan-Meier: Time to Development of Investigator-
Identified Rash by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.26.3 
Kaplan-Meier: Time to Development of Investigator-
Identified Rash by Duration of Prior Androgen Use 
Safety 
14.3.1.28 
Kaplan-Meier: Duration of Investigator-Identified Rash 
Safety 
14.3.1.40.1 
Kaplan-Meier: Time to First Occurrence of a GI 
Abdominal-Related Event 
Safety 
14.3.1.40.2 
Kaplan-Meier: Time to First Occurrence of a GI 
Abdominal-Related Event by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.40.3 
Kaplan-Meier: Time to First Occurrence of a GI 
Abdominal-Related Event by Duration of Prior 
Androgen Use 
Safety 


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Title 
Population 
 
14.3.1.42.1 
Kaplan-Meier: Duration of GI Abdominal-Related 
Event 
Safety 
14.3.1.42.2 
Kaplan-Meier: Duration of GI Abdominal-Related 
Event by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.42.3 
Kaplan-Meier: Duration of GI Abdominal-Related 
Event by Duration of Prior Androgen Use 
Safety 
14.3.1.43.1 
Plot: Occurrence of Treatment-Emergent GI 
Abdominal-Related Events 
Safety 
14.3.1.43.2 
Plot: Occurrence of Treatment-Emergent GI 
Abdominal-Related Events by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.43.3 
Plot: Occurrence of Treatment-Emergent GI 
Abdominal-Related Events by Duration of Prior 
Androgen Use 
Safety 
14.3.4.15.1 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities 
Safety 
14.3.4.15.2 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.4.15.3 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities by Duration of Prior 
Androgen Use 
Safety 
14.3.5.19.1 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 ALT 
Safety 
14.3.5.19.2 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 ALT by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.5.19.3 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 ALT by Duration of Prior Androgen Use 
Safety 
14.3.5.21.1 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 AST 
Safety 
14.3.5.21.2 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 AST by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.5.21.3 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 AST by Duration of Prior Androgen Use 
Safety 
14.3.5.23.1 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 Total Bilirubin 
Safety 
14.3.5.23.2 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 Total Bilirubin by Time Since Discontinuation of 
Androgen Use 
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Title 
Population 
 
14.3.5.23.3 
Kaplan-Meier: Time to First Occurrence of Grade 3 or 
4 Total Bilirubin by Duration of Prior Androgen Use 
Safety 
14.3.5.24.1 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities 
Safety 
14.3.5.24.2 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.5.24.3 
Plot of Liver Function Test Profiles for Subjects with 
Grade 3 or 4 Liver Abnormalities by Duration of Prior 
Androgen Use 
Safety 
14.3.5.25 
Hy’s Law Plot of Maximum Total Bilirubin vs. 
Maximum ALT 
Safety 
14.3.5.26 
Liver Test Safety Panel Over Time, Baseline vs. On-
Study 
Safety 
14.3.5.27 
Distribution of Liver Tests Over Time: ALT, AST, 
ALP, and Bilirubin 
Safety 
14.3.5.28 
Distribution of Cholesterol and Triglycerides Over 
Time 
Safety 
14.3.6.2 
Distribution Plots for Diastolic and Systolic BP Over 
Time 
Safety 
14.3.7.2 
Distribution Plots for QTcF Over Time 
Safety 
Tables 
14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events 
Safety 
14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse 
Events by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.1.1.3 
Overall Summary of Treatment-Emergent Adverse 
Events by Duration of Prior Androgen Use 
Safety 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety 
14.3.1.2.2 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.2.3 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term by Duration of Prior 
Androgen Use 
Safety 
14.3.1.3.1 
Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
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Title 
Population 
 
14.3.1.3.2 
Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.3.3 
Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term by Duration 
of Prior Androgen Use 
Safety 
14.3.1.4.1 
Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety 
14.3.1.4.2 
Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.4.3 
Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term by Duration 
of Prior Androgen Use 
Safety 
14.3.1.5.1 
Drug-Related Treatment-Emergent Serious Adverse 
Events by System Organ Class and Preferred Term 
Safety 
14.3.1.5.2 
Drug-Related Treatment-Emergent Serious Adverse 
Events by System Organ Class and Preferred Term by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.5.3 
Drug-Related Treatment-Emergent Serious Adverse 
Events by System Organ Class and Preferred Term by 
Duration of Prior Androgen Use 
Safety 
14.3.1.6.1 
Treatment-Emergent Grade 3 or Grade 4 Adverse 
Events by System Organ Class and Preferred Term 
Safety 
14.3.1.6.2 
Treatment-Emergent Grade 3 or Grade 4 Adverse 
Events by System Organ Class and Preferred Term by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.6.3 
Treatment-Emergent Grade 3 or Grade 4 Adverse 
Events by System Organ Class and Preferred Term by 
Duration of Prior Androgen Use 
Safety 
14.3.1.7.1 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
Adverse Events by System Organ Class and Preferred 
Term 
Safety 
14.3.1.7.2 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
Adverse Events by System Organ Class and Preferred 
Term by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.7.3 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
Adverse Events by System Organ Class and Preferred 
Term by Duration of Prior Androgen Use 
Safety 
14.3.1.8.1 
Treatment-Emergent Adverse Events Leading to the 
Interruption of Study Drug by System Organ Class and 
Preferred Term 
Safety 


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Title 
Population 
 
14.3.1.8.2 
Treatment-Emergent Adverse Events Leading to the 
Interruption of Study Drug by System Organ Class and 
Preferred Term by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.8.3 
Treatment-Emergent Adverse Events Leading to the 
Interruption of Study Drug by System Organ Class and 
Preferred Term by Duration of Prior Androgen Use 
Safety 
14.3.1.9.1 
Treatment-Emergent Adverse Events Leading to the 
Discontinuation of Study Drug by System Organ Class 
and Preferred Term 
Safety 
14.3.1.9.2 
Treatment-Emergent Adverse Events Leading to the 
Discontinuation of Study Drug by System Organ Class 
and Preferred Term by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.9.3 
Treatment-Emergent Adverse Events Leading to the 
Discontinuation of Study Drug by System Organ Class 
and Preferred Term by Duration of Prior Androgen Use 
Safety 
14.3.1.10.1 
Time to Discontinuation Due to an AE (KM Estimates) 
Safety 
14.3.1.10.2 
Time to Discontinuation Due to an AE (KM Estimates) 
by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.10.3 
Time to Discontinuation Due to an AE (KM Estimates) 
by Duration of Prior Androgen Use 
Safety 
14.3.1.12.1 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Severity 
Safety 
14.3.1.12.2 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Severity by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.12.3 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Severity by Duration of 
Prior Androgen Use 
Safety 
14.3.1.13.1 
Frequent Adverse Events by Preferred Term 
Safety 
14.3.1.13.2 
Frequent Adverse Events by Preferred Term by Time 
Since Discontinuation of Androgen Use 
Safety 
14.3.1.13.3 
Frequent Adverse Events by Preferred Term by 
Duration of Prior Androgen Use 
Safety 
14.3.1.14.1 
Drug-Related Frequent Adverse Events by Preferred 
Term 
Safety 
14.3.1.14.2 
Drug-Related Frequent Adverse Events by Preferred 
Term by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.14.3 
Drug-Related Frequent Adverse Events by Preferred 
Term by Duration of Prior Androgen Use 
Safety 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
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BCX7353-204  
 
 
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Title 
Population 
 
14.3.1.15 
Overall Summary of Treatment-Emergent Investigator-
identified Rash 
Safety 
14.3.1.16 
Treatment-Emergent Investigator-identified Rash by 
System Organ Class and Preferred Term 
Safety 
14.3.1.17 
Drug-Related Treatment-Emergent Investigator-
identified Rash by System Organ Class and Preferred 
Term 
Safety 
14.3.1.18 
Treatment-Emergent Investigator-identified Rash 
Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety 
14.3.1.19 
Drug-Related Treatment-Emergent Investigator-
identified Rash Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety 
14.3.1.20 
Treatment-Emergent Grade 3 or Grade 4 Investigator-
identified Rash by System Organ Class and Preferred 
Term 
Safety 
14.3.1.21 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
Investigator-identified Rash by System Organ Class 
and Preferred Term 
Safety 
14.3.1.22 
Treatment-Emergent Investigator-identified Rash 
Leading to the Interruption of Study Drug by System 
Organ Class and Preferred Term 
Safety 
14.3.1.23 
Treatment-Emergent Investigator-identified Rash 
Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term 
Safety 
14.3.2.24 
Treatment-Emergent Investigator-identified Rash 
Requiring the Use of Concomitant Medications 
Safety 
14.3.1.25 
Time to Development of Investigator-identified Rash 
(KM Estimates) 
Safety 
14.3.1.27 
Duration of Investigator-identified Rash 
Safety 
14.3.1.29.1 
Overall Summary of Treatment-Emergent GI 
Abdominal-related Events 
Safety 
14.3.1.29.2 
Overall Summary of Treatment-Emergent GI 
Abdominal-related Events by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.29.3 
Overall Summary of Treatment-Emergent GI 
Abdominal-related Events by Duration of Prior 
Androgen Use 
Safety 
14.3.1.30.1 
Treatment-Emergent GI Abdominal-related Events by 
System Organ Class and Preferred Term 
Safety 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
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BCX7353-204  
 
 
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Title 
Population 
 
14.3.1.30.2 
Treatment-Emergent GI Abdominal-related Events by 
System Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.30.3 
Treatment-Emergent GI Abdominal-related Events by 
System Organ Class and Preferred Term by Duration 
of Prior Androgen Use 
Safety 
14.3.1.31.1 
Drug-Related Treatment-Emergent GI Abdominal-
related Events by System Organ Class and Preferred 
Term 
Safety 
14.3.1.31.2 
Drug-Related Treatment-Emergent GI Abdominal-
related Events by System Organ Class and Preferred 
Term by Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.31.3 
Drug-Related Treatment-Emergent GI Abdominal-
related Events by System Organ Class and Preferred 
Term by Duration of Prior Androgen Use 
Safety 
14.3.1.32.1 
Treatment-Emergent GI Abdominal-related Events 
Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety 
14.3.1.32.2 
Treatment-Emergent GI Abdominal-related Events 
Serious Adverse Events by System Organ Class and 
Preferred Term by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.32.3 
Treatment-Emergent GI Abdominal-related Events 
Serious Adverse Events by System Organ Class and 
Preferred Term by Duration of Prior Androgen Use 
Safety 
14.3.1.33.1 
Drug-Related Treatment-Emergent GI Abdominal-
related Events Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety 
14.3.1.33.2 
Drug-Related Treatment-Emergent GI Abdominal-
related Events Serious Adverse Events by System 
Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.33.3 
Drug-Related Treatment-Emergent GI Abdominal-
related Events Serious Adverse Events by System 
Organ Class and Preferred Term by Duration of Prior 
Androgen Use 
Safety 
14.3.1.34.1 
Treatment-Emergent Grade 3 or Grade 4 GI 
Abdominal-related Events by System Organ Class and 
Preferred Term 
Safety 
14.3.1.34.2 
Treatment-Emergent Grade 3 or Grade 4 GI 
Abdominal-related Events by System Organ Class and 
Preferred Term by Time Since Discontinuation of 
Androgen Use 
Safety 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
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Title 
Population 
 
14.3.1.34.3 
Treatment-Emergent Grade 3 or Grade 4 GI 
Abdominal-related Events by System Organ Class and 
Preferred Term by Duration of Prior Androgen Use 
Safety 
14.3.1.35.1 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
GI Abdominal-related Events by System Organ Class 
and Preferred Term 
Safety 
14.3.1.35.2 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
GI Abdominal-related Events by System Organ Class 
and Preferred Term by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.35.3 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 
GI Abdominal-related Events by System Organ Class 
and Preferred Term by Duration of Prior Androgen Use 
Safety 
14.3.1.36.1 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Interruption of Study Drug by System 
Organ Class and Preferred Term 
Safety 
14.3.1.36.2 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Interruption of Study Drug by System 
Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.36.3 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Interruption of Study Drug by System 
Organ Class and Preferred Term by Duration of Prior 
Androgen Use 
Safety 
14.3.1.37.1 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term 
Safety 
14.3.1.37.2 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.37.3 
Treatment-Emergent GI Abdominal-related Events 
Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term by Duration 
of Prior Androgen Use 
Safety 
14.3.2.38.1 
Treatment-Emergent GI Abdominal-related Events 
Requiring the Use of Concomitant Medications 
Safety 
14.3.2.38.2 
Treatment-Emergent GI Abdominal-related Events 
Requiring the Use of Concomitant Medications by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.2.38.3 
Treatment-Emergent GI Abdominal-related Events 
Requiring the Use of Concomitant Medications by 
Duration of Prior Androgen Use 
Safety 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
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BCX7353-204  
 
 
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Title 
Population 
 
14.3.1.39.1 
Time to Development of GI Abdominal-related Events 
(KM Estimates) 
Safety 
14.3.1.39.2 
Time to Development of GI Abdominal-related Events 
(KM Estimates) by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.39.3 
Time to Development of GI Abdominal-related Events 
(KM Estimates) by Duration of Prior Androgen Use 
Safety 
14.3.1.41.1 
Duration of GI Abdominal-related Adverse Events 
Safety 
14.3.1.41.2 
Duration of GI Abdominal-related Adverse Events by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.41.3 
Duration of GI Abdominal-related Adverse Events by 
Duration of Prior Androgen Use 
Safety 
14.3.1.44.1 
Summary of GI Abdominal-Related Adverse Events 
and Unconfirmed HAE Attacks with Abdominal-Only 
Symptoms 
Safety 
14.3.1.44.2 
Summary of GI Abdominal-Related Adverse Events 
and Unconfirmed HAE Attacks with Abdominal-Only 
Symptoms by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.1.44.3 
Summary of GI Abdominal-Related Adverse Events 
and Unconfirmed HAE Attacks with Abdominal-Only 
Symptoms by Duration of Prior Androgen Use 
Safety 
14.3.1.45.1 
Summary of Treatment-Emergent Adverse Event Rate 
Per 100 person-years of Exposure (PYE) 
Safety 
14.3.1.45.2 
Summary of Treatment-Emergent Adverse Event Rate 
Per100 person-years of Exposure (PYE) by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.1.45.3 
Summary of Treatment-Emergent Adverse Event Rate 
Per 100 person-years of Exposure (PYE) by Duration 
of Prior Androgen Use 
Safety 
14.3.1.46.1 
Summary of Drug-Related Treatment-Emergent 
Adverse Event Rate Per 100 person-years of Exposure 
(PYE) 
Safety 
14.3.1.46.2 
Summary of Drug-Related Treatment-Emergent 
Adverse Event Rate Per 100 person-years of Exposure 
(PYE) by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.1.46.3 
Summary of Drug-Related Treatment-Emergent 
Adverse Event Rate Per 100 person-years of Exposure 
(PYE) by Duration of Prior Androgen Use 
Safety 
14.3.1.47.1 
Summary of Treatment-Emergent Serious Adverse 
Event Rate Per 100 person-years of Exposure (PYE) 
Safety 


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BioCryst Pharmaceuticals, Inc. 
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BCX7353-204  
 
 
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Title 
Population 
 
14.3.1.47.2 
Summary of Treatment-Emergent Serious Adverse 
Event Rate Per 100 person-years of Exposure (PYE) by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.1.47.3 
Summary of Treatment-Emergent Serious Adverse 
Event Rate Per 100 person-years of Exposure (PYE) by 
Duration of Prior Androgen Use 
Safety 
14.3.1.48 
Summary of Treatment-Emergent Adverse Events for 
Subjects Entering on Prophylactic Medications for 
HAE 
Safety 
14.3.5.1.1 
Summary of Observed and Change from Baseline in 
Laboratory Data: Clinical Chemistry 
Safety 
14.3.5.1.2 
Summary of Observed and Change from Baseline in 
Laboratory Data: Clinical Chemistry by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.5.1.3 
Summary of Observed and Change from Baseline in 
Laboratory Data: Clinical Chemistry by Duration of 
Prior Androgen Use 
Safety 
14.3.5.2 
Summary of Observed and Change from Baseline in 
Laboratory Data: Hematology and Coagulation 
Safety 
14.3.5.3 
Summary of Observed and Change from Baseline in 
Laboratory Data: Continuous Urinalysis Parameters 
Safety 
14.3.5.4 
Summary of Observed Laboratory Data: Categorical 
Urinalysis Parameters 
Safety 
14.3.5.5 
Summary of Observed and Change from Baseline in 
Laboratory Data: Additional Tests 
Safety 
14.3.5.6 
Summary of Observed and Change from Baseline in 
Laboratory Data: Complement Factors 
Safety 
14.3.5.7.1 
Shift from Baseline to Worst Postbaseline Assessment: 
Clinical Chemistry 
Safety 
14.3.5.7.2 
Shift from Baseline to Worst Postbaseline Assessment: 
Clinical Chemistry by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.5.7.3 
Shift from Baseline to Worst Postbaseline Assessment: 
Clinical Chemistry by Duration of Prior Androgen Use 
Safety 
14.3.5.8 
Shift from Baseline to Worst Postbaseline Assessment: 
Hematology and Coagulation 
Safety 
14.3.5.9 
Shift from Baseline to Worst Postbaseline Assessment: 
Urinalysis 
Safety 
14.3.5.10.1 
Summary of Treatment-Emergent Graded Laboratory 
Abnormalities 
Safety 


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Version 1.0 
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Title 
Population 
 
14.3.5.10.2 
Summary of Treatment-Emergent Graded Laboratory 
Abnormalities by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.5.10.3 
Summary of Treatment-Emergent Graded Laboratory 
Abnormalities by Duration of Prior Androgen Use 
Safety 
14.3.5.11.1 
Summary of Treatment-Emergent Grade 3 and 4 
Laboratory Abnormalities 
Safety 
14.3.5.11.2 
Summary of Treatment-Emergent Grade 3 and 4 
Laboratory Abnormalities by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.5.11.3 
Summary of Treatment-Emergent Grade 3 and 4 
Laboratory Abnormalities by Duration of Prior 
Androgen Use 
Safety 
14.3.5.12.1 
Summary of Treatment-Emergent Laboratory Toxicity 
Grade Increase from Baseline 
Safety 
14.3.5.12.2 
Summary of Treatment-Emergent Laboratory Toxicity 
Grade Increase from Baseline by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.5.12.3 
Summary of Treatment-Emergent Laboratory Toxicity 
Grade Increase from Baseline by Duration of Prior 
Androgen Use 
Safety 
14.3.5.13.1 
Summary of Fold × ULN for Liver Function Tests 
Safety 
14.3.5.13.2 
Summary of Fold × ULN for Liver Function Tests by 
Time Since Discontinuation of Androgen Use 
Safety 
14.3.5.13.3 
Summary of Fold × ULN for Liver Function Tests by 
Duration of Prior Androgen Use 
Safety 
14.3.5.14.1 
Summary of Fold Change from Baseline for Liver 
Function Tests 
Safety 
14.3.5.14.2 
Summary of Fold Change from Baseline for Liver 
Function Tests by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.5.14.3 
Summary of Fold Change from Baseline for Liver 
Function Tests by Duration of Prior Androgen Use 
Safety 
14.3.5.15.1 
Summary of Elevations in Post-Baseline Liver 
Function Tests 
Safety 
14.3.5.15.2 
Summary of Elevations in Post-Baseline Liver 
Function Tests by Time Since Discontinuation of 
Androgen Use 
Safety 
14.3.5.15.3 
Summary of Elevations in Post-Baseline Liver 
Function Tests by Duration of Prior Androgen Use 
Safety 
14.3.5.18.1 
Time to First Occurrence of Grade 3 or 4 ALT (KM 
Estimates) 
Safety 


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Title 
Population 
 
14.3.5.18.2 
Time to First Occurrence of Grade 3 or 4 ALT (KM 
Estimates) by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.5.18.3 
Time to First Occurrence of Grade 3 or 4 ALT (KM 
Estimates) by Duration of Prior Androgen Use 
Safety 
14.3.5.20.1 
Time to First Occurrence of Grade 3 or 4 AST (KM 
Estimates) 
Safety 
14.3.5.20.2 
Time to First Occurrence of Grade 3 or 4 AST (KM 
Estimates) by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.5.20.3 
Time to First Occurrence of Grade 3 or 4 AST (KM 
Estimates) by Duration of Prior Androgen Use 
Safety 
14.3.5.22.1 
Time to First Occurrence of Grade 3 or 4 Total 
Bilirubin (KM Estimates) 
Safety 
14.3.5.22.2 
Time to First Occurrence of Grade 3 or 4 Total 
Bilirubin (KM Estimates) by Time Since 
Discontinuation of Androgen Use 
Safety 
14.3.5.22.3 
Time to First Occurrence of Grade 3 or 4 Total 
Bilirubin (KM Estimates) by Duration of Prior 
Androgen Use 
Safety 
14.3.5.25.1 
Summary of Rate of Elevations in Post-Baseline Liver 
Function Tests Per 100 person-years of Exposure 
(PYE) 
Safety 
14.3.5.25.2 
Summary of Rate of Elevations in Post-Baseline Liver 
Function Tests Per 100 person-years of Exposure 
(PYE) by Time Since Discontinuation of Androgen 
Use 
Safety 
14.3.5.25.3 
Summary of Rate of Elevations in Post-Baseline Liver 
Function Tests Per 100 person-years of Exposure 
(PYE) by Duration of Prior Androgen Use  
Safety 
14.3.6.1 
Summary of Observed and Change from Baseline in 
Vital Signs 
Safety 
14.3.7.1 
Summary of Observed and Change from Baseline in 
Electrocardiograms 
Safety 
14.3.7.3 
Summary of ECG Findings 
Safety 
14.3.7.4 
Summary of Observed and Change from Baseline 
QTcF Categorical Findings 
Safety 
PK/PD Section 
Figures 
14.6.2.2 
Scatterplot of %KKI by BCX7353 Plasma 
Concentration/4  
PK/PD 


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Title 
Population 
 
Tables 
14.5.1.1 
Summary of Plasma BCX7353 Concentration (ng/mL) 
Safety 
14.5.2.1 
Plasma BCX7353 Concentration (ng/mL) Trough 
Samples above Kallikrein Inhibition EC50 
Safety 
14.6.1.1 
Summary of Plasma Kallikrein Inhibition (%) 
PD 
14.6.2.1 
Plasma Kallikrein Inhibition Trough Samples above 
50% and 80% 
PD 
 
Listings 
Title 
Population 
16.2.1.1 
Informed Consent and Screen Failures 
All Subjects 
16.2.1.2 
Subject Allocation, Site, and Country 
Safety 
16.2.1.3 
Prior BioCryst Studies 
Safety 
16.2.1.4 
Listing of Planned and Actual Treatment Assignments for 
Subjects with Incorrect Treatment 
Safety 
16.2.1.5 
Subject Disposition 
Safety 
16.2.1.6 
Analysis Populations 
Safety 
16.2.2.1 
Inclusion/Exclusion Criteria Not Met 
Safety 
16.2.2.2 
Protocol Deviations 
Safety 
16.2.4.1.1 
Demography 
All Subjects 
16.2.4.1.2 
Demography – Contraception 
All Subjects 
16.2.4.1.3 
Confirmation of Clinical Diagnosis of HAE 
All Subjects 
16.2.4.2.1 
Medical History Not Recorded in Prior BioCryst Studies 
Safety 
16.2.4.2.2 
HAE Medical History 
Safety 
16.2.4.2.3 
HAE Medication History – Past and Current On-Demand HAE 
Treatment 
Safety 
16.2.4.2.4 
HAE Medication History – Past Prophylactic HAE Treatment 
Safety 
16.2.4.3.1 
Medications Taken within 30 Days of Screening and 
Discontinued Prior to Study Drug Initiation 
Safety 
16.2.4.3.2 
Concomitant Medication Use 
Safety 
16.2.4.3.3 
Use of Concomitant Medications for HAE 
Safety 
16.2.4.3.4 
Prior Androgen Use for HAE 
Safety 
16.2.4.3.5 
HAE Medication–Current Prophylactic HAE Treatment 
Safety 
16.2.5.1 
Drug Accountability 
Safety 


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BioCryst Pharmaceuticals, Inc. 
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Title 
Population 
16.2.5.2 
Dosing Diary 
Safety 
16.2.5.3 
100 Person-Years of Exposure (PYE) 
Safety 
16.2.6.1.1 
HAE Attack Diary 
Safety 
16.2.6.1.2 
HAE Attack Diary Detail 
Safety 
16.2.6.1.3 
HAE Attack Level Summary – Subject-Reported Attacks 
Safety 
16.2.6.1.4 
HAE Attack Level Summary – Adjusted Attacks 
Safety 
16.2.6.1.5 
Attack Rate 
Safety 
16.2.6.1.6 
Subjects who Are Adjusted Attack-Free During Entire Dosing 
Period 
Safety 
16.2.6.1.7 
Days with Angioedema Symptoms from Adjusted Attacks 
Safety 
16.2.6.1.8 
Efficacy Endpoint Profile 
Safety 
16.2.6.1.9 
Subject-Level Additional Derived Endpoint Profile 
Safety 
16.2.6.2.1 
AE-QoL: Individual Question Responses and Days Missed 
Safety 
16.2.6.2.2 
AE-QoL: Domain Scores  
Safety 
16.2.6.3.1 
TSQM Global Satisfaction Individual Question Scores 
Safety 
16.2.6.3.2 
TSQM Effect, Side Effect, Convenience and Global 
Satisfaction Scores 
Safety 
16.2.7.1 
Adverse Events 
Safety 
16.2.7.2 
Serious Adverse Events 
Safety 
16.2.7.3 
Grade 3 or 4 Adverse Events 
Safety 
16.2.7.4 
Adverse Events Leading to Discontinuation of Study Drug 
Safety 
16.2.7.5 
Adverse Events Leading to Interruption of Study Drug 
Safety 
16.2.7.6 
Fatal Serious Adverse Events 
Safety 
16.2.7.7 
Adverse Events of Special Interest: Investigator-Identified 
Rash 
Safety 
16.2.7.8 
Gastrointestinal Abdominal-Related Adverse Events 
Safety 
16.2.7.9 
Adverse Events for Subjects with Elevated LFTs 
Safety 
16.2.7.10 
Listing of GI Abdominal-Related Events and Abdominal-Only 
Symptoms from Subject-reported HAE Attacks 
Safety 
16.2.7.11 
Adverse Events for Subjects on Prophylactic HAE 
Medications 
Safety 
16.2.8.1 
Clinical Chemistry 
Safety 
16.2.8.2 
Hematology 
Safety 
16.2.8.3 
Coagulation 
Safety 
16.2.8.4 
Urinalysis 
Safety 
16.2.8.5 
Other Laboratory Tests 
Safety 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
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Title 
Population 
16.2.8.6 
Complement Factors C3, C4, and C1-INH 
Safety 
16.2.8.7 
SERPING-1 
Safety 
16.2.8.8 
Pregnancy Tests 
Safety 
16.2.8.9 
Graded Laboratory Abnormalities 
Safety 
16.2.8.10 
Grade 3 or 4 Laboratory Abnormalities 
Safety 
16.2.8.11 
All Liver Function Test Results for Subjects Experiencing a 
Treatment-Emergent Grade 3 or 4 Liver Function Test 
Safety 
16.2.8.11.1 
All Liver Function Test Results for Subjects Experiencing a 
Treatment-Emergent Grade 3 or 4 Liver Function Test, 
Subjects with Prior Androgen Use 
Safety 
16.2.8.12 
Prior Androgen Use and Worst Post-Baseline ALT Elevation 
Safety 
16.2.8.13 
Vital Signs 
Safety 
16.2.8.14 
12-Lead Electrocardiogram 
Safety 
16.2.8.15 
QTcF Values >450msec or QTcF Change from Baseline 
Values >30msec 
Safety 
16.2.8.16 
Physical Exam 
Safety 
16.2.8.17 
Pharmacokinetic Sample Collection 
Safety 
16.2.8.18 
Plasma Kallikrein Inhibition (%) 
PD 
 


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Version 1.0 
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BCX7353-204  
 
 
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13.2. 
Data Display Specifications 
Mock (shell) versions of data displays for tables and listings will be provided in separate 
documents. 
 


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BioCryst Pharmaceuticals, Inc. 
Version 1.0 
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13.3. 
List of Preferred Terms, High Level Terms, and High Level Group Terms for GI 
Abdominal-Related AEs 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10000059 
Abdominal discomfort 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000060 
Abdominal distension 
Flatulence, bloating and distension 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000077 
Abdominal mass 
Abdominal findings abnormal 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10049714 
Abdominal migraine 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000081 
Abdominal pain 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000084 
Abdominal pain lower 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000087 
Abdominal pain upper 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10052489 
Abdominal rebound 
tenderness 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000090 
Abdominal rigidity 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10060926 
Abdominal symptom 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000097 
Abdominal tenderness 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10000133 
Abnormal faeces 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10058938 
Acetonaemic vomiting 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
70 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10000647 
Acute abdomen 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10052813 
Aerophagia 
Flatulence, bloating and distension 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10077605 
Anal incontinence 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10006326 
Breath odour 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10051650 
Chilaiditi's syndrome 
Abdominal findings abnormal 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10062937 
Cyclic vomiting 
syndrome 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10013810 
Dumping syndrome 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10013946 
Dyspepsia 
Dyspeptic signs and symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10013950 
Dysphagia 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10053155 
Epigastric discomfort 
Dyspeptic signs and symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10015137 
Eructation 
Dyspeptic signs and symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10050248 
Faecal volume decreased 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10049939 
Faecal volume increased 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10064670 
Faecal vomiting 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
71 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10056988 
Faecalith 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10056325 
Faecaloma 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10016100 
Faeces discoloured 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10016101 
Faeces hard 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10016102 
Faeces pale 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10074859 
Faeces soft 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10074216 
Fixed bowel loop 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10016766 
Flatulence 
Flatulence, bloating and distension 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10017999 
Gastrointestinal pain 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10067715 
Gastrointestinal sounds 
abnormal 
Abdominal findings abnormal 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10075724 
Gastrointestinal wall 
thickening 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10075726 
Gastrointestinal wall 
thinning 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10021746 
Infantile colic 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10063338 
Infantile spitting up 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
72 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10075315 
Infantile vomiting 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10073530 
Intestinal calcification 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10065611 
Intestinal congestion 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10067576 
Malignant dysphagia 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10028140 
Mucous stools 
Faecal abnormalities NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10069369 
Myochosis 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10028813 
Nausea 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10053634 
Oesophageal discomfort 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10065567 
Oesophageal food 
impaction 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10030180 
Oesophageal pain 
Gastrointestinal and abdominal pains (excl 
oral and throat) 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10034647 
Peristalsis visible 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10057030 
Pneumatosis intestinalis 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10064711 
Portal venous gas 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10066220 
Post-tussive vomiting 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
73 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10067171 
Regurgitation 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10038776 
Retching 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10078474 
Scaphoid abdomen 
Abdominal findings abnormal 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10047700 
Vomiting 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10047708 
Vomiting projectile 
Nausea and vomiting symptoms 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10078438 
White nipple sign 
Gastrointestinal signs and symptoms NEC 
Gastrointestinal signs and 
symptoms 
Gastrointestinal disorders 
10063541 
Bowel movement 
irregularity 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10007645 
Cardiospasm 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10008399 
Change of bowel habit 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10057078 
Colonic pseudo-
obstruction 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10010774 
Constipation 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10012110 
Defaecation urgency 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10051153 
Diabetic gastroparesis 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10012735 
Diarrhoea 
Diarrhoea (excl infective) 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
74 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10012741 
Diarrhoea haemorrhagic 
Diarrhoea (excl infective) 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10012743 
Diarrhoea neonatal 
Diarrhoea (excl infective) 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10060865 
Duodenogastric reflux 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10051244 
Dyschezia 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10013924 
Dyskinesia oesophageal 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10017367 
Frequent bowel 
movements 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10017753 
Gastric atony 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10017779 
Gastric dilatation 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10052406 
Gastric hypermotility 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10062931 
Gastric hypertonia 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10052405 
Gastric hypomotility 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10052402 
Gastrointestinal 
hypermotility 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10052105 
Gastrointestinal 
hypomotility 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10061173 
Gastrointestinal motility 
disorder 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
75 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10017885 
Gastrooesophageal 
reflux disease 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10062879 
Gastrooesophageal 
sphincter insufficiency 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10021333 
Ileus paralytic 
Non-mechanical ileus 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10021335 
Ileus spastic 
Non-mechanical ileus 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10021518 
Impaired gastric 
emptying 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10059158 
Infrequent bowel 
movements 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10022642 
Intestinal dilatation 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10023003 
Irritable bowel syndrome 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10027110 
Megacolon 
Non-mechanical ileus 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10072286 
Narcotic bowel 
syndrome 
Non-mechanical ileus 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10058934 
Neonatal intestinal 
dilatation 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10076953 
Obstructive defaecation 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10030136 
Oesophageal achalasia 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10071554 
Oesophageal atony 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 


Statistical Analysis Plan 
BioCryst Pharmaceuticals, Inc. 
Version 1.0 
CONFIDENTIAL 
BCX7353-204  
 
 
76 
 
Code 
Preferred Term (PT) 
High Level Term (HLT) 
High Level Group Term 
(HLGT) 
SOC 
10067752 
Oesophageal 
hypomotility 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10072419 
Oesophageal motility 
disorder 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10030184 
Oesophageal spasm 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10060696 
Presbyoesophagus 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10075246 
Pseudoachalasia 
Gastrointestinal dyskinetic disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10073166 
Pyloric sphincter 
insufficiency 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10037628 
Pylorospasm 
Gastrointestinal spastic and hypermotility 
disorders 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders 
10066142 
Sandifer's syndrome 
Gastrointestinal atonic and hypomotility 
disorders NEC 
Gastrointestinal motility and 
defaecation conditions 
Gastrointestinal disorders