Clinical trial NCT02870972
Conditions: Hereditary Angioedema (HAE)
Sponsor: BioCryst Pharmaceuticals
Start date: 2016-08-01; Completion date: 2017-08-01
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This 3-part study will evaluate the safety and efficacy of an oral treatment, BCX7353, in preventing angioedema attacks in subjects with hereditary angioedema (HAE). In Part 1 of the study, eligible subjects will be randomized to receive oral BCX7353 or placebo for 4 weeks. Assuming successful completion of Part 1, additional subjects will be randomized in Part 2 to one of 2 lower doses of BCX7353 or placebo. Part 3 will enroll additional subjects into one of three doses of BCX7353 or placebo. The study will compare the number of acute attacks in each treatment group, as well as a number of other clinical and pharmacologic outcomes, and the safety and tolerability of each dose of BCX7353 compared to placebo.

Detailed description:

Arms: arm 1: BCX7353 capsules, 350 mg dose administered once per day for 28 days arm 2: BCX7353 capsules, 250 mg dose administered once per day for 28 days arm 3: BCX7353 capsules, 125 mg dose administered once per day for 28 days arm 4: Placebo capsules, administered once per day for 28 days arm 5: BCX7353 capsules, 62.5 mg dose administered once per day for 28 days
Interventions: intervention 1: BCX7353 intervention 2: Placebo
Intervention descriptions: intervention 1: Plasma kallikrein inhibitor intervention 2: None

Protocol documents:
Prot_000.pdf: 
Protocol BCX7353-203 
BioCryst Pharmaceuticals, Inc. 
Version 5.0 
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BIOCRYST 
PHARMACEUTICALS, INC. 
 
1. 
TITLE PAGE 
Protocol No. BCX7353-203 
 
A RANDOMIZED, DOUBLE-BLIND,  
PLACEBO-CONTROLLED, DOSE-RANGING, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY, 
SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF BCX7353 AS A PREVENTATIVE 
TREATMENT TO REDUCE THE FREQUENCY OF ATTACKS 
IN SUBJECTS WITH HEREDITARY ANGIOEDEMA 
 
EudraCT Number: 2016-001272-29  
 
Version 5.0 : 05 July 2017 
 
 
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 BCX7353-203 
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Protocol Number: 
BCX7353-203 
Study Title: 
A randomized, double-blind, placebo-controlled, dose-ranging, parallel-group 
study to evaluate the efficacy, safety, tolerability, pharmacokinetics and 
pharmacodynamics of BCX7353 as a preventative treatment to reduce the 
frequency of attacks in subjects with hereditary angioedema 
IND Number: 
N/A 
EudraCT No. 
2016-001272-29 
Investigational Product: 
BCX7353 
Indication Studied: 
Hereditary Angioedema 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703, USA 
Development Phase: 
2 
Sponsor Medical Officer: 
Sylvia Dobo, MD 
Executive Director, Product Safety and Clinical Development 
BioCryst Pharmaceuticals 
Office: (919) 226-5860 
Cell: (773)304-8942 
Email: sdobo@biocryst.com 
Principal Investigator: 
Dr. Emel Aygören-Pürsün 
University Hospital Frankfurt Goethe University (Universitätsklinikum 
Frankfurt 
Klinik für Kinder-und Jugendmedizin 
Angioödem-Ambulanz 
Theodor-Stern-Kai7 
D-60596 Frankfurt, Germany 
Tel: +49-69-63016334 
Email: Aygoeren-Puersuen@em.uni-frankfurt.de 
Sponsor Project Manager: Desiree Clemons 
Clinical Study Manager 
BioCryst Pharmaceuticals 
Office: + 1 919-226-5836 
Email:dclemons@biocryst.com 
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) and International Conference on Harmonization 
Guidelines. Essential study documents are currently archived in accordance 
with applicable regulations 
Final Protocol Date: 
Version 1.0: 25 March 2016 
Version 1.1: 27 April 2016 (UK-Specific) 
Version 1.1 (also effective for Switzerland): 15 July 2016 
Version 2.0: 23 September 2016 
Version 3.0: 30 December 2016 
Version 4.0:  21 March 2017 (Non-Substantial) 
Version 5.0:  05 July 2017 




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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No:  
BCX7353-203 
Protocol Title: A randomized, double-blind, placebo-controlled, dose-ranging, parallel-group 
study to evaluate the efficacy, safety, tolerability, pharmacokinetics and 
pharmacodynamics, of BCX7353 as a preventative treatment to reduce the 
frequency of attacks in subjects with hereditary angioedema 
 
Date: 
Version 5.0: 05 July 2017 
 
 
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 Conference on Harmonization Guidelines for Good 
Clinical Practices, and all applicable regulatory requirements. 
 
 
_____________________________________________________________________ 
Investigator’s Signature 
Date 
 
 
_________________________________ 
Name (Print) 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. 
Name of Investigational Product: 
BCX7353 
Name of Active Ingredient: 
(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-
fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride 
Title of Study:  
A randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study to evaluate the 
efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of BCX7353 as a preventative 
treatment to reduce the frequency of attacks in subjects with hereditary angioedema 
Study Number: BCX7353-203 
EudraCT Number: 2016-001272-29 
Study center(s): Multiple centers in Europe, Australia and Canada 
Principal Investigator: Dr. Emel Aygören-Pürsün 
Studied period (years):  
Estimated date first subject enrolled: June 2016 
Estimated date last subject completed: March   2018 
Phase of development:  
2 
Objectives:  
Primary: 
• To evaluate the efficacy of once-daily prophylactic BCX7353 at up to 5 dose levels as measured 
by the number of attacks of hereditary angioedema (HAE) observed in patients with HAE 
enrolled in each treatment group 
Secondary: 
• To evaluate the safety and tolerability of BCX7353 over 28 days in subjects with HAE 
• To describe the pharmacokinetic (PK) profile of daily BCX7353 in subjects with HAE 
• To characterize the anticipated pharmacodynamic (PD) effects of BCX7353 in subjects 
with HAE 
• To characterize the dose-response relationship of BCX7353 in subjects with HAE 
• To evaluate effects of BCX7353 on quality of life 
Primary Endpoint:  
•   Number of confirmed HAE attacks  


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Methodology:  
Randomization 
Up to 36 subjects with Type 1 or 2 HAE who meet all eligibility criteria are planned to be enrolled in 
Part 1 of the study and will be randomized in a 1:1 ratio (placebo : active) to receive one of the 
following treatments: 
• Part 1, Treatment Group 1: placebo once per day (QD) orally for 28 days  
• Part 1, Treatment Group 2: 350 mg BCX7353 QD orally for 28 days 
After 24 subjects have completed through Day 28, there will be an administrative interim analysis of 
the accrued efficacy data by the Sponsor. If it is desired to more fully characterize the treatment effect 
of study drug (BCX7353 or placebo) or to verify assumptions made for sizing this proof-of-concept 
study, additional subjects will be enrolled to complete Part 1 (up to 36). Enrollment into Part 1 will 
continue until either a decision is made to halt enrollment in favor of opening Part 2 or enrollment 
reaches 36 subjects in Part 1. 
In Part 2, approximately 14 subjects with Type 1 or Type 2 HAE who meet all eligibility criteria are 
planned to be randomized in a 1:3:3 (placebo:active:active) ratio into 1 of the following 3 treatment 
groups:  
 
Part 2, Treatment Group 1: placebo QD orally for 28 days 
•
 
Part 2, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 
Part 2, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days 
•
If tolerability issues prevent full enrollment of Part 1 as described, future subjects randomized to active 
study drug in Part 1 may receive 250 mg orally once daily for 28 days. In this case, any dose level 
changes warranted for Part 2 will be instituted via protocol amendment. 
Following completion of enrolment in Part 2, Part 3 of the study may be initiated: 
In Part 3, approximately 20 subjects with Type 1 or Type 2 HAE who meet all eligibility criteria are 
planned to be randomized in a 1:3:3:3 (placebo: active: active: active) ratio into 1 of the following 
4 treatment groups:  
 
Part 3, Treatment Group 1: placebo QD orally for 28 days 
•
 
Part 3, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 
Part 3, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days  
•
 
Part 3, Treatment Group 4: 62.5 mg BCX7353 QD orally for 28 days 
•
Following completion of enrollment in Part 3, Part 4 of the study may be initiated in order to more 
fully define the dose-response relationship. The decision to enroll Part 4, including the doses selected 
for Part 4, will be based on PK, safety, and efficacy results through Part 3 of the study.  
If Part 4 is initiated, should the 62.5 mg and 125 mg BCX7353 dose groups in Part 3 be less efficacious 
than higher doses of BCX7353, approximately 14 subjects in Part 4 will be randomized in a 1: 6 
(placebo:active) ratio into 1 of the following 2 treatment groups: 
• 
Part 4, Treatment Group 1:  placebo QD orally for 28 days 
• 
Part 4, Treatment Group 2:  175 mg BCX7353 QD orally for 28 days 


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Alternatively, if Part 4 is initiated, should efficacy at the 62.5 mg BCX7353 dose group not be ruled 
out after analysis of Part 3 data, approximately 20 subjects in Part 4 will be randomized into 1 of the 
following 3 treatment groups as follows: 
• 
Part 4, Treatment Group 1:  placebo QD orally for 28 days (n = 2) 
• 
Part 4, Treatment Group 2: 175 mg BCX7353 QD orally for 28 days (n = 12) 
• 
Part 4, Treatment Group 3: 62.5 mg BCX7353 QD orally for 28 days (n = 6) 
Study Conduct Overview 
Following an up to 21-day screening period, eligible subjects, who have had entry criteria confirmed by 
the Sponsor, will be dosed on Day 1. Subsequent clinic visits will be held on Days 7, 14, 21 and 29, At 
the Day 14 visit, subjects will also have serial blood samples drawn immediately prior to and after the 
dose, including a visit on Day 15 for collection of a 24-hour postdose PK sample. A follow-up visit 
will be performed on Day 44. 
Subjects will record the occurrence and details of all angioedema attacks at least once daily beginning 
from the date of screening until the follow-up visit. On Days 1 through 28, subjects will also record the 
time of day that the study drug (BCX7353 or placebo) was taken and the number of capsules of study 
drug taken at each dose. Subject-reported study drug administration and HAE attacks will be captured 
in a diary. 
During the study, each subject will continue to use their prescribed acute attack medication to treat any 
attacks, under the medical management plan advised by their physician. All participants must have 
access to effective, approved acute treatments for attacks of angioedema as part of their routine medical 
care.  
. 
Subjects will only participate in one part of the study.  
All subjects who successfully complete treatment in the study will be offered the opportunity to 
participate in a future long-term study of BCX7353 where locally approved, provided that development 
of BCX7353 continues. 
Number of subjects (planned):  
Approximately 58 to approximately 90 subjects are planned to be enrolled and randomized in this 
study.  
Main criteria for inclusion: 
1. Able to provide written, informed consent. 
2. Males and non-pregnant, non-lactating females age 18 to 70 years. 
3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2 as documented at any time in 
the medical records or at the screening visit by a low C1 INH functional level (Type 2) or a low 
C1 INH antigenic level (Type 1). 
4. All subjects must have a documented HAE attack rate of at least 2 HAE attacks per month for 3 
consecutive months (defined as 93 days) within the 6 months prior to the screening visit. 


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5. Access to and ability to use 1 or more acute medications approved by the relevant competent 
authority for the treatment of attacks of HAE (icatibant, plasma-derived C1INH, or 
recombinant C1INH). 
6. Female and male subjects must agree to the contraception requirements and must meet the 
inclusion criteria regarding contraception, and contraception of female partners and sperm 
donation (as applicable), as outlined in Section 8.2.1. 
7. Any concomitant medication not stated as prohibited must be anticipated to be continued 
through the entire study and be of a stable dose and regimen for the duration of the entire 
study. 
8. In the opinion of the Investigator, the subject is expected 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 from the screening visit through randomization, 
including diary recording of HAE attacks beginning at the screening visit. 
Criteria for exclusion:  
1. Any clinically significant medical or psychiatric condition or medical history that, in the 
opinion of the Investigator or Sponsor, would interfere with the subject’s ability to participate 
in the study or increases the risk to the subject of participating in the study.  
2. Dementia, altered mental status, or any psychiatric condition, or stay in an institution further to 
an official or court order that would prohibit the understanding or rendering of informed 
consent or participation in the study. 
3. Use of C1 INH, androgens, or tranexamic acid for prophylaxis of HAE attacks within the 
7 days prior to the screening visit or initiation during the study. Androgen use is not permitted 
at any time during the study. Use of a C1 INH therapy for treatment of attacks is not excluded 
at any time. 
4. Clinically significant abnormal ECG at the screening visit. This includes, but is not limited to, 
a QTcF > 470 msec, a PR > 220 msec, or ventricular and/or atrial premature contractions that 
are more frequent than occasional, and/or as couplets or higher in grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other 
cardiovascular abnormality. 
6. Known family history of sudden death from causes other than HAE.  
7. History of or current implanted defibrillator or pacemaker. 
8. Any abnormal laboratory or urinalysis parameter at screening that, in the opinion of the 
Investigator, is clinically significant and relevant for this study. A calculated creatinine 
clearance of ≤ 60 mL/min or AST or ALT value ≥ 2 times the upper limit of the normal 
reference range value obtained during screening is exclusionary.  
9. Suspected C1INH resistance in the opinion of the Investigator and Sponsor. 
10. History of alcohol or drug abuse within the previous year prior to the screening visit, or current 
evidence of substance dependence or abuse (self-reported alcoholic intake > 3 drinks/day). 


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11. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B 
virus (HBV) or hepatitis C virus (HCV). 
12. Pregnant, planning to become pregnant within 30 days of the study, or nursing. 
13. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a prescription). 
14. History of severe hypersensitivity to any medicinal product. 
Medications prohibited for use during the study are addressed in Section 9.7.1. 
Investigational product, dosage and mode of administration:  
BCX7353 hydroxypropyl methylcellulose (HPMC) opaque capsules for oral administration.  
Part 1 and Part 2: The following doses will be administered orally once daily as 3 capsules (each 
capsule filled with drug substance to correspond to one-third of the total dose): BCX7353 350 mg (Part 
1), BCX7353 250 mg (Part 2) and BCX7353 125 mg (Part 2).  
Part 3: The following doses will be administered orally once daily as 2 capsules (each capsule filled 
with drug substance to correspond to one-half of the total dose): BCX7353 250 mg, BCX7353 125 mg, 
BCX7353 62.5 mg 
Part 4: BCX7353 will be administered orally once daily as 2 capsules (each capsule filled with drug 
substance to correspond to one-half of the total dose) per dose:  BCX7353 175 mg. Depending on the 
results through Part 3, a daily BCX7353 dose of 62.5 mg may also be administered. 
Duration of treatment:  
Subjects will receive 28 days of dosing with either BCX7353 or placebo. 
Reference therapy, dosage and mode of administration:  
Matched placebo capsules for oral administration. Placebo will be HPMC capsules to match active 
treatment. 
Criteria for evaluation: 
Efficacy: Efficacy will be evaluated by the number and rate of angioedema attacks and related details 
(eg, timing, duration of symptoms, anatomical location, treatment used), the number of subjects who 
are attack free, the number of attack free days, attack severity, and discontinuations due to lack of 
efficacy. All attacks will be reviewed and either confirmed or rejected for inclusion in the primary 
analysis dataset by an expert adjudication panel. 
Safety: Safety will be evaluated by adverse events (AEs), laboratory analyses [clinical chemistry, 
hematology, coagulation, urinalysis, creatine kinase-MB (CK-MB), troponin I and T, neutrophil 
gelatinase-associated lipocalin (NGAL)], vital signs, electrocardiograms (ECGs), physical 
examinations and pulmonary diffusion (DLCO) assessments. Relationships between safety assessment 
findings and HLA typing results may be examined.   
Pharmacokinetics: Plasma samples for steady-state BCX7353 concentrations will enable calculation 
of standard noncompartmental pharmacokinetic parameters. 
Pharmacodynamics: Pharmacodynamics will be evaluated by ex-vivo plasma kallikrein inhibition, 
cleaved high molecular weight kininogen, and C1 INH functional level. Additional exploratory assays 
to elucidate PD properties of BCX7353 may also be conducted on plasma samples drawn for PD 
analyses. 
Quality of Life: Composite scores and domain scores of the disease-specific Angioedema Quality of 
Life questionnaire (AE-QoL) and Depression, Anxiety, Stress Scales (DASS) questionnaire. 


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Statistical methods: 
Efficacy Analyses: 
Subjects will be randomized initially 1:1 to the 350mg BCX7353 and placebo groups. An interim 
review will be performed by the Sponsor after the first 24 subjects complete the study.  The number of 
dose groups and treatment allocations may be adjusted based on the interim review of the first 24 
subjects completed. 
Efficacy endpoints will be summarized and listed for each treatment group; Treatment Group 1 
(placebo) will be pooled across all study parts for the final analyses. In Part 2 and Part 3, Treatment 
Groups 2 (125 mg BCX7353) and 3 (250 mg BCX7353) will each be pooled for the final analyses. 
Similarly, Treatment Groups 4 and 3 (62.5 mg BCX7353) in Parts 3 and 4, respectively, will be pooled 
for the final analysis if a 62.5 mg dose is administered in Part 4 of the study. The between-treatment 
comparisons (active vs placebo and between active dose groups) for continuous efficacy variables will 
be performed using an analysis of variance (ANOVA) or analysis of covariance (ANCOVA) model 
including the qualifying attack rate as a covariate in the model. The between treatment comparisons for 
the proportion of subjects who are attack free will be compared using a Fisher’s exact test. 
Safety Analyses: Treatment Group 1 from all study parts (placebo) will be pooled for the final safety 
analyses. In Part 2 and Part 3, Treatment Groups 2 (125mg BCX7353) and 3 (250 mg BCX7353) will 
each be pooled for the final analyses. Similarly, Treatment Groups 4 and 3 (62.5 mg BCX7353) in 
Parts 3 and 4, respectively, will be pooled for the final analysis if a 62.5 mg dose is administered in 
Part 4 of the study. 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term and system organ classification. The occurrence of treatment-emergent AEs will be summarized 
by treatment group using MedDRA preferred terms, system organ classifications, and severity. 
Separate summaries of treatment-emergent serious adverse events (SAEs) and AEs considered to be 
related to study drug will be generated. All AEs will be listed for individual subjects showing both 
verbatim and preferred terms.  
Descriptive summaries of vital signs, ECG parameters, and clinical laboratory results will be presented 
by study visit and treatment group. Laboratory abnormalities will be graded according to the Division 
of Microbiology and Infectious Diseases [DMID] Adult Toxicity Table [November 2007]. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by 
treatment group. Laboratory toxicity shifts from baseline to post baseline assessments will be 
summarized by study visit and treatment group. DLCO results will be summarized and presented as 
change from baseline in mL/min. 
Physical examination results will be presented in listings.   
Concomitant medications will be coded using the World Health Organization (WHO) dictionary. These 
data will be summarized by treatment group. 
Pharmacokinetic Analyses: 
Plasma pharmacokinetic parameters for each subject will be estimated over the sampling interval using 
non-compartmental analysis (WinNonlin, Pharsight Corp). Parameters will be summarized by 
treatment, dose and study day using descriptive statistics.  
Dose proportionality will be performed using a power model and an ANOVA model based on dose 
normalized PK parameters. Additional analyses may be conducted as appropriate. 
Pharmacodynamic Analyses: 
On–treatment plasma kallikrein inhibition will be expressed as percent inhibition compared to subject 
baseline activity. All PD data will be summarized by subject, treatment, day, and time (plasma 
kallikrein inhibition only). Descriptive statistics will be reported. Mean and individual PD vs. time 


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profiles will be plotted by treatment group. 
Exposure-response analyses of the relationships between efficacy endpoints or PD markers and 
BCX7353 plasma concentrations will be explored using model-based techniques as applicable.  
Quality of Life Analyses: 
The change from baseline in the domain scores of the AE-QoL and the DASS as well as the composite 
score of each instrument will be compared between the treatment and placebo groups. Individual items 
will be plotted to understand their contribution to the domain sub-scores.  


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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 ................................................................................3 
1.2. 
Clinical Study Protocol Agreement ..............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................19 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background .................................................................................................................23 
5.2. 
Nonclinical Findings for BCX7353 ............................................................................25 
5.2.1. 
Nonclinical Pharmacology ..........................................................................................25 
5.2.2. 
Safety Pharmacology ..................................................................................................25 
5.2.3. 
Nonclinical Pharmacokinetics ....................................................................................26 
5.2.4. 
Nonclinical Toxicology ..............................................................................................27 
5.3. 
Clinical Findings for BCX7353 ..................................................................................29 
5.3.1. 
Study BCX7353-101 ..................................................................................................29 
5.3.2. 
Study BCX7353-102 ..................................................................................................31 
5.3.3. 
Study BCX7353-203 ..................................................................................................32 
5.3.3.1. 
Interim Safety Results .................................................................................................32 
5.3.3.2. 
Interim Pharmacokinetic, Pharmacodynamic and 
Pharmacokinetic/Pharmacodynamic Results ..............................................................33 
5.3.3.3. 
Interim Efficacy Results .............................................................................................33 
5.4. 
Rationale for Study .....................................................................................................34 
5.4.1. 
Rationale for Study Drug Doses .................................................................................35 
5.4.1.1. 
Rationale for Target Concentrations Proposed as Efficacious ...................................35 
5.4.1.2. 
Rationale for Proposed Doses: Parts 1-3 ....................................................................37 
5.4.1.3. 
Rationale for Proposed Doses: Part 4 .........................................................................38 
5.4.2. 
Rationale for Study Design .........................................................................................39 
5.4.3. 
Study Population Rationale ........................................................................................40 
5.4.3.1. 
Rationale for Allowance and Restriction of Concomitant Medications for 
HAE ............................................................................................................................41 


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5.4.4. 
BCX7353 Risk/Benefit Analysis ................................................................................41 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions ............................................................41 
5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 ....................................................41 
5.4.5. 
Benefits of Trial Participation ....................................................................................46 
5.4.6. 
Overall Benefit-Risk Assessment ...............................................................................46 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................47 
6.1. 
Objectives ...................................................................................................................47 
7. 
INVESTIGATIONAL PLAN .....................................................................................48 
7.1. 
Overall Study Design and Plan: Description ..............................................................48 
7.2. 
Endpoints ....................................................................................................................52 
7.2.1. 
Primary Efficacy Endpoint .........................................................................................52 
7.2.2. 
Secondary Efficacy Endpoints ....................................................................................53 
7.2.3. 
Safety Endpoints .........................................................................................................53 
7.2.4. 
Other Secondary Endpoints ........................................................................................53 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................54 
8.1. 
Number of Subjects ....................................................................................................54 
8.2. 
Subject Selection ........................................................................................................54 
8.2.1. 
Inclusion Criteria ........................................................................................................54 
8.2.2. 
Exclusion Criteria .......................................................................................................56 
8.3. 
Subject Withdrawal Criteria .......................................................................................57 
8.3.1. 
Subject Discontinuation from Study ...........................................................................57 
8.3.2. 
Subject Discontinuation from Study Drug .................................................................57 
8.3.2.1. 
Discontinuation Due to QT Prolongation ...................................................................58 
8.3.2.2. 
Discontinuation Due to Rash ......................................................................................58 
9. 
TREATMENT OF SUBJECTS ..................................................................................59 
9.1. 
Description of Study Drug ..........................................................................................59 
9.2. 
Description of Study Drug Packaging, Labeling, and Storage. ..................................59 
9.3. 
Blinding and Randomization ......................................................................................60 
9.3.1. 
Blinding ......................................................................................................................60 
9.3.2. 
Randomization ............................................................................................................60 
9.4. 
Study Drug (Investigational Medicinal Product) Administration and 
Treatment Compliance ................................................................................................61 
9.5. 
Study Drug Dose Modification ...................................................................................62 


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9.5.1. 
Subject-Level Dose Modification ...............................................................................62 
9.5.2. 
Part-Level Dose Modification ....................................................................................62 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability ...............................62 
9.7. 
Concomitant Medications ...........................................................................................63 
9.7.1. 
Prohibited Medications ...............................................................................................63 
9.7.2. 
Other Restrictions .......................................................................................................64 
10. 
STUDY CONDUCT ...................................................................................................65 
10.1. 
Overview .....................................................................................................................65 
10.2. 
Schedule of Assessments ............................................................................................65 
10.3. 
Study Visits .................................................................................................................70 
10.3.1. 
Screening ....................................................................................................................70 
10.3.2. 
Baseline (Day 1) .........................................................................................................71 
10.3.3. 
Study Day 7 Visit ........................................................................................................72 
10.3.4. 
Study Day 14 Visit ......................................................................................................73 
10.3.5. 
Study Day 15 ..............................................................................................................74 
10.3.6. 
Study Day 21 Visit ......................................................................................................74 
10.3.7. 
Study Day 29 Visit ......................................................................................................74 
10.3.8. 
Follow-up/Early Termination Visits ...........................................................................75 
11. 
ASSESSMENTS .........................................................................................................76 
11.1. 
Investigator-Completed Assessments .........................................................................76 
11.1.1. 
Physical Examination .................................................................................................76 
11.1.2. 
HAE Medical and Medication History .......................................................................76 
11.1.3. 
Weight/Body Mass Index ...........................................................................................76 
11.1.4. 
12-lead Electrocardiograms ........................................................................................76 
11.1.5. 
Vital Signs ..................................................................................................................77 
11.1.6. 
Clinical Laboratory Assessments ...............................................................................77 
11.1.7. 
Screening for Human Immunodeficiency Virus, Hepatitis B, and Hepatitis 
Serology ......................................................................................................................79 
11.1.8. 
Pregnancy Testing ......................................................................................................79 
11.1.9. 
C1 INH Testing ...........................................................................................................79 
11.1.10. 
Other Laboratory Assessments ...................................................................................79 
11.1.11. 
Pulmonary Diffusion ..................................................................................................79 
11.1.12. 
Rash Assessment ........................................................................................................80 


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11.1.13. 
Pharmacokinetics ........................................................................................................81 
11.1.14. 
Pharmacodynamics .....................................................................................................81 
11.1.15. 
HLA Typing ................................................................................................................82 
11.1.16. 
Possible Exploratory Pharmacogenomics Testing ......................................................82 
11.2. 
Subject-Completed Assessments ................................................................................82 
11.2.1. 
Quality of Life Questionnaires ...................................................................................82 
11.2.2. 
HAE Attack and Dosing Diaries .................................................................................82 
12. 
ASSESSMENT OF SAFETY .....................................................................................84 
12.1. 
Adverse Events ...........................................................................................................84 
12.1.1. 
Definitions ..................................................................................................................84 
12.1.1.1. 
Adverse Event .............................................................................................................84 
12.1.1.2. 
Serious Adverse Event ................................................................................................85 
12.1.1.3. 
Adverse Events of Special Interest .............................................................................85 
12.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events .............................................................................85 
12.1.3. 
Definition of Severity .................................................................................................86 
12.1.4. 
Definition of Relationship to Study Drug (Investigational Medicinal 
Product) .......................................................................................................................87 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................87 
12.1.5.1. 
Reporting Events of Special Interest ..........................................................................88 
12.1.6. 
Pregnancy ...................................................................................................................88 
12.1.7. 
Serious Breaches .........................................................................................................89 
12.1.8. 
Treatment Interruptions ..............................................................................................89 
12.1.9. 
Emergency Procedures ...............................................................................................89 
12.2. 
Toxicity Management .................................................................................................89 
12.2.1. 
Rash ............................................................................................................................90 
12.2.2. 
Overdose .....................................................................................................................90 
12.3. 
Data Monitoring Committee .......................................................................................90 
13. 
STATISTICS ..............................................................................................................91 
13.1. 
Sample Size Considerations .......................................................................................91 
13.2. 
Statistical Methods ......................................................................................................92 
13.2.1. 
Interim Analyses .........................................................................................................92 


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13.2.2. 
Analysis Populations ..................................................................................................92 
13.2.2.1. 
Full Analysis Set .........................................................................................................92 
13.2.2.2. 
Safety Population ........................................................................................................92 
13.2.2.3. 
Pharmacokinetic Population .......................................................................................92 
13.2.2.4. 
Pharmacodynamic Populations ...................................................................................93 
13.2.3. 
Subject Demographic and Disposition Data ...............................................................93 
13.2.4. 
Analysis of Efficacy Variables ...................................................................................93 
13.2.5. 
Analysis of Safety Variables ......................................................................................94 
13.2.6. 
Pharmacokinetic Analysis ..........................................................................................94 
13.2.7. 
Pharmacodynamic Analysis ........................................................................................95 
13.2.8. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................95 
13.2.9. 
Quality of Life Analyses .............................................................................................96 
14. 
STUDY ADMINISTRATION ...................................................................................97 
14.1. 
Regulatory and Ethical Considerations ......................................................................97 
14.1.1. 
Regulatory Authority Approvals ................................................................................97 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals ...................................97 
14.1.3. 
Subject Informed Consent ..........................................................................................97 
14.1.4. 
Payment to Subjects ....................................................................................................98 
14.1.5. 
Investigator Reporting Requirements .........................................................................98 
14.2. 
Study Monitoring ........................................................................................................98 
14.3. 
Quality Assurance .......................................................................................................98 
14.4. 
Study Termination and Site Closure ...........................................................................99 
14.5. 
Records Retention .......................................................................................................99 
14.6. 
Confidentiality of Information ....................................................................................99 
14.7. 
Study Publication ......................................................................................................100 
15. 
REFERENCES .........................................................................................................101 
16. 
APPENDICES ..........................................................................................................104 
16.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) .......................104 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and specialist terms .............................................................................19 
Table 2. 
Preliminary BCX7353 Trough Concentrations Obtained in Study BCX7353-
203 Through Part 2 and Relationship to Pre-defined Target Concentrations 
Proposed as Efficacious ..............................................................................................37 
Table 3: 
Schedule of Assessments for Study BCX7353-203 ...................................................66 
Table 4: 
Clinical Laboratory Evaluations .................................................................................78 
Table 5: 
Power assessment based on sample size and on-study attack rate .............................91 
Table 6: 
Power assessment based on sample size and attack free proportion ..........................91 
Table 7: 
Pharmacokinetic Parameters .......................................................................................95 
 


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LIST OF FIGURES 
Figure 1: 
Estimated exposure-response relationship for C1INH (CSL830 and Cinryze) ..........36 
Figure 2: 
Proportion of Simulated Clinical Trial Subjects Anticipated to Meet or 
Exceed Target Trough Concentrations .......................................................................38 
Figure 3: 
Study BCX7353-203 Study Design ............................................................................50 
Figure 4: 
Study Schema—Parts 1, 2, 3 and 4 .............................................................................52 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: 
Abbreviations and specialist terms 
Abbreviation  
Explanation 
AAS 
angioedema activity score 
ABW 
actual body weight 
ADR 
adverse drug reaction 
AE 
adverse event 
AE-QOL 
Angioedema Quality of Life questionnaire 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AR 
adverse reaction 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0−t 
area under the concentration versus time curve from time zero to time “t” 
AUC0-inf 
area under the concentration versus time curve extrapolated to infinite time 
AUCtau 
area under the plasma concentration versus time curve over the dosing interval (tau) 
% AUCexp 
percentage of AUC extrapolated between AUC0-last and AUC0-inf 
BCRP 
Breast cancer resistance protein 
BID 
twice daily 
BK 
bradykinin 
BMI 
body mass index 
BMP 
di-docosahexaenoyl (22:6)- Bis(mono)acylglycerol phosphate 
BQL 
below the quantification limit 
C1 INH 
C1 esterase inhibitor 
CI 
confidence interval 
Clast 
last measurable concentration of drug 
CK-MB 
creatine kinase-MB 
CLcr 
creatinine clearance 
CL/F 
apparent oral clearance after administration of the drug 
Cmax 
maximum plasma concentration of the drug 
CNS 
central nervous system 
CPK 
creatine phosphokinase 


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Abbreviation  
Explanation 
CRA 
Clinical research associate 
CRO 
clinical research organization 
Cav,ss 
average steady-state plasma drug concentration during multiple-dose administration 
Ctau 
observed drug concentration at the end of the dosing interval (tau) 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DASS 
Depression, Anxiety, Stress Scales 
DDI 
drug-drug interaction 
DLCO 
pulmonary diffusion testing 
DMC 
Data monitoring committee 
DMID 
Division of Microbiology and Infectious Diseases 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulation hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GPCR 
G-protein-coupled receptor 
HAE 
hereditary angioedema 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HK 
high-molecular weight kininogen 
HLA 
Human leukocyte antigen 
HPMC 
hydroxypropyl methylcellulose 
IB 
Investigator’s brochure 
IC50 
50% inhibitory concentration 


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Abbreviation  
Explanation 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine system 
Ki 
inhibition constant value 
KRBC/P 
partitioning constant between erythrocytes and plasma 
λz 
terminal elimination rate constant 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
NGAL 
neutrophil gelatinase–associated lipocalin 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
PBMC 
peripheral blood mononuclear cells 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
pharmacokinetic 
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 
prothrombin time 
QD 
once daily 
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 
QTcF 
QT interval corrected by Fridericia's formula 
RR 
interval between successive heart beats using the R-wave peaks 


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Abbreviation  
Explanation 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error 
SOC 
system order class 
SUSAR 
suspected unexpected severe adverse reaction 
T1/2 
estimate of the terminal elimination half-life of the drug 
TEAE 
treatment emergent adverse event 
Tmax 
time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution of the drug 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background 
Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent 
episodes of swelling of the skin, pharynx, larynx, gastrointestinal 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 (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 bradykinin 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). 
The primary inhibitor of kallikrein in plasma is the SERPING1 gene product, C1 esterase 
inhibitor (C1 INH) (Cicardi and Johnston 2012). C1 INH is a serine protease inhibitor (serpin) 
that normally prevents uncontrolled contact activation and BK production by covalently binding 
to and inactivating kallikrein (Patston, Gettins et al. 1991). Patients with HAE have mutations in 
the regulatory or coding regions of the C1 INH gene that result in either a failure to produce 
C1 INH or the production of nonfunctional C1 INH (Pappalardo, Cicardi et al. 2000). The 
amount of functional C1 INH produced by the unaffected allele is insufficient to control serine 
protease activity, including that of kallikrein, that is induced by even asymptomatic levels of 
vascular endothelial contact activation (Cicardi and Johnston 2012). As a result, even when a 
patient does not experience any symptoms, plasma HK levels may be lower than normal and BK 
is detectable (Cugno, Hack et al. 1993, Nussberger, Cugno et al. 1998, Kaplan, Joseph et al. 
2002, Nussberger, Cugno et al. 2002, Suffritti, Zanichelli et al. 2014). During symptomatic 
attacks, which may be triggered by trauma, infection, changes in hormone levels (e.g., with oral 
contraceptive use or with the menstrual cycle), or emotional stress, kallikrein activation, HK 
cleavage and BK production increase, and circulating BK levels are dramatically elevated 
(Cugno, Nussberger et al. 2003, Bork, Meng et al. 2006, Cicardi and Johnston 2012, Martello, 
Woytowish et al. 2012).  


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The effective management of HAE involves the prevention and/or treatment of symptomatic 
attacks (Cicardi, Bork et al. 2012). Kallikrein is a proven target in the treatment of HAE. As 
noted above, C1 INH is a covalent kallikrein inhibitor, and plasma-derived purified C1 INH 
(Cinryze®, Berinert®) and a human recombinant C1 INH (Ruconest®) are licensed for the 
treatment of HAE attacks in the European Union (EU). In the United States (US), Berinert® and 
Ruconest® are licensed for this indication. Ecallantide is an engineered recombinant protein 
noncovalent binding kallikrein inhibitor with homology to tissue factor pathway inhibitor and is 
licensed in the US for treatment of acute attacks of HAE by subcutaneous injection (Martello, 
Woytowish et al. 2012, Riedl 2012). Administration of ecallantide is associated with an 
approximately 4% rate of anaphylaxis.  
Icatibant (Firazyr®) is also an attack medication option for most patients in the US and EU. 
Icatibant is a subcutaneously-administered synthetic peptide that works distinctly from the other 
HAE treatments in that it functions as a bradykinin B2 receptor antagonist.  
In the EU and the US, licensed therapy for prevention of HAE attacks is limited to a purified 
plasma-derived C1 INH (Cinryze®) administered intravenously every 3 to 4 days (STN125267). 
Oral attenuated androgens such as danazol are also licensed for prevention of HAE attacks in 
some countries. While administration of androgens is convenient, unacceptable adverse effects 
(including androgenic hormonal effects [masculinization], intracranial hypertension and risk of 
hepatocellular adenoma/carcinoma) and contraindications (including pregnancy) limit their 
clinical use (Maurer and Magerl 2011, Cicardi, Bork et al. 2012).  
A Phase 2, double-blind, placebo-controlled study (Study BCX4161-203 [OPuS-1]) in subjects 
with HAE confirmed that inhibition of plasma kallikrein by an oral prophylactic treatment can 
significantly reduce attack rates. In that study, subjects with high attack rates (>1 week) were 
treated with avoralstat (BCX4161), a potent, small-molecule inhibitor of human plasma 
kallikrein discovered at BioCryst Pharmaceuticals, Inc (BioCryst). Overall, avoralstat was shown 
to be efficacious, reducing attacks in most subjects (88%), irrespective of the attack definition 
(subject-reported, adjudicated and treated) and was generally safe and well-tolerated.  
In a subsequent Phase 3, 12-week, parallel-group study of avoralstat (OPuS-2) as prophylaxis 
against HAE attacks, avoralstat did not reduce the rate of attacks relative to placebo treatment. 
The failure of this study to demonstrate a treatment difference is likely related to: the limiting 
physicochemical and pharmacokinetic properties of avoralstat (low solubility and half-life); 
difficulty in adhering to an administration schedule requiring dosing on an empty stomach three 
times per day; and inhibition of plasma kallikrein that was neither maximal nor sustained across 
a dosing interval. Further investigations of either novel oral kallikrein inhibitors that do not 
suffer from those limitations, or novel avoralstat formulations that overcome the limitations of 
the formulation studied to date, are warranted.  
BCX7353 is a potent, synthetic, second-generation small molecule inhibitor of plasma kallikrein 
discovered at BioCryst whose pharmacokinetic (PK) profile is superior to avoralstat’s. Chronic 
inhibition of kallikrein with an orally bioavailable small molecule such as BCX7353 is expected 
to have significant benefits for patients with HAE by reducing the frequency of attacks or even 
completely eliminating the occurrence of attacks and improving quality of life. 


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5.2. 
Nonclinical Findings for BCX7353 
The results of nonclinical pharmacology, pharmacokinetics, and toxicology studies of BCX7353 
are described briefly below; additional details can be found in the Investigator’s Brochure (IB). 
The Guidance to Investigators section of the IB provides clinical context for the findings and 
relevance to dosing subjects in clinical protocols of BCX7353.  
Nonclinical studies have demonstrated potent and specific inhibition of plasma kallikrein, high 
bioavailability after oral dosing with the potential for once-daily dosing, and a tolerability and 
safety profile that supports continued clinical development with appropriate safety monitoring. 
5.2.1. 
Nonclinical Pharmacology 
BCX7353 is a potent and highly specific inhibitor of human plasma kallikrein activity. 
BCX7353 shows subnanomolar potency in isolated enzyme assays against the intended target, 
human plasma kallikrein, with an inhibition constant (Ki) of 0.44 nM; the 50% inhibitory 
concentration (IC50) of BCX7353 against plasma kallikrein is 0.88 nM.  
BCX7353 also inhibits kallikrein activity in activated human plasma from normal subjects, with 
a mean half-maximal effective concentration (EC50) value of 5.83 nM, and in activated plasma 
from 14 subjects diagnosed with HAE, with mean (± standard error [SE]) EC50 value of 
15.9 ± 0.57 nM. Similarly, BCX7353 is a potent inhibitor of HK/PKK-dependent BK production 
on human umbilical vein endothelial cells, with a mean (± SE) EC50 of 5.56 ± 1.2 nM.  
The IC50 of BCX7353 against a range of other serine proteases varies from approximately 
4,500-fold to more than 56,000-fold greater than for plasma kallikrein.  
5.2.2. 
Safety Pharmacology 
A battery of in vitro and in vivo (rat and cynomolgus monkey) safety pharmacology studies were 
conducted to evaluate BCX7353, and included studies as outlined in the International 
Conference of Harmonization (ICH) guidance S7A. 
BCX7353 has very low affinity for G-protein coupled receptors (GPCRs), with Ki of > 3 µM for 
100 of 103 target GPCRs; for the cannabinoid CB1, melanocortin MC5, and somatostatin SST1 
receptors, affinity of BCX7353 was 1.56, 1.92, and 2.09 µM, respectively. These Ki values are at 
least 3,545 higher than for plasma kallikrein, therefore there is low concern for interactions with 
these GPCRs. 
In vitro, BCX7353 inhibits the human ether-à-go-go-related gene (hERG) channel, with an IC50 
value of 0.29 µM. However, there was no demonstrable increase in action potential duration in 
rabbit cardiac Purkinje fibers at 100 µM, more than 500 times the hERG IC50. Additional studies 
of calcium and sodium channels showed mixed effects. In conscious monkeys, a single dose of 
15 mg/kg or repeated doses of 30 mg/kg daily for 28 days had no adverse effects on the 
cardiovascular system. Doses > 30 mg/kg increased the duration of electrocardiogram (ECG) 
intervals including the QTc interval, but these effects were not considered adverse as the 
maximum increase was 10% versus the pretest group mean.  
Central nervous system (CNS) and respiratory safety pharmacology studies in the rat indicate 
that BCX7353 has a low potential to affect either the respiratory system or the CNS. The no-
observed-effect-level (NOEL) in both studies was 450 mg/kg. 


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5.2.3. 
Nonclinical Pharmacokinetics 
Following a single oral dose of [14C]BCX7353 in rats, approximately 90% of the administered 
radioactive dose was recovered within the 168 hour time course of the study. A large component 
of the dose was recovered in the urine (41.1%). Recovery in feces was 44.7%. The excretion of 
radioactivity via the bile accounted for approximately half of the excretion in feces. Metabolic 
evaluations showed that, in the rat, BCX7353 is subject to metabolic oxidative deamination, 
oxidation, and/or conjugation of cyclopropanecarboxylic acid. The estimated oral bioavailability 
of BCX7353 was 62%.  
After [14C]BCX7353 oral administration to monkeys, 24.1% of the radioactivity was recovered 
in the urine. The majority of the dose was recovered in feces, 59.6%. The metabolic profile in 
monkeys was similar to rats with a number of metabolic products in plasma, urine, and feces, 
suggesting that BCX7353 is subject to metabolic oxidative deamination and oxidation processes, 
and/or conjugation of cyclopropanecarboxylic acid. The estimated oral bioavailability was 52%.  
The IC50 of BCX7353 for inhibition of P450 cytochromes is < 1 µM for cytochrome P450 (CYP) 
2C9 and CYP2C19, and is < 3 µM for CYP2D6 and CYP3A. The time-dependent inhibition 
screen with BCX7353 suggests it may irreversibly inhibit CYP3A, but not CYP2C9 or 
CYP2C19. Irreversible inhibition typically requires resynthesis of the CYP enzyme to return full 
functionality. CYP3A metabolizes over 50% of known marketed drugs. 
Based upon (1) the measured systemic levels achieved in Study BCX7353-101, (2) the likely 
gastrointestinal (intraluminal) levels after oral dosing, (3) the in vitro inhibition potential 
outlined above, and (4) the recommendations provided in the Food and Drug Administration 
(FDA) drug interaction guidance (FDA 2012), there is a potential for a drug-drug interaction 
(DDI) with drugs that are affected by CYP3A, CYP2C9, CYP2C19 and CYP2D6. Therefore, an 
initial clinical DDI study is planned to quantify the DDI potential of BCX7353 at clinically 
relevant doses.  
In human liver S9 fractions with and without cofactors the percent substrate loss was 12%, and 
in vitro half-life (min) was > 60 min. Substrate loss of approximately 10% was observed in 
incubations of BCX7353 with recombinant CYP enzymes in the absence of cofactors (ie, 
nonspecific loss due to routes other than CYP metabolism). Incubation with recombinant human 
CYP3A4 showed 22.4% loss of BCX7353. Other recombinant human CYP enzymes (CYP1A2, 
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) resulted in a loss of 
15% or less. Thus the net loss of BCX7353 due to CYP metabolism was low over a 120 minute 
period, approximately 5 to 12%.  
BCX7353 inhibited p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MATE1, 
and MATE2-K with calculated IC50 values of 0.550 µM, 13.8 µM, 3.98 µM, and 5.19 µM, 
respectively. There was less than 50% inhibition of the OATP1B1, OATP1B3, OAT1, OAT3, 
and OCT2 in the presence of BCX7353. Of the transporters that BCX7353 inhibits, P-gp and 
BCRP are widely distributed throughout the body, and contribute to efflux of substrates in the 
intestine which can limit absorption, enhance biliary and urinary excretion of substrates, and 
limit brain penetration. Since, in vitro, BCX7353 is a substrate as well as an inhibitor of the 
transport proteins P-gp and BCRP, albeit at high micromolar inhibitory concentrations for the 
latter, medications that rely upon the BCRP or p-gp transport proteins or medications known to 
clinically induce or inhibit transport proteins will be excluded from clinical trials, based on 


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decision tree calculations outlined in the draft FDA Drug Interaction Guidance (2012). The 
MATE1 and MATE2-K transporters are largely expressed in the kidney proximal tubules, and 
enhance urinary excretion of substrates. Unbound systemic concentrations of BCX7353 are well 
below the concentrations required for MATE1 and MATE2-K inhibition, which suggests limited 
potential for an interaction with the transporters. Additionally, as data on the MATE transporters 
emerges, there has been limited guidance with regards to evaluation of whether in vitro 
inhibition data is indicative of a potential clinical interaction. 
In efflux experiments, BCX7353 was found to be a substrate of P-gp and BCRP. BCX7353 was 
not appreciably transported by OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and 
MATE2-K. 
5.2.4. 
Nonclinical Toxicology 
BCX7353 was not mutagenic in bacteria AMES assay and did not induce chromosomal 
aberrations in human peripheral blood lymphocytes cells. There was also no evidence of 
clastogenic activity in vivo as assessed in the micronucleus assay. Thus, BCX7353 has a low 
concern for genotoxicity.  
The phototoxicity potential of BCX7353 was assessed in BALB/c 3T3 mouse fibroblasts and it 
was found that BCX7353 has no phototoxic potential. 
In rats and cynomolgus monkeys, the effects of repeated oral doses for durations of 28 days and 
13 weeks have been investigated, in accordance with the Organisation for Economic Co-
operation and Development Test Guidelines and Principles of Good Laboratory Practice (GLP).  
Rats were dosed once-a-day for 28-days at dose levels of 5, 10, 25, and 75 mg/kg/day. With the 
exception of the highest dose, administration of BCX7353 was well-tolerated. Administration of 
75 mg/kg caused mortality, weight loss, reduced weight gain and decreased food consumption. 
Before their deaths, most of these animals were reported to have audible, shallow or difficult 
breathing. Evidence of inflammation, and changes secondary to hepatocellular and myocyte 
damage were observed mostly at 75 mg/kg/day in both sexes. These microscopic effects in liver 
and muscle correlated with increased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST). At ≥ 25 mg/kg/day there was minimal to mild bile duct 
degeneration/necrosis in males and females without changes in liver transaminases. Minimal to 
mild tubular regeneration and minimal to mild tubular vacuolation were present in the kidneys of 
males and females at 75 mg/kg/day. Vacuolation was characterized by microvesiculation of the 
cytoplasm of tubular epithelial cells of the cortex. In addition, tubular regeneration and 
vacuolation were present in the kidneys and myofiber degeneration/necrosis were present in 
multiple tissues including the heart, skeletal muscle, tongue, larynx, esophagus, and the 
glandular stomach of males and females at 75 mg/kg/day. Minimal to mild vacuolation was 
present in multiple tissues including the choroid plexus of the brain, the pituitary gland, 
pancreas, parotid salivary gland, and the adrenal cortex at ≥25 mg/kg/day. At 75 mg/kg/day, 
minimal to severe generalized lymphoid depletion was present in the thymus and spleen. All of 
these effects showed evidence of partial or full reversibility during a 2-week recovery period. 
Due to the adversity of effects at 25 mg/kg/day in the bile duct, the no observed adverse effect 
level (NOAEL) after dosing BCX7353 for 28 days in rats was considered to be 10 mg/kg/day. At 


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this dose level, the combined male and female mean Cmax and AUC0-24 values on Day 28 were 
186 ng/mL and 2,230 ng•hr/mL, respectively. 
In the 13-week study, once daily oral gavage administration of BCX7353 to Wistar Han rats was 
well tolerated for 91 days at dose levels of 0, 2.5, 7.5, and 20 mg/kg/day. No BCX7353-related 
morbidity, clinical observations, body weight changes, food consumption differences, 
ophthalmic findings, or clinical pathology findings were observed at any dose level. At 7.5 and 
20 mg/kg/day, BCX7353 induced a dose-related increase in the putative phospholipidosis 
biomarker BMP in the urine of male and female rats. Liver weights were increased and bile duct 
hypertrophy was noted in the liver of males and females at 20 mg/kg/day. Bile duct hyperplasia 
was present in females at 20 mg/kg/day, and vacuolated hepatic macrophages were present in 
males and females at 20 mg/kg/day. By electron microscopy, myelinosomes were observed 
within the cytoplasm of Kupffer cells. These liver findings were not considered adverse due to 
the minimal to mild degree of change, the lack of clinical pathology findings, and since no 
findings were present after recovery.  
Therefore, the NOAEL after dosing BCX7353 by oral gavage for 91 days in rats is considered to 
be 20 mg/kg/day. At this NOAEL, the combined male and female mean Cmax and AUC0-24hr 
values on Day 90 were 567 ng/mL and 11,200 ng•hr/mL respectively. 
Oral dosing of 10, 30 and 100 mg/kg/day to cynomolgus monkeys for 28-days was well tolerated 
with the exception of emesis at 100 mg/kg/day. At the highest dose there were also mild 
increases of platelets, mild decreases in albumin and mild increases in globulin, mild increases in 
phosphorus in females and a mild glucosuria in males. Mild to moderate increases of ALT at 30 
and 100 mg/kg/day were noted, and AST was increased at 100 mg/kg/day. Increases in liver 
transaminases correlated to microscopic changes in the liver. Elevated AST could also be related 
to skeletal muscle degeneration observed microscopically.  
There were microscopic changes in several organs and tissues. In the liver of males there were 
large hepatocytes with foamy to large cytoplasmic vacuoles and hyperplasia of oval cells at 
100 mg/kg/day. There were an increased number of necrotic hepatocytes at 30 and 
100 mg/kg/day. In females there was increased vacuolation consistent with increased glycogen at 
all dose levels. The kidney of male monkeys was a target organ at 30 and 100 mg/kg, as there 
was degeneration/regeneration of tubules, characterized by vacuolated cytoplasm and 
regenerated tubular epithelial cells. In the kidney of females there were basophilic tubules, casts 
and inflammation. There were increased numbers of cellular infiltrates at 30 and 100 mg/kg/day 
in both sexes which correlated with an increased kidney weight at 100 mg/kg/day. In the small 
intestines, villi were expanded by foamy, pigmented macrophages. Minimal infiltrates were 
observed in the duodenum of males and females at 100 mg/kg/day. Minimal to mild infiltrates in 
the jejunum were observed in males at 30 and 100 mg/kg/day and females at 100 mg/kg/day. 
Minimal to mild infiltrates in the ileum were observed in males and females at 30 and 
100 mg/kg/day. Skeletal muscle (rectus femoris, tongue and larynx) showed evidence of 
degeneration and/or regeneration of the myofibers in males and females at 100 mg/kg/day and in 
males at 10 mg/kg/day. These effects at 30 and 100 mg/kg/day were considered adverse. These 
microscopic changes in the different tissues and organs all showed partial reversibility following 
a 3-week recovery, and there were no residual effects considered adverse. Due to the adversity of 
effects at 30 mg/kg/day in liver the NOAEL was considered to be 10 mg/kg/day and the 


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associated plasma exposures (Cmax and AUC0-24) values on Day 28 were 84 ng/mL and 
1,350 ng•hr/mL, respectively.  
In the 13-week study, administration of BCX7353 was well tolerated when given daily to 
cynomolgus monkeys by oral gavage for 91 days at dose levels of 0, 2.5, 7.5, and 20 mg/kg/day. 
The only test article related findings were increases in ALT in both sexes at 20 mg/kg/day, and 
increases in the putative phospholipidosis biomarker BMP in the urine of male and female 
monkeys at 7.5 and 20 mg/kg/day, without any microscopic correlate. The increases in ALT 
were noted at day 28 and were partially resolved by the end of dosing and fully resolved at the 
end of recovery. BMP increases showed evidence of resolution by the end of the recovery 
period. Since there were no microscopic findings to correlate with ALT or BMP increases, they 
were not considered adverse.  
Therefore, the NOAEL after oral gavage dosing BCX7353 in primates when given for 91 days is 
20 mg/kg/day, the highest dose level administered. At 20 mg/kg/day, the combined male and 
female mean Cmax and AUC0-24hr values on Day 91 were 192 ng/mL and 3,350 ng•hr/mL 
respectively. 
Definitive embryo-fetal development studies were conducted in pregnant Sprague Dawley rats 
and New Zealand White rabbits. In rats there was no evidence of embryo-fetal mortality, 
fetotoxicity, or dysmorphogenesis at any dose level. Adverse maternal toxicity was observed at 
75 mg/kg/day. Based on these results, the NOAEL for maternal toxicity was 25 mg/kg/day and 
the NOAEL for embryo-fetal development was 75 mg/kg/day. In rabbits there was no evidence 
of embryo-fetal mortality, fetal growth effect, or dysmorphogenesis at any dose level. There was 
no evidence of maternal toxicity at 50 mg/kg/day and no effect on embryo-fetal development at 
< 100 mg/kg/day.  
5.3. 
Clinical Findings for BCX7353 
Two clinical studies of BCX7353 have been completed (Study BCX7353-101 and Study 
BCX7353-102). Brief summaries are provided below.  
5.3.1. 
Study BCX7353-101 
 Study BCX7353-101 was a 3-part, Phase 1, double-blind, placebo-controlled dose-ranging study 
of BCX7353 conducted in healthy subjects. Part 1 of the study assessed the safety, PK, and 
pharmacodynamics (PD) of a single ascending dose of BCX7353 (10 mg, 30 mg, 100 mg, 
250 mg, 500 mg, or 1000 mg), and included a food-effect assessment in the 250-mg cohort. Part 
2 of the study assessed the safety, PK, and PD of multiple ascending doses of BCX7353 given 
over 7 days. In Part 2, study doses of 125 mg once daily (QD) × 7 days, 250 mg QD × 7 days, 
500 mg QD × 7 days, and 350 mg QD × 14 days BCX7353 were evaluated. Part 3 of the study 
evaluated the safety, PK, and PD of single (100 and 500 mg) and multiple doses of BCX7353 
250 mg given over 7 days in healthy Japanese subjects. Preliminary data are available for all 
parts of the study. 
Overall, in Parts 1, 2, and 3 a total of 96 subjects were treated with single doses of BCX7353 up 
to 1000 mg, or multiple doses up to 500 mg for 7 days, or 350 mg for 14 days. Oral 
administration of BCX7353 was generally well tolerated with no treatment-emergent serious 
adverse events (TESAEs). Most treatment-emergent adverse events (TEAE) were Grade 1 in 


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severity; following single doses, 2 subjects in the 100-mg dose group (Part 1) experienced 
Grade 2 AEs (nausea and vomiting in 1 subject and seasonal allergy in the other subject) and in 
the multiple ascending dose cohorts 4 subjects (Part 2) and 1 subject (Part 3) experienced a 
Grade 2 TEAE and 1 subject (Part 2) a Grade 3 TEAE.  
The Grade 3 event occurred in the 500-mg group and was a cutaneous rash with no mucosal 
involvement, no desquamation, or constitutional symptoms or laboratory abnormalities. This 
event was consistent with a Type IV hypersensitivity reaction, and resolved following treatment 
with oral and topical steroids. In the 500-mg group (Part 2), 1 subject experienced a Grade 2 
headache, and 1 subject experienced Grade 2 upper abdominal pain upper and diarrhea 
(2 TEAEs) which led to the subject’s discontinuation from study drug dosing. Additionally, 
Grade 2 syncope was experienced by 1 subject in the 250-mg group and Grade 2 upper 
abdominal pain in 1 subject in the 350-mg group. The Grade 2 upper abdominal pain led to the 
subject’s discontinuation. In Part 3 following multiple dosing with 250 mg BCX7353, 1 subject 
experienced a Grade 2 maculo-papular rash. In Parts 1 and 2, the most commonly reported 
TEAEs were gastrointestinal disorders (eg, nausea and diarrhea) and nervous system disorders 
(eg, headaches). There was no apparent dose response with regards to any individual AE; 
however, more gastrointestinal adverse events (AEs) were reported in the higher dose cohorts. In 
Part 3, the most commonly reported TEAE was medical device site reaction (eg, skin irritation 
from the ECG electrode site). The next most frequently reported TEAE was a rash-like reaction 
in 3 subjects; however, only 1 was considered related to IMP. Across all parts of the study, there 
were no trends in laboratory abnormalities and the only Grade 3 or 4 laboratory abnormalities in 
BCX7353-treated subjects were 2 Grade 3 lipase values in the 350-mg group (Part 2) 3 days after 
discontinuing treatment that normalized or improved the following day. No significant increase 
of > 60 msec in QTcF was observed across dose groups and 1 subject in the 350 mg dose group 
(Part 2) had a single treatment emergent QTcF > 450 msec 3 days after discontinuing treatment 
(ie, 455 msec). Across all cohorts and treatments, no subject had a clinically significant ECG 
abnormality. With the exception of 1 subject with a >20% decrease in pulmonary diffusion 
testing (DLCO) result, no other clinically significant changes in DLCO results were noted from 
baseline to end of dosing in the multiple day cohorts. In addition, no differences were seen 
comparing changes in DLCO in BCX7353-treated with placebo-treated subjects.  
In Western subjects (Parts 1 and 2) following single oral doses of BCX7353 up to 1000 mg and 
multiple oral doses of up to 500 mg QD administered under fasting conditions, Cmax was reached 
approximately 2 to 5 hours after dosing. There was a prolonged absorption phase followed by a 
distribution/elimination phase. A second “peak” occurred around 5 hours after dosing, after the 
time of a meal. The double-hump PK profiles suggest that BCX7353 may undergo enterohepatic 
recirculation. BCX7353 plasma concentrations then declined biphasically. The effective half-life 
of BCX7353 was calculated to be 41 to 75 hours, based upon the 3.0- to 5.1-fold increase in 
exposure with 7 to 14 days of BCX7353 dosing. Across Part 2 cohorts, analysis of trough values 
indicated that steady-state conditions were achieved from 6 to 12 days post first dose. 
In Part 1, examination of point estimates for dose-normalized Cmax and AUC0-inf indicated that 
both Cmax and AUC0-inf increased in a more than dose-proportional manner over the 30 mg to 
1000 mg dose range; point estimates and associated 95% confidence interval (CI) ranges suggest 
reasonable dose-proportionality with doses between 250 mg and 500 mg for Cmax. In Part 2 
cohorts dosed for 7 days, there was a slightly greater than dose proportional increase in exposure 


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(AUCtau and Cmax) over the 125-mg to 500-mg dose range. With 4-fold increases in dose, there 
was a 5.1 and 5.3-fold increase in the geometric mean values for AUCtau and Cmax, respectively.  
After a high-fat breakfast, there was no significant effect on AUC0-24; the geometric mean value 
(coefficient of variation [CV]%) for AUC0-24 was 995 (25) ng•hr/mL under fasting conditions 
compared with 944 (28) ng•hr/mL under fed conditions. Also, no effect was observed on the 
geometric mean Cmax values. Given that there was no appreciable difference in the PK with or 
without a high-fat meal, the recommendation in future clinical studies will be to administer 
BCX7353 with food. Administration with food may mitigate any potential for gastrointestinal 
AEs. 
BCX7353 concentration-time profile following single and multiple dose administration in 
Japanese subjects (Part 3) was similar to those observed in the Western subjects (Parts 1 and 2). 
Maximal plasma BCX7353 concentrations were achieved at approximately 2 to 6 hours 
postdose. The second peak observed during absorption occurs after the administration of a meal. 
BCX7353 plasma concentrations then declined bi-exponentially with a geometric mean terminal 
elimination half-life of 73 hours following repeated dosing at 250 mg QD. After repeated dosing, 
the geometric mean accumulation ratio in AUCtau was approximately 4-fold, which is consistent 
with the observed long half-lives. In comparison to Western subjects dosed 250 mg for 7 days, 
the plasma exposure appeared to be slightly higher in Japanese subjects who received the same 
oral administration of BCX7353 (geometric mean AUCtau of 4180 vs 3710 ng•hr/mL and 
geometric mean Cmax of 261 vs 217 ng/mL). 
The effect of BCX7353 on the target enzyme, plasma kallikrein, was evaluated by comparing 
specific amidolytic activity in plasma samples taken after drug administration to baseline 
samples. A rapid and substantial inhibition of plasma kallikrein activity was observed following 
single 250 mg or higher doses of BCX7353. The response was generally dose dependent with a 
more sustained effect observed over the 24-hour period with the 500-mg and 1000-mg single 
doses. 
Oral administration of multiple doses of BCX7353 at 125 mg QD for 7 days imparted 
measureable plasma kallikrein inhibition through a dosing interval, achieving mean maximal 
reductions of approximately 70% around the time of Tmax. Higher doses of BCX7353 
(250 mg QD or higher) provided more potent inhibition that was more consistently sustained 
through a dosing interval, achieving approximately 90% inhibition across an interval on average. 
Similar levels of kallikrein inhibition were observed in Japanese subjects (Part 3) as compared to 
Western subjects (Parts 1 and 2) given comparable doses. Potent kallikrein inhibition of 
approximately 90% was consistently sustained throughout the dosing interval after 
administration of BCX7353 at 250 mg QD. The BCX7353 concentration and kallikrein 
inhibition relationship was well-described by a sigmoidal Emax model; drug effect on the target 
enzyme was highly correlated with exposure (r = 0.921 for Parts 1, 2, and 3 combined). 
5.3.2. 
Study BCX7353-102 
Study BCX7353-102 evaluated the effect of multiple oral doses of BCX7353 on hepatic and 
intestinal CYP3A4 (intravenous [IV] and oral [PO] midazolam, respectively), CYP2C9 
(tolbutamide), CYP2C19 (omeprazole) and CYP2D6 (dextromethorphan) enzyme activity using 
probe substrate drugs in healthy subjects.   


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A total of 21 subjects were enrolled and 18 subjects completed the study; withdrawal from study 
drug were for nonstudy-drug related reasons. BCX7353 was generally safe and well tolerated. 
Most AEs were Grade 1 in severity and no SAEs or Grade 3 or 4 AEs were reported. There was 
1 Grade 2 TEAE assessed as probably related to BCX7353: a subject developed a diffuse 
maculo-papular rash 48 hours after completing 9 days of BCX7353. The rash was pruritic with 
no mucosal involvement, no desquamation, and no abnormalities on exam. The subject had no 
constitutional symptoms or clinically significant lab abnormalities. The rash resolved rapidly 
following a single dose of cetirizine 10 mg.  
Preliminary analysis of the PK data indicate that BCX7353 is an inhibitor of CYP3A4, CYP2C9, 
CYP2C19, and CYP2D6 to varying degrees. Following administration of ≥ 8 days of BCX7353, 
exposure of all probe substrates was increased, indicating that metabolism was inhibited. Based 
on the draft FDA Drug Interaction Guidance and preliminary PK of the probe substrates, 
BCX7353 is a strong inhibitor of CYP2D6 (> 5-fold increase in AUC), a moderate inhibitor of 
CYP2C9, CYP2C19, and intestinal CYP3A4 (exposure increased between 2- and 5-fold), and a 
weak inhibitor of hepatic CYP3A4 (< 2-fold increase in exposure). 
5.3.3. 
Study BCX7353-203 
Interim efficacy, safety, PK, PD, and PK/PD results are available for Parts 1 and 2 of this 
ongoing proof-of-concept Phase 2 study in subjects with HAE. As of the cut-off date of 
19 May 2017, 51 subjects with HAE were randomized and had received up to 28 days of 
treatment with BCX7353 once daily; 18 subjects received BCX7353 350 mg, 6 subjects received 
BCX7353 250 mg, and 7 subjects received BCX7353 125 mg. In addition, 20 subjects with HAE 
had received placebo.  Part 3 of the study is currently ongoing. 
5.3.3.1. 
Interim Safety Results 
Overall, once daily dosing of BCX7353 up to 350 mg for 28 days was well tolerated. There were 
no SAEs reported in Parts 1 or 2 of the study, no Grade 4 TEAEs, and no TEAEs leading to 
death. The majority of TEAEs were Grade 1 in severity. Three subjects experienced 7 Grade 3 
TEAEs, all in the 350-mg dose arm: constipation, abdominal pain, nausea, vomiting, alanine 
aminotransferase (ALT) elevation, gastrointestinal infection and migraine. Three subjects 
discontinued study drug due to an AE, all in the 350-mg dose arm: Grade 3 abdominal pain and 
vomiting, Grade 1 liver disorder, and Grade 3 ALT elevation. 
Gastrointestinal-related AEs (primarily mild in severity) were reported more frequently in the 
350-mg arm suggesting a dose response. Some GI events, namely nausea and abdominal pain, 
are also hallmarks of abdominal HAE attacks which were reported more commonly in the 
350-mg dose arm (see Section 5.3.3.3 below). It is possible that subjects may have mis-attributed 
GI TEAEs as abdominal attacks. The incidence of GI events as well as abdominal attacks 
decreased in the 2 lower dose cohorts compared to the 350-mg dose cohort.  
In addition, liver transaminase elevations were noted primarily in the 350-mg dose arm, but may 
have been confounded by both baseline elevated ALT and AST as well as a much higher rate of 
past and/or recent androgen use, neither of which were controlled for in the study. No drug 
rashes were reported in HAE patients as of the interim cutoff. No QTcF increase from baseline 
or absolute QTcF interval was considered clinically significant, and no TEAEs of arrhythmia 
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5.3.3.2. 
Interim Pharmacokinetic, Pharmacodynamic and 
Pharmacokinetic/Pharmacodynamic Results 
In subjects with HAE, the exposure of BCX7353 was consistent with that observed in healthy 
subjects. There was a greater than dose proportional increase in exposure (AUCtau and Cmax) over 
the 125-mg to 350-mg dose range, with an approximate 4-fold increase in exposure with a 
2.8-fold increase in dose. The greater than proportional increase in exposure was observed from 
125-mg to 250-mg, while the increase in exposure over the 250-mg to 350-mg dose range was 
proportional to the increase in dose. Trough concentrations collected on Days 14, 15, 28 and 29 
indicated that steady state was reached by Day 14 in subjects at all dose levels. The geometric 
mean 24-hour concentrations (Ctau) were maintained at levels at or above a target therapeutic 
concentration range of 41 ng/mL to 71 ng/mL, estimated to be approximately 4-to 8-fold the 
EC50 required for plasma kallikrein inhibition.   
Exposure of BCX7353 in subjects with HAE was overall consistent with the exposure observed 
in healthy subjects. BCX7353 exposure following administration of a 350-mg dose for at least 
14 days in subjects with HAE was 0.98-fold the AUCtau observed in healthy subjects following 
administration for 14 days. Despite differences in dose proportionality seen over the multiple 
dose range in healthy subjects and patients, exposure following either a 125-mg or 250-mg dose 
for at least 14 days in Study BCX7353-203 was 0.86-fold and 1.15-fold the AUCtau, respectively, 
that was observed following administration of the same doses for 7 days to healthy subjects, 
when subjects were likely at or approaching steady state.   
Exposure-response analyses of the relationship between kallikrein inhibition and BCX7353 
plasma concentrations was evaluated in an exploratory ex-vivo kallikrein inhibition assay by 
comparing specific amidolytic activity in plasma samples taken after drug administration to that 
in baseline samples. BCX7353 showed potent inhibition of plasma kallikrein. Following at least 
14 days of administration of the 250-mg and 350-mg doses, plasma kallikrein inhibition was 
maintained over the dosing interval, with maximal inhibition of approximately 90% occurring 
around the median Tmax that were sustained above 75% for the 24-hour dosing period. The mean 
maximum kallikrein inhibition was observed around the median Tmax with the 125-mg dose, and 
was approximately 60%, with mean kallikrein inhibition at 24 hours of approximately 40%. In 
general, kallikrein inhibition in subjects with HAE was consistent with the inhibition observed in 
Study BCX7353-101 in healthy subjects. A preliminary BCX7353 concentration and kallikrein 
inhibition relationship has been described by a sigmoidal Emax model with predicted EC50 values 
between 9.7 and 10.8 ng/mL.  The drug effect on kallikrein inhibition was highly correlated with 
exposure (r = 0.85); inclusion of the 62.5 mg dose in Part 3 is expected to further refine the 
model by providing a greater number of concentrations in the linear range of the model. 
5.3.3.3. 
Interim Efficacy Results 
Interim results for the primary efficacy endpoint, number of confirmed HAE attacks, and the 
secondary efficacy endpoint of number of HAE attacks analyzed by anatomical location, are 
presented for Parts 1 and 2 as of the cut-off date of 19 May 2017. 
Statistically significant and clinically meaningful reductions in the rate of attacks were observed 
in subjects treated with BCX7353 compared to placebo. Reductions in attack rates were observed 
at all doses tested, compared to placebo. In the Full Analysis Set (FAS) for the Entire Dosing 
Period (Days 1-28), the Least Squares Mean (LSM) attack rate for placebo was 0.898 per week, 


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and a reduction in the confirmed attack rate of 0.434 attacks/week (48.4%, p < 0.001) was 
observed for all BCX7353 doses combined compared to placebo. Reductions in confirmed attack 
rates by treatment group were: 350-mg dose group n = 18, 0.384 attacks/week, 42.8% reduction 
compared to placebo (p = 0.007); 250-mg dose group n = 6, 0.417 attacks/week, 46.4% reduction 
compared to placebo (p = 0.039); and 125-mg dose group n = 7, 0.579 attacks/week, 64.5% 
reduction compared to placebo (p= 0.003). Consistent results were observed in the Per Protocol 
(PP) population and during the Effective Dosing Period (Days 8-28), the duration at which study 
drug was at steady state. 
A prespecified secondary endpoint analyzed the rate of confirmed attacks by anatomical 
location, specifically attacks that included abdominal symptoms versus attacks with only 
peripheral symptoms. This analysis identified a dose-ordered difference in attack rate by 
anatomical location. A differential response in attack rate reductions was observed for attacks 
with objective peripheral symptoms compared to attacks with abdominal symptoms, particularly 
at the two higher doses (250 mg and 350 mg).  
In the FAS for the Entire Dosing Period, at the 350-mg dose a LSM reduction in peripheral 
attacks of 0.390 attacks/week (72.0%, p = 0.002) compared to placebo was observed, versus a 
0.007 attacks/week (1.9%, p = 0.947) increase in abdominal attacks. At the 250-mg dose a 
reduction in peripheral attacks of 0.363 attacks/week (67.0%, p = 0.045) compared to placebo 
was observed, versus a 0.053 attacks/week (15.0%, p = 0.704) reduction in abdominal attacks, 
and at the 125-mg dose a reduction in peripheral attacks of 0.456 attacks/week (84.0%, 
p = 0.008) compared to placebo was observed, versus a 0.123 attacks/week (34.7%, p = 0.354) 
reduction in abdominal attacks. When reviewed in the context of reported TEAEs, the apparently 
poor response to treatment with BCX7353 in abdominal attacks may be due to a misattribution 
of GI-related side effects of the study drug as symptoms of an abdominal attack because of 
overlapping symptoms. 
5.4. 
Rationale for Study 
BCX7353 is a second-generation small molecule developed as an orally administered inhibitor of 
plasma kallikrein for the prevention of angioedema attacks in adult and adolescent patients with 
HAE Type I and II. Kallikrein is a proven target for the treatment of HAE; the kallikrein 
inhibitor ecallantide is approved in the US for subcutaneous injection for the treatment of HAE 
attacks, and C1 INH treatments also target kallikrein. BCX7353 has activity against plasma 
kallikrein at low nM concentrations (see Section 5.2.1) that are attainable and sustained in 
humans following oral administration. As noted earlier (see Section 5.1), the plasma kallikrein 
inhibitor avoralstat was shown to be efficacious in the OPuS-1 study, reducing attacks in most 
subjects and was generally safe and well-tolerated. These data support further investigations of 
oral plasma kallikrein inhibitors as prophylactic interventions in patients with HAE. 
Study BCX7353-203 is the initial proof-of-concept study of BCX7353 in adult subjects with 
HAE. This study is designed to evaluate the treatment effect of BCX7353 on HAE attacks over a 
28-day period, relative to that on placebo treatment.. Multiple dose levels of BCX7353 will be 
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5.4.1. 
Rationale for Study Drug Doses  
5.4.1.1. 
Rationale for Target Concentrations Proposed as Efficacious 
In healthy subjects in Study BCX7353-101, inhibition of plasma kallikrein was highly correlated 
with plasma BCX7353 concentrations (r = 0.92). Therefore, sustaining BCX7353 concentrations 
near or greater than a target level over a dosing interval is hypothesized to reduce attacks of HAE 
in subjects with little or no functional C1 INH, the endogenous inhibitor of kallikrein and 
ultimately, bradykinin production. 
Trough concentrations expected to be efficacious were determined on the basis of C1 INH 
plasma concentrations in healthy subjects and HAE patients and the relative potency of C1 INH 
and BCX7353 against plasma kallikrein determined in vitro. The underlying hypothesis is that 
restoring normal levels of kallikrein inhibitory activity will restore a normal phenotype and 
eliminate angioedema attacks in patients with HAE.  
The original rationale for the calculation of efficacious target concentrations for this protocol 
was as follows: In the plasma kallikrein inhibition assay using HAE patient plasma, the EC50 of 
C1 INH was measured to be 213 nM and for BCX7353 was 15.9 nM, a 13.4-fold potency 
difference. The lower limit of the normal range (LLN) of C1 INH is 1680 nM; therefore, the 
LLN for C1 INH corresponds to a BCX7353 concentration of 125 nM, or 71 ng/mL 
(approximately 8 x EC50). If the BCX7353 Ctau could be maintained above 71 ng/mL, total 
plasma kallikrein inhibitory activity would be in the normal range. This level of BCX7353 would 
be sufficient to replace normal function in HAE patients who have zero functional C1 INH. The 
average patient with HAE has functional C1 INH levels of about 30% of the normal mean 
(720 nM). In the average patient, the difference between this level and the LLN of C1 INH is 
960 nM, which corresponds to about 73 nM or 41 ng/mL (approximately 4 x EC50) of BCX7353. 
In summary, maintaining Ctau at either ≥ 41 ng/mL or ≥ 71 ng/mL (4 – 8 x EC50) should restore 
the normal phenotype in the average HAE patient, and most HAE patients, respectively.   
Since this protocol was initiated, newly available data suggest that a lower target concentration 
range of BCX7353 may be efficacious. Results of a Phase 3 blinded randomized 2-period cross-
over study of a subcutaneous formulation of C1INH (CSL830) (COMPACT study) were recently 
reported. This study demonstrated an approximately 89-95% reduction in HAE attacks during 
the C1INH treatment period in patients with a qualifying minimum attack rate of at least 2 
attacks per month at entry and an on-study attack rate of 3.6-4.0 attacks per month in the placebo 
period (Zuraw et al, 2016). An estimated exposure-response analysis of the mean trough C1INH 
level from this study indicated that the observed clinical responses correlated with C1INH trough 
levels of approximately 5.3 – 6.3 fold EC50 of C1INH on plasma kallikrein (210 nM) in the same 
assay as used to estimate the EC50 of BCX7353 on the same target enzyme Figure 1. Baseline 
mean levels of endogenous C1INH in this population were reported to be at approximately 
25.4% of normal mean (~13.1 x EC50), ie equivalent to approximately 3.3 x EC50. Thus, high 
levels of efficacy were achieved in these severely affected HAE patients with the addition of 
exogenous C1INH equivalent to 2-3 x EC50 at trough. These data support a rationale that doses 
of BCX7353 resulting in a trough level of 2-3 x EC50 may also be efficacious, on a background 
mean level of endogenous C1INH of approximately 3.3 x EC50. 


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Figure 1: 
Estimated exposure-response relationship for C1INH (CSL830 and Cinryze) 
 
 
As outlined in Section 5.3.3, unblinded safety, PK, PD, and efficacy data are available through 
completion of dosing in Part 2 of the current study, including doses of 350 mg (n = 18), 250 mg 
(n = 6) and 125 mg (n = 7). HAE attack rates were reduced at all BCX7353 dose levels relative 
to placebo, with the greatest reduction observed at the 125 mg QD dose level. At all doses, the 
fold above EC50 was exceeded by greater than 2-3 x EC50 and the minimum target concentrations 
of 41 and 71 ng/mL were also consistently exceeded at doses ≥ 250 mg QD (Table 2). Taken 
together, this data suggests that lower target concentrations than originally anticipated (ie 4x 
EC50 or lower) may be efficacious. This trough concentration corresponded to kallikrein 
inhibition of approximately 40%. However, it should be noted that data at doses < 350 mg has 
been obtained from a very small population thus far; completion of Part 3 will approximately 
double the number of subjects receiving 125 and 250 mg and will provide efficacy and trough 
PK and PD data on a small number of subjects dosed 62.5 mg QD. 


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Table 2. 
Preliminary BCX7353 Trough Concentrations Obtained in Study BCX7353-
203 Through Part 2 and Relationship to Pre-defined Target Concentrations 
Proposed as Efficacious 
BCX7353 
Dose 
n 
Mean (SD) 
trough 
[BCX7353] 
ng/mL 
Mean (SD) 
trough EC50,  
x-fold 
Mean (SD) x-fold 
over target of 
71 ng/mL at trough 
Mean (SD) x-fold over 
target of 41 ng/mL at 
trough 
350 mg 
17 
177 (58.84) 
19.0 (7.04) 
2.51 (0.874) 
4.34 (1.51) 
250 mg 
6 
132 (38.74) 
14.2 (5.18) 
1.90 (0.704) 
3.29 (1.22) 
125 mg 
7 
42.8 (16.52) 
4.63 (2.00) 
0.61 (0.234) 
1.06 (0.406) 
 
5.4.1.2. 
Rationale for Proposed Doses: Parts 1-3 
This dose ranging study will evaluate the safety and efficacy of daily BCX7353 doses of 
62.5 mg, 125 mg, 250 mg, and 350 mg compared to placebo. The rationale for selection of these 
doses is based upon the safety observed in Study BCX7353-101 and the achievement of 
potentially efficacious BCX7353 plasma concentrations.  
In Study BCX7353-101, dosing regimens of up to 500 mg BCX7353 QD for 7 days and 350 mg 
BCX7353 QD for 14 days were generally safe and well-tolerated. Gastrointestinal effects were 
reported more frequently at higher dose levels, although these events were predominantly mild 
and may be mitigated with concomitant food intake. No other dose-related safety concerns were 
noted, and the maximum tolerated dose was not reached in Study BCX7353-101, supporting 
selection of 350 mg to 500 mg BCX7353 QD as an upper dose to be considered for future 
clinical evaluation. 
Using BCX7353 trough concentrations achieved in Part 2 of Study BCX7353-101, Monte-Carlo 
simulations were performed to estimate the percentage of clinical trial subjects who may meet or 
exceed the target trough concentrations equivalent to 4 and 8 x EC50 (41 ng/mL and 71 ng/mL). 
Linear regression parameter estimates obtained across dose ranges that produced relatively 
dose-proportional increases in exposure (125 mg to 250 mg and 250 to 500 mg) were used to 
interpolate trough estimates for putative doses in between those studied. Additional extrapolation 
for a dose range from 125 mg down to a dose of 25 mg was added to this analysis to estimate the 
percentage of clinical trial subjects who may meet or exceed the target trough concentrations 
equivalent to 2 and 3 x EC50 (18 ng/mL and 27 ng/mL). Results of simulations with 1000 
subjects per dose point (100 mg, 200 mg, 300 mg, and 400 mg QD, and 25 mg, 37.5 mg, 50 mg, 
62.5 mg, 75 mg, 87.5 mg, 100 mg, 112.5 mg and 125 mg QD, symbols) are provided graphically 
in Figure 2, together with fitted dose-response regressions (lines). Daily doses of approximately 
125 mg and greater should provide trough concentrations above 41 ng/mL in approximately 70% 
of patients and therefore, selection of daily doses of 125 mg or higher for evaluation in the 
current study are supported. However, if maintenance of 71 ng BCX7353/mL is required to 
prevent attacks, doses of approximately 300 mg QD and greater will provide those levels in 
≥ 90% of patients and therefore, selection of a 350 mg daily dose for evaluation in the current 
study is supported. To ensure that a full dose response is evaluated in this Phase 2 dose ranging 


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study, addition of a lower, 62.5 mg dose, which should provide trough concentrations above 
18 ng/mL in approximately 65% of patients, is deemed reasonable. Enrolment of additional 
subjects at doses of 250 mg and 125 mg per day in Part 3 will aid in a full characterization of the 
dose response to enable selection of doses for future studies (Figure 2).  
 Figure 2: 
Proportion of Simulated Clinical Trial Subjects Anticipated to Meet or 
Exceed Target Trough Concentrations 
 
5.4.1.3. 
Rationale for Proposed Doses: Part 4 
The results of Part 3 will provide robust safety and efficacy data at BCX7353 doses of 125 and 
250 mg QD. Both dose levels have been well-tolerated to date during a 28-day dosing regimen. 
Current safety data suggest that gastrointestinal AEs and liver enzyme abnormalities are dose-
related, with the 125-mg dose level currently not associated with either finding and the 350-mg 
dose level most associated with these findings.  
At all dose levels assessed in Parts 1 and 2, HAE attack rates were significantly reduced relative 
to placebo, with the greatest overall reduction observed at 125 mg QD, corresponding to ~4-fold 
EC50 on plasma kallikrein and a mean of 42% kallikrein inhibition at the end of a dosing interval. 
A closer evaluation of the attacks reported by 18 subjects receiving 350mg BCX7353 revealed 
that BCX7353 had a high degree of efficacy on peripheral attacks, with no effect on abdominal 
attacks, potentially due to mis-attribution of abdominal TEAEs as attacks.  A 250 mg QD dose 


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did provide proportionally less exposure than a 350 mg dose, however kallikrein inhibition was 
generally indistinguishable over a dosing interval. 
Therefore, the optimal BCX7353 dose is predicted to be one in which GI TEAEs are reduced but 
where effective plasma concentrations and kallikrein inhibition are maintained to prevent true 
HAE attacks from occurring. Based on available data this is likely to be in the 125 to 250 mg QD 
dose range.  Following completion of enrollment in Part 3, Part 4 may be initiated in order to 
fully define the dose-response relationship with a dose intermediate to 125 and 250 mg.  The 
decision to enroll Part 4, including the doses selected for Part 4, will be based on the PK, safety 
and efficacy results through Part 3 of the study. 
Part 4 will be implemented if the 62.5 mg dose is shown to be less efficacious than the higher 
doses and the 125 mg dose efficacy is not sustained through the completion of Part 3, in order to 
further define the dose-response relationship. A 175 mg dose is proposed for study in Part 4, 
based upon predictions for exposure and kallikrein inhibition that are intermediate between the 
125 and 250 mg doses.  Results of simulations based upon PK data at the 125 and 250 mg doses 
in the current study and in Study BCX7353-101, suggest that 93% of subjects dosed with 175 mg 
QD will have trough concentrations above 4 x EC50, in contrast to 70% for a 125 mg dose. A 
175 mg QD dose is also predicted to inhibit kallikrein by 62%, approximately midway between 
125 mg (42%) and 250 mg QD (76%). 
As discussed in Section 5.4.1.1, a dose < 125 mg BCX7353 QD may be efficacious based upon 
the HAE attack rate observed at this dose level in Part 2 and given that concentrations sufficient 
to block kallikrein through a dosing interval are greater than that now thought to be minimally 
efficacious (2 to 3 x EC50 [18 ng/mL and 27 ng/mL]). A 62.5 mg QD dose is the only dose 
< 125 mg QD being evaluated in the ongoing Part 3 of the study. It is unlikely that this dose will 
provide target BCX7353 concentrations in a significant proportion of subjects treated with this 
dose (see Figure 2). Nevertheless, this concentration and efficacy threshold has not yet been 
established and given that only 6 subjects will be dosed with 62.5 mg QD in Part 3, additional 
subjects may need to be dosed with 62.5 mg QD in Part 4 to elucidate the benefit: risk profile of 
this dose level.  
If the interim review indicates that Part 4 is not needed, it will not be conducted.  
5.4.2. 
Rationale for Study Design 
This is a Phase 2a study designed to assess the safety, efficacy, and PK of BCX7353 for the 
prophylactic treatment of subjects with HAE over a 28-day treatment period.  
A parallel group design was considered the most appropriate study design to evaluate BCX7353 
relative to other doses of BCX7353 and relative to placebo because of its very long half-life. The 
terminal half-life of BCX7353 was estimated at approximately 60 hours at doses ranging from 
100 mg to 1000 mg in the single ascending dose Part 1 of Study BCX7353-101. Given this long 
half-life it would be more difficult to minimize carry-over effects in a study utilizing a cross-over 
design.   
Since Study BCX7353-203 is the initial proof-of-concept study of BCX7353 in adult subjects 
with HAE, enrollment of subjects known to the study investigators as having frequent HAE 
attacks allows evaluation of the BCX7353 treatment effect of the highest proposed clinical dose 
(350 mg) over a short period (28 days) relative to placebo. This will prudently establish proof-of-


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concept and risk/benefit at the dose of BCX7353 modeled to provide the most complete plasma 
kallikrein suppression through a daily dosing interval, 350 mg QD.  A tiered enrollment 
approach of analyzing data from the first 24 subjects completing either placebo or BCX7353 
350 mg QD treatment prior to enrolling a maximum of 36 subjects will help to limit the number 
of subjects exposed to an investigational product that has undetermined efficacy. Additional 
BCX7353 doses down to 62.5 mg QD will be evaluated in subjects once the risk/benefit balance 
has been ascertained at this highest dose. 
5.4.3. 
Study Population Rationale 
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 males and females in this clinical trial to gain an early assessment of 
potential safety and PK differences.  
Although there is no evidence of feto-toxicity with BCX7353, pregnant women will be excluded 
from participation. BCX7353 is early in clinical development and the benefit/risk profile has not 
been characterized in the general HAE population to allow pregnant women to receive 
BCX7353. Additionally, any female subject who becomes pregnant during the course of the 
study will be immediately removed from study drug and followed through the end of the 
pregnancy. 
Women of childbearing potential may be enrolled in this trial only if they agree to utilize at least 
an acceptable effective contraceptive method. The specific types of allowable acceptable 
effective contraception outlined in Section 8.2.1 are in accordance with the Clinical Trial 
Facilitation Group (CTFG) Recommendations Related to Contraception and Pregnancy Testing 
in Clinical Trials document.  
The allowance of an acceptable effective contraception method in this trial is based on the 
completion and outcome of nonclinical studies in accordance with the general recommendations 
of the ICH M3(R2) guideline that “all female reproduction toxicity studies and the standard 
battery of genotoxicity tests should be completed prior to the inclusion, in any clinical trial, of 
women of childbearing potential not using highly effective birth control or whose pregnancy 
status is unknown.” The completed studies for BCX7353 include a standard battery of 
genotoxicity testing, 13-week repeat dose toxicity studies in two species, embryofetal 
development studies in two species, and a fertility and early embryonic development study in 
rats. As described, the results from all studies indicates no risk to the unborn, thus supporting the 
option for highly effective or acceptable effective methods of contraception to be used during 
BCX7353 clinical trials. 
Based on past and ongoing studies conducted in HAE patients, it is anticipated that female 
subjects will comprise at least 50% of the patient population in this study. 


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5.4.3.1. 
Rationale for Allowance and Restriction of Concomitant Medications for HAE 
While there are approved therapies in the US and EU 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 
recent 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: 
‘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.’(Zuraw, Banerji et al. 2013) 
In the current study, all participants must have access to effective, approved treatments for 
attacks of angioedema as part of their routine medical care. 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 multiple 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).  
5.4.4. 
BCX7353 Risk/Benefit Analysis 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions 
Given that BCX7353 is a small molecule kallikrein inhibitor with a completed Phase 1 single 
and multiple dose study, there is an acceptably low risk of severe adverse reactions. Potential 
risks are outlined below.  
5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 
The initial toxicology studies in rats and monkeys suggest that the primary target organs of 
BCX7353 toxicity were liver (both hepatocyte necrosis and bile duct hyperplasia), kidney, and 
skeletal muscle, with toxicities also observed in cardiac and smooth muscle, and the lymphoid 
system. However, with longer duration of dosing (13 weeks) (albeit with a different drug lot than 
used in the 28-day studies) there were no significant adverse effects noted. In monkeys dosed 
20 mg/kg/day for 13 weeks, there were no adverse effects noted. In rats dosed at 20 mg/kg/day 
for 13 weeks, only bile duct hypertrophy, hyperplasia and vacuolated macrophages in the liver 
were noted and these were not considered adverse. No clinically significant toxicities in these 
organs have been noted during the first in human trial. Mild gastrointestinal symptoms, including 
diarrhea, abdominal pain, and nausea were noted, particularly at higher doses. In addition, 
delayed hypersensitivity drug rash was reported.   
Liver: At 20 mg/kg/day of BCX7353 dosed to rats for 13 weeks, bile duct hypertrophy, 
hyperplasia, and vacuolated macrophages were present in the liver with evidence of PLD in 
Kupffer cells on EM. There were no hepatic enzyme or biliary lab marker changes and all these 
effects were reversible as evidenced in the 6-week recovery animals. At 25 mg/kg/day of 
BCX7353 dosed to rats for 28 days, there was minimal to mild bile duct degeneration/necrosis 
and inflammation. At higher doses of 75 mg/kg day, there was minimal bile duct hyperplasia, 


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hepatocyte necrosis, and hepatocellular vacuolation that correlated to increased AST and ALT on 
clinical chemistry.  
At 20 mg/kg/day dosed to monkeys for 13 weeks, ALT levels were mildly increased in both 
sexes at Week 4 but demonstrated partial resolution at the terminal collection despite continued 
dosing, lacked correlative microscopic changes in the liver at the terminal necropsy, and were 
normal at the recovery collection. In the previous study where monkeys were dosed for 28 days 
there were enlarged hepatocytes with foamy to large cytoplasmic vacuoles and hyperplasia of 
oval cells at 100 mg/kg/day. Hepatocellular necrosis was noted at 30 mg/kg/day, but only those 
effects at 100 mg/kg/day were considered adverse. These changes also correlated with increased 
transaminases on clinical chemistry. In addition, monkeys had mild decreases in albumin and 
mild increases in globulin levels at 100 mg/kg/day.  
Liver enzymes, bilirubin, gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) 
are being followed closely in clinical trials to monitor for any hepatocellular and biliary system 
changes. There have been no clinically significant abnormalities observed in any of these 
analytes during the Phase 1 study. In the 50 subjects treated with BCX7353 for 7 to 14 days, the 
highest ALT (104 IU/L) and AST (48 IU/L) occurred on Day 14 in 1 subject who was in the 
350 mg × 14-day cohort. There was no evidence of any clinically significant abnormality in 
hepatic synthetic function as monitored by prothrombin time, albumin, and total protein levels in 
blood.  
 
In the ongoing study, two of the first 23 subjects treated in Part 1 (350 mg BCX7353) 
experienced a treatment-emergent Grade 3 (one subject) or Grade 4 (one subject) lab 
abnormality in GGT, along with lower Grade increases in AST, ALT and ALP.  
The first subject is a 64 year old man with a medical history of hypertension, depression, right 
bundle branch block, and erectile dysfunction. Concomitant medications included tadalafil and 
escitalopram. One week prior to starting blinded study drug he stopped his calcium channel 
blocker and switched to irbesartan/HCTZ for blood pressure control. He was on danazol until 
approximately 40 days prior to starting study drug. He developed a Grade 1 gastroenteritis 
(symptoms of vomiting and diarrhea: possibly related) on Day 10. The study drug was 
interrupted. He restarted study drug on Day 18 with a reoccurrence of vomiting and diarrhea 
5 hours post dose. Labs on Day 14 demonstrated Grade 3 GGT, Grade 2 ALT, Grade 1 ALP and 
normal AST and bilirubin. He was taken off study drug on Day 18. Since then, he has done well 
with normal LFTs on  Day 29 with the exception of a Grade 1 GGT. 
 
The second subject is a 51 year old woman with a medical history of active colitis treated with 
mesalamine.  She had no recent use of androgens. She did well during the study and had no 
reported AEs, although she complained of fatigue at the Day 29 visit. At baseline, she had Grade 
1 ALT, GGT and Direct bilirubin elevations. Her AST and ALP were normal. Her LFTs were 
stable at the Day 14 visit. At the Day 29 visit, her lab results demonstrated a Grade 4 GGT, 
Grade 3 ALT and Grade 1 AST and ALP. Since then, she has done well and her follow-up labs 
have all normalized with the exception of a Grade 3 GGT. 
 
Additionally, no significant laboratory abnormalities or significant liver transaminase elevations 
were observed in Part 2 (250 mg BCX7353 and 125 mg BCX7353), except for a single subject 
randomized to BCX7353 250 mg.  The subject was a 60 year-old woman who had a baseline 


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ALT of 97 IU/L (Grade 2 [2.9 X ULN]) and AST 46 IU/L (G1 [1.4 X ULN]). She experienced 
nausea and lethargy during the first week of dosing. Her ALT rose to 116 IU/L (G3 [ 3.5 X 
ULN]) and AST to 61 IU/L (G1 [1.8 X ULN]) at week 7. The investigator continued her on 
study drug and her AEs resolved and LFTs remained elevated but stable. Two weeks after study 
drug was completed, she still had an ALT of 107 IU/L (G3[ 3.2 X ULN]). Several weeks later, 
her ALT and AST were normal.  
After a DMC review of blinded data on December 13, 2016, triggered as per criteria listed in 
Section 12.2, the DMC recommended the study dosing continue unchanged but that liver 
enzymes be monitored on a weekly basis while subjects are on study drug. Therefore, the 
frequency of monitoring of liver function has been changed from every 2 weeks to weekly in this 
study. This additional safety monitoring was instituted by a memo from the Sponsor to all sites 
on December 16, 2016, and was formalized in Protocol Amendment 2, (Version 3.0). 
Kidney: Although there was no evidence for any renal injury in the 13 week studies in either rats 
or monkeys, in the 28 day studies both rats and monkeys had renal tubular 
degeneration/regeneration with vacuolated cells, which was adverse at 75 mg/kg/day for rats and 
100 mg/kg/day for monkeys. This appeared to correlate to glycosuria. In addition, female 
monkeys had significant mononuclear infiltration resulting in a 35% increase in kidney weight 
from controls at 100 mg/kg/day. 
In the Phase 1 trial, no clinically significant abnormalities of renal function, as measured by 
serum creatinine and creatinine clearance (CLcr) have been found. Additional measurements to 
date of renal injury were also performed; serial evaluations of spot urine microalbumin to 
creatinine ratio, a marker for glomerular injury, and neutrophil gelatinase–associated lipocalin 
(NGAL), a novel marker for tubular injury, did not demonstrate any evidence of renal injury. 
Renal assessments including creatinine, CLcr, and NGAL will be regularly monitored in this 
study.  
Skeletal muscle: Although there was no evidence for any skeletal muscle injury in the 13 week 
studies in either rats or monkeys, in the 28 day studies both rats and monkeys had 
degeneration/necrosis and/or regeneration noted in multiple skeletal muscle groups. In the rat, 
these changes were also noted in cardiac muscle. Both the skeletal and cardiac muscle changes 
were adverse at 75 mg/kg/day in rats. The skeletal muscle changes were adverse in the monkey 
at 100 mg/kg/day. The muscle degeneration was suspected to contribute to the elevated AST on 
serum chemistry.  
In the Phase 1 trial neither AST nor creatine phosphokinase (CPK) demonstrated any clinically 
significant elevations. In addition, no subjects have experienced any AEs of potential muscular 
injury. 
Given the preclinical data, AST and CPK will be regularly monitored in this study. 
Heart: Although there was no evidence for any cardiac muscle injury in the 13 week studies in 
either rats or monkeys, in the 28-day study in rats, degeneration/necrosis and/or regeneration 
were noted in cardiac muscle and were considered adverse at 75 mg/kg/day. At high doses of 
BCX7353, monkeys did have decreases in blood pressure and heart rate, with corresponding 
ECG changes consisting of slowing of the heart rate and lengthening of the RR, QT and QTc 
intervals and QRS duration.  


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In addition to cardiac muscle changes and physiologic changes in heart rate and blood pressure, 
it should be noted that in vitro, BCX7353 inhibited the hERG channel inhibition, although the 
cardiac action potential was not prolonged. Since hERG inhibition has been associated with 
Torsades de pointes, ECGs will be performed until the effects in humans are better characterized.  
There was no evidence of foamy or vacuolated cells in the heart in either the rat or the monkey.  
Cardiac monitoring in the Phase 1 study did not demonstrate any arrhythmias or ischemia. 
Although there were some subjects with a QTcF interval increase between 30 and 60 msec, none 
of these subjects had an absolute QTcF > 450 msec and all subjects had transient value(s) which 
returned to <30 msec increase on the same day or the following day.  
Troponin T values were normal at all time points in all Phase 1 subjects. One subject in the 
single-dose 1000 mg group had a transient elevation in Troponin I on Day 2 to 0.06 µg/L (upper 
limit of normal [ULN] = 0.04 µg/L) that returned to within normal limits on Day 4 and remained 
< 0.01 µg/L through follow-up. The subject was clinically asymptomatic, had no Troponin T or 
creatine kinase (CK-MB) elevations, and had no ECG evidence of ischemia.  
Six subjects treated with BCX7353 in the Phase 1 study had treatment emergent elevations from 
baseline of CK-MB, 2 receiving single doses of 100 mg, 2 subjects receiving 250 mg for 7 days, 
1 subject receiving 500 mg for 7 days and 1 subject receiving 350 mg for 14 days. In 5 of the 6 
subjects this corresponded to elevated CK ranging from 1.3 to 7.6 × ULN. In addition, 3 of these 
6 subjects had elevated CK-MB at baseline. None of these subjects had an elevation of Troponin 
I or Troponin T or any evidence of ischemia or cardiac muscle damage. In all cases this was 
noted at the follow-up visit after discharge from the Phase 1 unit. In 1 subject receiving 350 mg 
for 14 days, the CK-MB was elevated to 6.5 µg/L (normal range = 0.0–2.9 µg/L) at the follow-
up visit which was not due to an abnormal CK level. This subject had an elevated CK-MB at 
baseline of 4.0 µg/L, which improved during study drug dosing. All other labs were normal at 
the follow-up visit. In particular, Troponin I and Troponin T were normal and there was no 
evidence of cardiac ischemia. It is unclear why the CK-MB was elevated in this subject but 
cardiac ischemia is unlikely.  
This study will exclude subjects with evidence of cardiac disease as indicated by medical history, 
family history of sudden death or abnormal screening ECG. Monitoring with ECG, troponin and 
CK-MB will be regularly monitored in this study.  
Lymphoid system: Although there was no evidence for any lymphoid system abnormalities in 
the 13 week studies in either rats or monkeys, in the rat 28-day study lymphoid depletion was 
noted in the thymus and spleen at 75 mg/kg/day. In contrast, the monkeys generally had 
hyperplastic lymphoid tissue (spleen and lymph nodes) which was not considered adverse.  
In the Phase 1 study, no clinically significant changes in any hematologic parameter or lymphoid 
tissue were noted. No organomegaly and no lymphadnopathy were noted on physical exam. 
Complete blood counts and general physical examinations will be regularly monitored in this 
study. 
Presumed Phospholipidosis: In the 28 day studies in both rats and monkeys, there were foamy 
macrophages and vacuolated infiltrates found in multiple organs and various tissues, presumed to 
be signs of PLD. Vacuolated macrophages were noted in the liver, lungs, duodenum, jejunum, 
ileum, cecum, nonglandular stomach, mandibular lymph node, mesenteric lymph node, spleen, 


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and ovaries of rats. Vacuolation was present in the choroid plexus, the pituitary gland, the 
adrenal cortex, pancreas acinar cells and ductal cells of the parotid salivary gland in rats. In 
monkeys, foamy cells were noted in the liver, lymphoid tissue and small intestines. In most 
tissues, these infiltrates did not appear to be adverse and there were no clinical or blood 
chemistry findings that correlated. However, the infiltrates in the intestinal villi, which were not 
considered adverse in rats, caused significant villous thickening in monkeys at 100 mg/kg/day 
that appeared to correlate to possible malabsorption, manifested as decreased weight and low 
body nutrients. Importantly, the PLD was fully or partially reversible in both species. The partial 
reversibility in monkeys may have been due to the continued presence of BCX7353 in plasma 
even at Day 50 of the 28-day dosing study. 
In the 13-week studies in rats, the liver showed vacuolated macrophages with electron 
microscopic features consistent with PLD. In the monkey there was no physical correlate as there 
were no microscopic abnormalities and no foamy macrophages or vacuolated cellular infiltrates. 
Increased urinary levels of BMP, an investigational biomarker for PLD, were demonstrated in 
both rats and monkeys dosed with BCX7353 for 13 weeks.    
PLD is not adverse in and of itself and there are approved products that cause this phenomenon 
without any associated toxicity. It currently cannot be directly measured in an effective and 
noninvasive way and there are no validated biomarkers in humans (Chatman, Morton et al. 
2009). Since PLD is not a toxic manifestation and cannot be easily measured in humans, end 
organ toxicity is monitored. PLD may manifest by expanding the thickness of intestinal 
absorption and pulmonary diffusion tissues. This may result in various clinical findings, such as 
possible decreased nutrient absorption when PLD is present in intestinal villi.  
In the Phase 1 trial, there were no events suggesting PLD in either the intestines or lungs. No 
clinically significant changes in weight or evidence of malabsorption occurred. In addition, 
DLCO was performed as an experimental marker of foamy macrophage deposition in the lung. 
Except for a single subject in the 125-mg dose group who had a 22% decrease from baseline, no 
other clinically significant changes were noted from baseline to end of dosing in the multiple-day 
cohorts. This subject had no signs or symptoms suggestive of a diffusion deficit. In addition, no 
differences were seen comparing changes in DLCO in BCX7353-treated with placebo-treated 
subjects.  
The primary method of ensuring subject safety will be to monitor organ toxicity and subject 
well-being through adverse event reporting and vital signs including weight. In addition, 
monitoring with DLCO will be employed as an experimental marker to gauge lung foamy 
macrophages. 
Gastrointestinal symptoms: Gastrointestinal symptoms, primarily mild, were noted in all 
cohorts in the Phase 1 study when BCX7353 was given over 7 to 14 days. Symptoms were 
primarily lower gastrointestinal (diarrhea and flatulence) at 500 mg QD × 7 days and primarily 
upper gastrointestinal (abdominal pain, dyspepsia) at 350 mg QD × 14 days without any 
pertinent laboratory or physical exam findings. In the Japanese 250 mg × 7-day cohort, a single 
subject had abdominal pain. All subjects reporting these events took study drug in a fasting state. 
Two subjects discontinued, one after a single 500-mg dose of BCX7353 due to diarrhea and 
abdominal pain, and one after 10 days of 350 mg BCX7353 due to abdominal pain. Neither 
subject had any clinically significant laboratory abnormalities. PK analyses of both 250 mg doses 
administered in Part 1 of Study BCX7353-101 demonstrated no impact on drug exposure from 


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taking BCX7353 with food. Therefore, in order to help mitigate any gastrointestinal effects, 
particularly upper abdominal effects, BCX7353 should be taken with food.  
Drug rash:  
A benign maculopapular exanthema consistent with a delayed type drug rash has been seen in 
3 subjects taking multiple doses of BCX7353 to date. In Studies BCX7353-101 and 
BCX7353-102, a total population of BCX7353 exposed subjects who have received at least 7 
days of BCX7353 doses is 68, equating to an incidence rate of 4.4%.  In all cases, symptoms 
were observed or reported approximately 2 days after daily BCX7353 dosing ended: one subject 
who completed 500 mg QD BCX7353 x 7 days (Study BCX7353-101), one subject of Japanese 
heritage who completed 250 mg QD BCX7353 x 7 days (Study BCX7353-101), and one subject 
who recently completed 9 days of BCX7353 350 mg QD (Study BCX7353-102). In all cases, no 
systemic or constitutional symptoms, no organ involvement, no desquamation or mucosal 
involvement was observed, no clinically significant laboratory abnormities were present and the 
rash rapidly resolved. Two subjects received an oral antihistamine and 1 subject received oral 
and topical steroids. 
Hypersensitivity is a risk with any drug. In all three cases, the rashes have been limited and 
resolved quickly. Subjects should report any rashes, pruritus, or skin changes. Evaluation of any 
suspected drug-induced rash will be required with high resolution photography and clinical 
laboratory assessments in order to better define this risk; skin biopsy of a fresh lesion should be 
obtained for histopathologic examination, where possible. In addition, human leukocyte antigen 
(HLA) typing of all future enrolled subjects in multiple dose trials is being undertaken to 
understand whether any specific HLA genotypes play a role in the development of cutaneous 
hypersensitivity and could be used to identify patients at higher risk.  
5.4.5. 
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 active study drug for 28 days, 
although subjects will not know if they are receiving BCX7353 or placebo.  
Participation in this study will not exclude study subjects from being able to participate in longer 
term open-label studies of BCX7353, if further development of the drug is warranted. The 
development of BCX7353 may be of benefit to the wider community/patients with HAE.  
5.4.6. 
Overall Benefit-Risk Assessment 
The risks seen to date in both preclinical and clinical studies at the study doses were primarily 
mild, monitorable, and reversible. Even findings in animals such as PLD that are not directly 
monitorable will be followed by robust assessment of organ health and function. Although there 
may be no direct benefit to any individual subject, the information obtained from this trial will 
support the development of BCX7353 for HAE, a serious, debilitating and potentially life 
threatening disease.  
The overall risk benefit balance is therefore considered to be acceptable. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Objectives 
The primary objective of this study is as follows:  
 To evaluate the efficacy of once-daily prophylactic BCX7353 at up to 5 dose levels, 
•
as measured by the number of attacks of HAE observed in patients with HAE 
enrolled in each treatment group 
The secondary objectives of this study are as follows:  
 To evaluate the safety and tolerability of BCX7353 over 28 days in subjects with 
•
HAE 
 To describe the PK profile of daily BCX7353 in subjects with HAE 
•
 To characterize the anticipated PD effects of BCX7353 in subjects with HAE 
•
 To characterize the dose-response relationship of BCX7353 in subjects with HAE 
•
 To evaluate effects of BCX7353 on quality of life 
•
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan: Description 
This is a Phase 2, randomized, double-blind, placebo-controlled parallel-group, dose-response 
study to evaluate the safety, tolerability, PK, PD, and efficacy of BCX7353 in subjects with 
HAE. HAE patients with a documented recent history of frequent angioedema attacks who have 
provided written informed consent will be evaluated for participation in this study at a screening 
visit.  
Up to 36 subjects with HAE are planned to be enrolled in Part 1 of the study and will be 
randomized 1:1 (placebo: active) to receive one of the following treatments: 
 Part 1, Treatment Group 1: placebo QD orally for 28 days 
•
 Part 1, Treatment Group 2: 350 mg BCX7353 QD orally for 28 days 
•
After 24 subjects have completed through the Day 28 dose, there will be an administrative 
interim analysis of the accrued efficacy data by the Sponsor. If it is desired to more fully 
characterize the treatment effect of BCX7353 relative to placebo or to verify assumptions made 
for sizing this proof-of-concept study, additional subjects will be enrolled to complete Part 1 (up 
to 36). Enrollment into Part 1 will continue until either a decision is made to halt enrollment in 
favor of opening Part 2 or enrollment reaches 36 subjects in Part 1. Additionally, upon 
completion of Part 1 (36 subjects dosed), enrollment into Part 2 of the study may immediately 
commence.  
In Part 2, approximately 14 subjects who meet all eligibility criteria are planned to be 
randomized in a 1:3:3 (placebo:active:active) ratio into 1 of the following 3 treatment groups: 
 Part 2, Treatment Group 1: placebo QD orally for 28 days 
•
 Part 2, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 Part 2, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days 
•
If tolerability issues prevent full enrollment of Part 1 as described or study drug is poorly 
tolerated due to gastrointestinal effects, future subjects randomized to active study drug in Part 1 
may receive 250 mg orally once daily for 28 days. In this case, any dose level changes warranted 
for Part 2 will be instituted via protocol amendment.  
Following completion of enrolment in Part 2, Part 3 of the study may be initiated: 
In Part 3, approximately 20 subjects who meet all eligibility criteria are planned to be 
randomized in a 1:3:3:3 (placebo:active:active:active) ratio into 1 of the following 4 treatment 
groups: 
 Part 3, Treatment Group 1: placebo QD orally for 28 days 
•
 Part 3, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 Part 3, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days  
•
 Part 3, Treatment Group 4: 62.5 mg BCX7353 QD orally for 28 days 
•


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Following completion of enrollment in Part 3, Part 4 of the study may be initiated in order to 
more fully define the dose-response relationship. The decision to enroll Part 4, including the 
doses selected for study, will be based on results through Part 3 of the study.  
Should the 62.5 mg and 125 mg BCX7353 dose groups in Part 3 be less efficacious than higher 
doses of BCX7353 and Part 4 is initiated, approximately 14 subjects in Part 4 will be randomized 
in a 1:6 ratio into 1 of the following 2 treatment groups: 
• Part 4, Treatment Group 1:  placebo QD orally for 28 days (n=2) 
• Part 4, Treatment Group 2: 175 mg BCX7353 QD orally for 28 days (n=12) 
Alternatively, should the 62.5 mg BCX7353 dose group not be shown to be less efficacious after 
analysis of Part 3 data and Part 4 is initiated, approximately 20 subjects in Part 4 will be 
randomized in a 1:6:3 (placebo:active:active) ratio into 1 of the following 3 treatment groups as 
follows: 
• Part 4, Treatment Group 1:  placebo QD orally for 28 days (n = 2) 
• Part 4, Treatment Group 2: 175 mg BCX7353 QD orally for 28 days (n = 12) 
• Part 4, Treatment Group 3: 62.5 mg BCX7353 QD orally for 28 days (n = 6) 
The overall study design is presented in Figure 3; Figure 4 depicts the schema for conduct of 
each study part. 
 


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Figure 3: 
Study BCX7353-203 Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1: enrollment/data prior to interim
data through Day 28, n = 24:
n = 12 dosed 350 mg BCX7353 QD
n  = 12 dosed placebo QD
Interim 
administrative 
analysis of efficacy 
by Sponsor
Complete Part 1
n = 36 subjects
n = 18 dosed 350 mg BCX7353 QD x28 days       
n  = 18 dosed placebo QD x28 days
Enrollment in 
Part 1 will 
continue 
through efficacy 
interim analysis
Complete Part 2 dose-ranging
n = approximately 14 subjects
n = 6 dosed 250 mg BCX7353 QD x28 days
n = 6 dosed 125 mg BCX7353 QD x28 days 
n  = 2 dosed placebo QD x28 days
Treatment effect of 
study drug must be 
further defined
Treatment effect of 
BCX7353 and 
placebo differentiated
Treatment effect of 
BCX7353 and 
placebo differentiated
Enrollment in 
Part 2 may 
commence 
immediately 
after completion 
of enrollment of 
Part 1 
Complete Part 3 dose-ranging
n = approximately 20 subjects
n = 6 dosed 250 mg BCX7353 QD x28 days
n = 6 dosed 125 mg BCX7353 QD x28 days
n = 6 dosed 62.5 mg BCX7353 QD x28 days 
n  = 2 dosed placebo QD x28 days
Treatment effect of 
BCX7353 and 
placebo differentiated
Enrollment in 
Part 3 may 
commence 
immediately 
after completion 
of enrollment of 
Part 2 
Additional dose 
response data 
desired; 62.5 mg QD 
dose was less 
efficacious than 
higher doses
Additional dose 
response data 
desired; efficacy at 
62.5 mg QD can not 
be excluded
Complete Part 4 
n = approximately 14 subjects
n = 12 dosed 175 mg BCX7353 QD x28 days
n  = 2 dosed placebo QD x28 days
Complete Part 4
n = approximately 20 subjects
n = 12 dosed 175 mg BCX7353 QD x28 days
n = 6 dosed 62.5 mg BCX7353 QD x28 days 
n  = 2 dosed placebo QD x28 days


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Following an up to 21-day screening period, eligible subjects, who have had entry criteria 
confirmed by the Sponsor, will be dosed on Day 1. Subsequent study visits will be held on 
Days 7, 14, 21 and 29. At the Day 14 visit, subjects will also have serial blood samples drawn 
immediately prior to and after the dose, including a visit on Day 15 for collection of a 24-hour 
postdose PK sample. A follow-up visit will be performed on Day 44. 
Subjects will record the occurrence and details of all angioedema attacks at least once daily 
beginning from the date of screening until the follow-up visit. On Days 1 through 28, subjects 
will also record the time of day the study drug (BCX7353 or placebo) was taken and the number 
of capsules of study drug taken at each dose. Subject-reported study drug administration and 
HAE attacks will be captured in a diary. 
During the study, each subject will continue to use their prescribed acute attack medication to 
treat any attacks, under the medical management plan advised by their physician. All participants 
must have access to effective, approved treatments for attacks of angioedema as part of their 
routine medical care.  
Subject will only participate in one part of the study. 
All subjects who successfully complete treatment in the study will be offered the opportunity to 
participate in a future long-term study of BCX7353 where locally approved, provided that 
development of BCX7353 continues. 


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Figure 4: 
Study Schema—Parts 1, 2, 3 and 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2. 
Endpoints 
7.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the number of confirmed HAE attacks during the treatment 
period in the Full Analysis Set (FAS) population. The number of HAE attacks will be analyzed 
by treatment group using appropriate descriptive statistics as follows:  weekly attack rate, counts 
Follow-up
Day 44
                                                              Screening                       Baseline          Day 7             Day 14          Day 2        Day 29          Follow-up
                                                                   visit
   
            visit                visit                 visit               visit             visit                 visit
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 350 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 1
Follow-up
Day 44
                                                              Screening                      Baseline          Day 7              Day 14            Day 21      Day 29          Follow-up
                                                                   visit
   
           visit                 visit                visit                 visit           visit                   visit
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 125 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 3
BCX7353 62.5 mg QD
Follow-up
Day 44
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 250 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 2
BCX7353 125 mg QD
BCX7353 250 mg QD
                                                             Screening                      Baseline          Day 7              Day 14            Day 21      Day 29          Follow-up
                                                                  visit
   
           visit                 visit                visit                 visit           visit                   visit
Follow-up
Day 44
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 175 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 4
(if conducted)
BCX7353 62.5 mg QD*
                                                             Screening                      Baseline          Day 7              Day 14            Day 21      Day 29          Follow-up
                                                                  visit
   
           visit                 visit                visit                 visit           visit                   visit
*A 62.5 mg dose will only be included in Part 4 if the data from Part 3 does not exclude efficacy atthis dose level  


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of attacks, proportion of subjects with no attacks, and number of attack-free days. The relative 
change in attack rate from placebo will also be calculated for each active arm. The FAS includes 
all randomized subjects who receive at least 1 dose of study drug and have post baseline HAE 
attack data.  
To ensure that consistent, objective assessments are used in accepting subject-reported attack 
data, a panel of expert physicians in the treatment of HAE patients will adjudicate all 
subject-reported attacks prior to their inclusion in primary efficacy analyses. The adjudication 
will be based upon all data provided by the subjects in their study diaries that document reported 
HAE attacks. A separate charter will describe membership, roles, and processes to be followed 
by the adjudication panel. 
7.2.2. 
Secondary Efficacy Endpoints 
Secondary endpoints will include the following: 
 Number of attacks requiring attack medication  
•
 Duration of attacks 
•
 Severity of attacks 
•
 Attack onset relative to the time of last dose of study drug 
•
 Discontinuations due to lack of efficacy 
•
 Symptoms and anatomical locations of attacks 
•
 Number of emergency room visits and/or hospitalizations 
•
7.2.3. 
Safety Endpoints 
Safety endpoints will include the number and proportion of subjects: who discontinue due to a 
treatment-emergent AE; who experience a treatment-emergent serious adverse event (SAE); who 
experience a Grade 3 or 4 treatment-emergent AE; and who experience treatment emergent 
Grade 3 or 4 laboratory abnormalities. 
7.2.4. 
Other Secondary Endpoints 
Other secondary endpoints will include quality of life scales, as measured by the Angioedema 
Quality of life (AE-QoL) (Weller, Groffik et al. 2012) and Depression, Anxiety, Stress Scales 
(DASS) (Crawford and Henry 2013). In addition, serial PK parameters and PD endpoints will be 
reported.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Approximately 58 to 90 subjects are planned to be randomized and enrolled in this study: up to 
36 subjects in Part 1 (350 mg or placebo) and approximately 14 subjects in Part 2, approximately 
20 subjects in Part 3, and approximately 14 or 20 subjects in Part 4 (number predicated on results 
from 62.5 mg BCX7353 Treatment Group in Part 3). In the event that the active study drug dose 
is modified in Part 1 to 250 mg, up to 36 additional subjects may be enrolled into Part 1 (see 
Section 9.5.2) for a total of 126 subjects enrolled in this study (78 to 84 subjects receiving active 
study drug). 
Subjects who withdraw from the study may be replaced at the Sponsor’s discretion. Any subject 
that has withdrawn from the study as a result of a treatment-emergent AE (regardless of severity 
or causality) may not be replaced. 
The following inclusion and exclusion criteria will be used to screen subjects for the study. 
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. Able to provide written, informed consent 
2. Males and non-pregnant, non-lactating females age 18 to 70 years 
3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2 as documented at any 
time in the medical records or at the screening visit by a low C1 INH functional level 
(Type 2) or a low C1 INH antigenic level (Type 1) 
4. A documented HAE attack rate of at least 2 HAE attacks per month for 3 consecutive 
months (defined as 93 days) within the 6 months prior to the screening visit as 
documented in acceptable source records.  
Source records of historical HAE attacks must exist (for all subjects) that permit a qualifying 
HAE attack rate to be calculated. Any of the following will be acceptable source records of 
HAE attacks: clinic notes with a numerical rate of attacks, acute attack medicine 
administration records, or a historically-completed subject record of attacks. This record 
should indicate the dates of attacks, at a minimum. 
 
NOTE: under no circumstances can the attack criterion threshold for enrollment be disclosed 
to any subject 
5. Access to and ability to use 1 or more acute medications approved by the relevant 
competent authority for the treatment of attacks of HAE (icatibant, plasma-derived C1 
INH or recombinant C1 INH).  


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6. Female participants must meet at least 1 of the following requirements: 
a. Be a woman of childbearing potential (defined as a nonmenopausal 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) 
 progesterone-only (implantable or injectable only) hormonal contraception 
associated with inhibition of ovulation initiated at least 60 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 screening 
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. 
b. Be a woman of nonchildbearing potential (defined as postmenopausal for > 2 years or 
having a screening FSH > 40 mIU/mL if postmenopausal ≤ 2 years or have had a 
hysterectomy, bilateral oophorectomy, or documented ovarian failure). 
c. Be a woman declaring herself as either sexually abstinent or exclusively having 
female sexual partners. Abstinence in this study is defined as "true abstinence: when 
this is in line with the preferred and usual lifestyle of the subject."  
7. Male subjects must comply with the following requirements during the study and for a 
duration of 90 days after last dose of study drug: 
a. Subjects with female partners of childbearing potential (defined as postmenopausal 
≤ 2 years or a nonmenopausal female who has not had a hysterectomy, bilateral 
oophorectomy, or documented ovarian failure) must agree to utilize at least 1 
acceptably effective contraceptive method. At least 1 or more of the following 
methods are acceptable:  
 surgical sterilization (i.e., vasectomy or bilateral tubal occlusion of a female 
partner) 
 placement of an IUD or IUS 
 any form of hormonal contraception (oral, implantable, injectable, intravaginal, or 
transdermal) 
 use of a condom with or without spermicidal foam/gel/film/cream/suppository 


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 partner’s use of an occlusive cap [diaphragm, or cervical/vault caps] with spermicidal 
(foam/gel/film/cream/suppository)  
b. Male subjects who declare themselves as sexually abstinent are acceptable for the 
purposes of this study. Abstinence in this study is defined as “true abstinence: when 
this is in line with the preferred and usual lifestyle of the subject.”  
c. Male subjects who exclusively have male partners must consent to using a condom 
during intercourse throughout the duration of the study. 
d. Must abstain from sperm donation during the study and for a period of 90 days after 
last dose of study drug. 
8. Any concomitant medication not stated as prohibited must be anticipated to be continued 
through the entire study and be of a stable dose and regimen for the duration of the entire 
study.  
9. In the opinion of the Investigator, the subject is expected 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 from the screening visit through 
randomization, including diary recording of HAE attacks beginning at the screening visit. 
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. Any clinically significant medical or psychiatric condition or medical history that, in the 
opinion of the Investigator or Sponsor, would interfere with the subject’s ability to 
participate in the study or increases the risk to the subject of participating in the study.  
2. Dementia, altered mental status, or any psychiatric condition, or stay in an institution 
further to an official or court order that would prohibit the understanding or rendering of 
informed consent or participation in the study. 
3. Use of C1 INH, androgens, or tranexamic acid for prophylaxis of HAE attacks within 
the 7 days prior to the screening visit or initiation during the study. Androgen use is not 
permitted at any time during the study. Use of a C1 INH therapy for treatment of attacks 
is not excluded at any time. 
4. Clinically significant abnormal ECG at the screening visit. This includes, but is not 
limited to, a QTcF > 470 msec, a PR > 220 msec, or ventricular and/or atrial premature 
contractions that are more frequent than occasional, and/or as couplets or higher in 
grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any 
other cardiovascular abnormality. 
6. Known family history of sudden death from causes other than HAE.  
7. History of or current implanted defibrillator or pacemaker. 


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8. Any abnormal laboratory or urinalysis parameter at screening that, in the opinion of the 
Investigator, is clinically significant and relevant for this study. A calculated CLcr (see 
Section 11.1.6) of ≤ 60 mL/min or AST or ALT value ≥ 2 times the upper limit of the 
normal reference range value obtained during screening is exclusionary.  
9. Suspected C1INH resistance in the opinion of the Investigator and Sponsor. 
10. History of alcohol or drug abuse within the previous year prior to the screening visit, or 
current evidence of substance dependence or abuse (self-reported alcoholic intake 
> 3 drinks/day). 
11. Positive serology for human immunodeficiency virus (HIV) or active infection with 
hepatitis B virus (HBV) or hepatitis C virus (HCV). 
12. Pregnant, planning to become pregnant within 30 days of the study, or nursing. 
13. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a 
prescription). 
14. History of severe hypersensitivity to any medicinal product. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Subject Discontinuation from Study  
Participation in the study is strictly voluntary. The only reason permitted for withdrawal from the 
study is a subject’s withdrawal of consent to contribute additional study information. A subject 
who withdraws consent prior to study completion will be requested to attend an early termination 
visit to complete all end-of-study evaluations. In all cases, the reason for withdrawal must be 
recorded in the subject’s medical records (source documents) and also in the electronic case 
report form (eCRF). 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.  
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 may be withdrawn from study drug for any of the following bulleted reasons, which 
will be recorded in the source documents and eCRF. In all cases, subjects who discontinue study 
drug will be requested to complete all regularly scheduled visits and procedures outlined in 
Table 3. 
 Emergence of any laboratory abnormality or adverse event 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 
 Intercurrent illness that would, in the judgment of the Investigator, affect assessments 
•
of clinical status to a significant degree 


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 Subject noncompliance with study drug or to the protocol 
•
 Discontinuation at the request of the Sponsor, competent authorities in the Member 
•
State(s) concerned, or the institutional review board (IRB)/independent ethics 
committee (IEC)  
8.3.2.1. 
Discontinuation Due to QT Prolongation 
Any subject will be discontinued from further study drug dosing if the following QTcF criteria 
are met: 
 The subject has a QTcF > 500 msec  
•
or  
 The subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
•
from the mean QTcF value obtained from triplicate ECGs obtained predose on Day 1.  
8.3.2.2. 
Discontinuation Due to Rash 
Subjects who experience a Grade 2 or Grade 3 rash thought to be due to study drug will be 
discontinued from study drug and treated according to best medical practice. This may vary 
depending on the type of rash or reaction noted. All subjects with a suspected drug rash should 
undergo specific rash evaluation as described in Section 11.1.12. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
BCX7353 is an oral small molecule inhibitor of plasma kallikrein. All subjects will receive 
28 days of BCX7353 capsules or matching placebo for oral administration at one of the 
following doses:  
 BCX7353 placebo QD orally (Parts 1, 2, 3 and 4) 
•
 BCX7353 350 mg QD orally (Part 1) 
•
 BCX7353 250 mg QD orally (Parts 2 and 3) 
•
 BCX7353 175 mg QD orally (Part 4, if conducted) 
•
 BCX7353 125 mg QD orally (Parts 2 and 3) 
•
 BCX7353 62.5 mg QD orally (Part 3; Part 4 if conducted) 
•
 
The study drug in this study consists of BCX7353 and placebo capsules. The active ingredient 
for this study is BCX7353, supplied by BioCryst. BCX7353 is a white to tan powder. 
The BCX7353 capsules will be provided as hydroxypropyl methylcellulose (HPMC), size 00, 
opaque capsules. In Parts 1 and 2, capsules will be filled with drug substance to correspond to 
one-third of the total daily assigned treatment dose. Three capsules of BCX7353 will be 
administered orally QD for 28 days. In Parts 3 and 4, capsules will be filled with drug substance 
to correspond to one-half of the total daily assigned treatment dose. Two capsules of BCX7353 
will be administered orally QD for 28 days.  
The matching placebo will also be provided as HPMC, size 00, opaque capsules to match the 
BCX7353 capsules. The matching placebo will contain microcrystalline cellulose. Three 
capsules (Parts 1 and 2) or two capsules (Parts 3 and 4) of matching placebo will be administered 
orally QD for 28 days. 
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. 
Parts 1 and 2: The study drug will be packaged in bottles of 27 capsules per bottle and each kit 
will contain 2 bottles of study drug.  
Parts 3 and 4: The study drug will be packaged in bottles of 32 capsules per bottle and each kit 
will contain 1 bottle of study drug.  
Each kit will be labeled with the information required per local law and may include: Sponsor 
name, study protocol number, description of the contents, a statement regarding the 
investigational (clinical trial) use of the study drug, expiry date and kit treatment number. 
Study drug will be stored between 15°C−25°C (room temperature). 


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Further details on the study drug will be provided in the study drug manual. 
9.3. 
Blinding and Randomization 
9.3.1. 
Blinding 
This is a double-blind study. As such, study drug assignment will be blinded to the Investigator, 
study staff, study subjects, and clinical research organization (CRO) staff. Sponsor employee(s) 
will also be blinded to the treatment allocation of individual subjects, with the exception of 
Sponsor staff responsible for managing clinical supplies. Employees who are not blinded to drug 
assignment will have no access to any other subject-level information for the duration of the 
study.  
In order to make informed decisions about the conduct of the study after 24 subjects complete 
dosing in Part 1, Sponsor employees not regularly interacting with site staff may be unblinded at 
the time that the data package is available for review at the administrative interim analysis. 
Likewise, Sponsor employees may be unblinded at any time after the administrative interim 
during completion of Part 1 to enable decisions about initiation of or continued enrollment into 
Part 2. 
9.3.2. 
Randomization 
Up to 36 subjects will be randomized in Part 1 in 1:1 (placebo:active) ratio to one of the 
following treatments: 
• Part 1, Treatment Group 1: placebo QD orally for 28 days  
• Part 1, Treatment Group 2: 350 mg BCX7353 QD orally for 28 days 
In Part 2, approximately 14 subjects are planned to be randomized in a 1:3:3 
(placebo:active:active) ratio into 1 of the following 3 treatment groups:  
 Part 2, Treatment Group 1: placebo QD orally for 28 days 
•
 Part 2, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 Part 2, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days 
•
In Part 3, approximately 20 subjects are planned to be randomized in a 1:3:3:3 (placebo: active: 
active: active) ratio into 1 of the following 4 treatment groups:  
 Part 3, Treatment Group 1: placebo QD orally for 28 days 
•
 Part 3, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
•
 Part 3, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days  
•
 Part 3, Treatment Group 4: 62.5 mg BCX7353 QD orally for 28 days 
•
In Part 4, if conducted, approximately 14 subjects are planned to be randomized in a 1:6 
(placebo:active) ratio into 1 of the following 2 treatment groups: 
• Part 4, Treatment Group 1: placebo QD orally for 28 days 
• Part 4, Treatment Group 2: 175mg BCX7353 QD orally for 28 days 


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OR the Alternative Part 4, if conducted, approximately 20 subjects are planned to be randomized 
in a 1:6:3 (placebo:active:active) ration into 1 of the following 3 treatment groups: 
• Part 4, Treatment Group 1: placebo QD orally for 28 days 
• Part 4, Treatment Group 2: 175mg BCX7353 QD orally for 28 days 
• Part 4, Treatment Group 3: 62.5mg BCX7353 QD orally for 28 days 
In all study parts, randomization will proceed in accordance with a computer-generated 
randomization schedule prepared by a nonstudy statistician. 
A subject will be randomized by the Sponsor or designee during the screening period. Subject 
randomization will occur only after: 
•  Entry of the following data into the eCRF: qualifying historical HAE attack data, 
concomitant and past medications, historical C1 INH functional and antigenic assay 
results (if available), and the data collected on the HAE medication and medication 
history form.  
AND 
• 
Sponsor review of eligibility of potential subjects based upon the entered eCRF data and 
any subsequent follow-up necessary with the Investigator or clinical site.  
Subject randomization will trigger shipment of a study drug kit (used for 14 days) to the site. 
Specific details of the randomization and kit shipment processes will be communicated to the 
sites. 
A study drug kit will contain sufficient treatment for 14 days (including overage to cover the 
visit window) and each subject will initially be assigned a drug kit to cover the first 14 days of 
treatment. Each subject will be assigned a total of 2 drug kits.  
Information on unblinding in the event of a SAE is provided in Section 12.1.9. 
9.4. 
Study Drug (Investigational Medicinal Product) Administration and 
Treatment Compliance 
Subjects will take all study drug doses at home with the exception of study drug that will be 
administered under Investigator (or designee) supervision during scheduled on-treatment clinic 
visits on Days 1, 14 and 15 (and Day 28 if applicable). Subjects will be instructed to take 
3 capsules (Parts 1 and 2) or 2 capsules (Parts 3 and 4) of study drug orally QD in the morning 
for 28 days. Subjects will be instructed to take study drug with food, or within 30 minutes after 
consuming food. On Days 1, 14 and 29, subjects should fast for 8 hours prior to their blood draw 
for laboratory testing.  
The first dose of study drug will be administered in the clinic on Day 1. For study Days 14 and 
15, subjects should be instructed to refrain from taking study drug prior to their visit to obtain a 
trough and/or serial blood draws at steady state.  
On in-clinic dosing days (Days 1, 14 and 15), subjects will be required to consume food within 
30 minutes prior to dosing (but after any blood draws for safety laboratory testing); the 
requirements for type and amount of food is to be provided to the subject (e.g., number of 


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servings of protein, carbohydrate, and/or fat) will be communicated in a separate document. On 
all other days, subjects should take the study drug in the morning with food (or within 
30 minutes after consuming food). It is recommended that the study drug be administered with 
food in order to help minimize gastrointestinal effects. If gastrointestinal-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 the standing regular dosing schedule on the next day. 
Subjects will be instructed to record in their diary the time of day study drug was taken, and the 
number of capsules of study drug taken.  
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. 
9.5. 
Study Drug Dose Modification 
9.5.1. 
Subject-Level Dose Modification 
Subjects should be instructed to take the study drug dose and regimen as indicated by the 
protocol. No dose reductions are allowed on a subject-level basis. Temporary treatment 
interruptions may be permissible on a case-by-case basis in consultation with the Sponsor (see 
Section 12.1.8). 
9.5.2. 
Part-Level Dose Modification 
If the prevalence of gastrointestinal effects prevents full enrollment of Part 1 or study drug is 
poorly tolerated due to gastrointestinal effects, the Sponsor may reduce the Part 1 dose of 
BCX7353 to 250 mg QD for all future subjects randomized to active drug. Poor tolerability may 
be defined as prevalent mild events that affect quality of life. The data monitoring committee 
(DMC) will be convened to review gastrointestinal effects meeting the criteria outlined in 
Section 12.2. 
A decision to reduce the Part 1 active dose to 250 mg QD will be communicated in writing to all 
sites with a date of implementation for newly enrolled subjects. Subjects in the 28-day treatment 
period at the time of implementation will continue on the study drug they received beginning on 
Day 1. Up to 36 subjects may be treated at 250 mg or placebo QD (1:1 ratio) in Part 1, regardless 
of the number of subjects previously randomized to 350 mg or placebo QD in Part 1.  
Any dose level changes warranted for Parts 2, 3 or 4 will be instituted via protocol amendment. 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability 
Accountability of returned drug kits will be performed by site personnel at study visits on 
Days 14 and 29. Returned drug kits must be retained and reviewed during monitoring visits by 
the clinical research associate (CRA, Section 14.2). 


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The Investigator/pharmacist must maintain accurate records of the disposition of all IMPs 
received from the Sponsor, issued to the subject (including date), and any drug accidentally 
destroyed. The Sponsor will supply a specific drug accountability form. At the end of the study, 
information describing study drug supplies (e.g., kit numbers) and disposition of supplies for 
each subject must be provided, signed by the Investigator or designee, and collected by the study 
monitor. If any errors or irregularities in any shipment of study medication to the site are 
discovered at any time, the CRO Project Manager and/or Sponsor must be contacted 
immediately. 
At the end of the study or at other times as agreed by all involved parties, all medication not 
dispensed or administered will be collected with supervision of the CRA and returned to the 
Sponsor (or designee) or destroyed on site as dictated by the appropriate Standard Operating 
Procedure at the participating institution.  
9.7. 
Concomitant Medications 
All subjects in the study must refrain from taking prohibited concomitant medications as outlined 
in Section 9.7.1.  
Any concomitant medication not listed as prohibited must be anticipated to be continued through 
the study and be of a stable dose and regimen for the duration of the study. 
Details of all prior (within 60 days of screening) and concomitant medication use, including all 
medications administered for the treatment of AEs, will be recorded in the source 
documentation/eCRF.  
9.7.1. 
Prohibited Medications 
The following medications are prohibited in advance of screening through completion of the 
study given the potential for modulation of HAE attacks and/or exacerbation of HAE: 
1. Use of C1 INH, androgens, or tranexamic acid for prophylaxis of HAE attacks within the 
7 days prior to the screening visit or initiation during the study. Androgen use is not 
permitted at any time during the study. Use of a C1 INH therapy for treatment of attacks 
is not excluded at any time. 
2. Use of an estrogen-containing hormonal contraceptive within 60 days of the screening 
visit or initiation during the study. 
3. Initiation of a progesterone-containing hormonal contraceptive within 60 days of the 
screening visit or initiation during the study. Progesterone eluding IUDs may be placed at 
any time. Conversion from an oral progesterone contraceptive that inhibits ovulation to 
an injectable or implantable progesterone contraceptive is allowed up to 1 week prior to 
study drug initiation.  
4. Use of an angiotensin-converting enzyme inhibitor at screening or initiation during the 
study.   
The following are prohibited medications based upon nonclinical data generated with BCX7353: 
1. Daily use of a medication that is clinically known to induce or inhibit drug transporters P-
gp or BCRP 7 days prior to Day 1 or initiation during the study. 


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An updated list of such medications can be found at: 
http://dbts.ucsf.edu/fdatransportal/transporters/ABCB1/ and 
http://dbts.ucsf.edu/fdatransportal/transporters/ABCG2/; see clinical drug-drug 
interactions, Interacting Drug column.  
2. Daily use of a medication that primarily relies upon BCRP or P-gp transport proteins for 
systemic disposition 7 days prior to Day 1 or initiation during the study. 
An updated list of such medications can be found at: 
http://dbts.ucsf.edu/fdatransportal/transporters/ABCB1/ and 
http://dbts.ucsf.edu/fdatransportal/transporters/ABCG2/; see clinical drug-drug 
interactions, Affected Drug column.  
3. Use of a medication that is clinically known or possibly to prolong the QT interval 7 days 
prior to Day 1 or initiation during the study. 
Medications falling into the drugs with a known risk of torsades de pointes, drugs with a 
possible risk of torsades de pointes are listed at:  
https://www.crediblemeds.org/index.php/?cID=328 (please note this website requires 
registration) 
4.   Daily use of a medication that primarily relies upon (ie is a substrate for) CYP2C9,  
      CYP2C19, CYP2D6 and CYP3A4 for metabolism 7 days prior to Day 1 or initiation  
      during the study.   
A list of medications can be found at: http://medicine.iupui.edu/clinpharm/ddis/clinical-
table; see substrate columns for the previously named CYPs. Please also note that 
desogestrel is a CYP2C substrate. Subjects who take a desogestrel-based contraceptive at 
screening may switch to an injectable or implantable progesterone-only contraceptive at 
any time prior to randomization. 
A drug interaction study designed to elucidate the clinical relevance of the nonclinical 
CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition data with BCX7353 is 
imminently planned for dosing. If the results of this study indicate that one or more CYP 
enzymes are not clinically inhibited by BCX7353, the medications metabolized by the 
unaffected CYP will no longer be prohibited for use on study.  A memo outlining the 
findings and impact on prohibited medications will be sent to each study Investigator. 
In addition, current participation in any other investigational drug study or having received 
another investigational drug within 30 days of the screening visit is prohibited. 
9.7.2. 
Other Restrictions 
Subjects will abstain from all bergamottin containing fruits and fruit juices (e.g., Seville oranges, 
grapefruit, grapefruit juice, pomelos, marmalade) from 7 days prior to Day 1 through the last 
follow-up visit. 
 


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10. 
STUDY CONDUCT 
10.1. 
Overview 
This is a randomized, placebo-controlled study. A subject’s participation in this study is expected 
to be up to 65 days (inclusive of the screening and follow-up periods). Each eligible subject who 
consents to participate in the study will receive either 28 days of BCX7353 or placebo. All 
subjects will undergo a screening period of up to 21 days and a 16-day follow up period. During 
the 28-day dosing period, all subjects will be required to attend 6 visits: Day 1, Day 14 (safety, 
PK, and PD assessments), Day 7 and 21 (liver function assessment, AE, concomitant medication 
and diary compliance assessments), Day 15 (24-hour PK visit), and a final visit on the day 
following cessation of dosing, Day 29. All subjects will return for a follow-up visit on Day 44.  
10.2. 
  Schedule of Assessments 
The schedule of assessments for this study is summarized in Table 3. 
 


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Table 3: 
Schedule of Assessments for Study BCX7353-203 
Assessment 
Screening 
Baseline 
Day 1u 
 
Follow-up  
(or Early 
Term [ET]) 
Day  
−21 to −1 
Day 1 
Pre-
Dose 
Day 1 
Post-
dose 
Day 7 
± 1 days 
Day 14 
± 2 days 
Day 15t 
Pre-dose 
Day 21   
± 1 days 
Day 29 
+ 1 day 
Day 44 
+ 7 days 
Informed consenta 
X 
 
 
 
 
 
 
 
 
Clinic visitb 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/ Exclusion criteria & prohibited 
medications 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
HAE medical and medication history 
X 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
Xd 
 
 
Xd  
 
 
Xd 
Xd 
Drugs of abuse screene 
X 
 
 
 
 
 
 
 
 
HIV/HCV/ HBV serology 
X 
 
 
 
 
 
 
 
 
C1 INH antigenic and/or functional levelf 
X 
X 
 
 
 
 
 
X 
 
Physical examinationg 
X 
Xg 
 
 
Xg 
 
 
Xg 
Xg 
12-lead ECGh 
X 
X 
 
 
X 
 
 
X 
X 
Vital signsi 
X 
X 
 
 
X 
 
 
X 
X 
Pregnancy testj 
X 
X 
 
 
X 
 
 
X 
X 
FSHk 
X 
 
 
 
 
 
 
 
 
DLCO 
X 
 
 
 
 
 
 
Xl 
 
Chemistry, hematology and coagulation 
laboratory evaluationse 
X 
X 
 
 
X 
 
 
X 
X 
Liver Function Teste 
 
 
 
X 
 
 
X 
 
 
Troponin I & Troponin T 
 
X 
 
 
X 
 
 
X 
X 


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Assessment 
Screening 
Baseline 
Day 1u 
 
Follow-up  
(or Early 
Term [ET]) 
Day  
−21 to −1 
Day 1 
Pre-
Dose 
Day 1 
Post-
dose 
Day 7 
± 1 days 
Day 14 
± 2 days 
Day 15t 
Pre-dose 
Day 21   
± 1 days 
Day 29 
+ 1 day 
Day 44 
+ 7 days 
C3 
 
X 
 
 
 
 
 
 
 
HLA typingm 
 
X 
 
 
 
 
 
 
 
Optional sample for possible exploratory 
pharmacogenomic testingv 
 
X 
 
 
 
 
 
 
 
NGAL 
 
X 
 
 
X 
 
 
X 
X 
CK-MB 
 
X 
 
 
X 
 
 
X 
X 
Urinalysise 
X 
X 
 
 
X 
 
 
X 
X 
Attack frequency confirmation 
X 
 
 
 
 
 
 
 
 
Sponsor approval and randomizationn 
X 
 
 
 
 
 
 
 
 
HAE attack and dosing diary 
instruction/review/collectiono 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary completionp 
 
AE-QoL and DASS 
 
X 
 
 
Xx 
 
 
X 
 
Plasma for PK analysisq 
 
X 
 
 
Xt 
Xt 
 
X 
 
Plasma for kallikrein inhibitionq 
 
X 
 
 
Xt 
Xt 
 
X 
 
Plasma for additional PD analysisr 
 
X 
 
 
X 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
study drug accountability/dispensing 
 
 
X 
 
Xw 
 
 
X 
X (ET) 
study drug dosings 
 
 
 
 
a Signing of the main informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures are 
performed. Subjects will also be asked to sign a separate consent form permitting collection of a blood sample at baseline for possible exploratory 
pharmacogenomic analysis (this consent form may be signed at any time during the study prior to drawing the sample).  


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b Clinic visits are scheduled for screening and Days 1, 7, 14, 21, 29, and 44. Additionally, a Day 15 visit for a 24-hour PK and PD sample post 14 dose will 
occur. If the subject is unable to provide serial PK samples on Day 14, steady state PK samples may be obtained on Day 28, with a 24-hour PK sample drawn at 
the scheduled visit on Day 29. d Weight only. 
e Analytes to be measured can be found in Table 4. Subjects are required to fast overnight for at least 8 hours prior to blood draw on Days 1, 14, and 29. 
f If no prior laboratory results confirming HAE diagnosis are available at screening, C1 INH level and function will be drawn. At baseline (Day 1) and Day 29, 
all subjects will have a sample for C1 INH function drawn. 
g Physical examinations conducted after the screening visit will be targeted to reported signs and symptoms. A complete physical examination will be performed 
at screening only. 
h Bedside 12-lead ECGs will be conducted in triplicate predose on Day 1; all other ECGs will be captured as single assessments. Any scheduled blood draws 
should occur after obtaining the ECG. Subjects should rest quietly for 10 minutes in a supine position prior to ECGs being performed. 
i Vital signs include measurement of heart rate, blood pressure and temperature. Temperature will be measured only at screening and on Day 1. 
j A serum pregnancy test will be administered to women of childbearing potential or who are postmenopausal ≤ 2 years at screening; all other pregnancy tests 
performed during the study may be urine pregnancy tests (for women of childbearing potential only). 
k  FSH will be measured in women declaring themselves postmenopausal ≤ 2 years. 
l   If the site cannot perform DLCO onsite, the Day 29 sample may also be assessed any time from Day 24 to Day 32. 
m A blood sample for HLA-typing will be drawn at the Baseline/Day 1 visit; if a blood sample is not obtained at Baseline, the sample may be drawn at any time  
    during the study. 
n Subjects will be randomized by the Sponsor on or after the screening visit and is contingent upon review of screening visit data entered into the eCRF 
subsequent questions the Sponsor may have (see Section 9.3.2). Randomization will trigger shipment of a kit of study drug for the first 14 days and an 
automatic resupply to arrive on-site at approximately study Day 10 after entry into the eCRF system that the subject has had a Day 1 visit. More details on 
randomization and kit shipment will be provided to the site. 
o The Investigator (or designee) will provide a diary for collection of HAE attacks (screening through follow-up) and study drug dosing (Days 1-28) at screening, 
Day 1, Day 14 and Day 29. Diaries will be collected on Day 1 (screening diary), Day 14, Day 29 and follow-up. At each visit and phone call, the Investigator 
(or designee) will review proper recording of attacks and dosing (as applicable) in the diary. 
p At any time the diary is in a subject’s possession, they will enter HAE attacks and relevant details and dosing information (as applicable) at least once per day. 
q On Day 14, a blood sample for plasma PK and plasma kallikrein analysis will be drawn prior to dosing (< 5 min) and at 1, 2, 3, 4, 5, 6, 8, and 24 hours postdose 
(i.e., on Day 15); Day 29 will be trough samples. If the subject is unable to provide serial PK samples on Day 14, steady state PK samples may be obtained on 
Day 28, with a 24-hour PK sample drawn at the scheduled visit on Day 29. In this case, trough PK samples will be drawn on Day 14. If the subject has a Day 
29 visit for the 24-hour PK sampling, concomitant medications and AEs should also be assessed at the visit. Within 6 hours postdose, an acceptable window 
around each PK draw is ± 10 minutes. After 6 hours, an acceptable window is ± 20 minutes. Plasma PK and plasma kallikrein samples will be collected prior to 
in clinic dosing on Day 1 and Day 14. The Day 29 samples will be collected approximately 24 hours post-last dose. 
r A sample for possible exploratory analysis used to elucidate PD properties of BCX7353 will be drawn. 
s Subjects will take their study drug in the clinic on Day 1, Day 14 and Day 15 (Day 28 if subjects must complete serial PK on the last dose). Subjects will take 
all other doses at home as instructed. The last day of study drug dosing is Day 28. 
t Subjects unable to undergo the serial PK blood draw on study Day 14 will only have a predose or trough blood sample drawn; a steady-state serial PK blood 
collection will then be obtained on Day 28 with a 24-hour blood draw conducted at the scheduled visit on Day 29. In the event the serial PK is not conducted on 
Day 14, the Day 15 visit is not required. 
u If the site is unable to conduct all procedures for an individual subject at Baseline on Day 1 because of logistical reasons, refer to Section 10.3.2 for procedures 
that may be conducted on Day −1. 


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v A blood sample for possible exploratory pharmacogenomic testing will be drawn at the Baseline/Day 1 sample only if consent is obtained for this optional 
testing; 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.  
w Study drug may be dispensed to the subject on Day 15 after in-clinic dosing in lieu of dispensing on Day 14 if preferred. 
x The AE-QoL questionnaire will not be administered at the Day 14 visit. 


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10.3. 
Study Visits 
10.3.1. 
Screening 
Prospective subjects should be screened within 21 days prior to Day 1. Written informed consent 
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 participation in the 
study will then undergo assessments at a screening visit to determine eligibility. Signing of the 
ICF may occur prior to the screening visit, which is defined as the visit where site-conducted 
screening procedures are performed.  
The Investigator (or designee) will conduct the following assessments at the screening visit, 
including:  
 Review of inclusion and exclusion criteria and prohibited medications 
•
 Review of HAE attack frequency documentation 
•
 HAE medical and medication history  
•
 Medical history  
•
 Complete physical exam 
•
 12-lead ECG  
•
 Height/weight/BMI estimation  
•
 Vital signs (blood pressure, heart rate and temperature) 
•
 Serum pregnancy test for female subjects of child-bearing potential 
•
 Blood collection for clinical chemistry, hematology, coagulation, HBV/HIV/HCV 
•
serology, C1 INH level and function (if no historical results), FSH (for women who 
declare that they have been post-menopausal ≤ 2 years) 
 DLCO testing (either at the screening visit or during the screening period [See 
•
Section 11.1.11]) 
 Urine collection for urinalysis and drugs of abuse screen 
•
 Recording of adverse events and concomitant medications  
•
 HAE attack diary provision and instruction 
•
 Signing of informed consent for collection of optional sample for possible 
•
exploratory pharmacogenomic analysis (baseline blood draw) 
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.   
A subject will be randomized during the screening period by the Sponsor (or designee). Subject 
randomization will occur only after entry of the required data obtained during the screening 
period into the eCRF (see Section 9.3.2) and any discussion the Sponsor feels is necessary with 


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the Investigator to ensure suitability of the screened subject for the study. Subject randomization 
will trigger shipment of a study drug kit (for the first 14 days) to the site so the study drug is 
available on site for the Day 1 Baseline visit.  
All screening procedures are outlined in Table 3 and are described in Section 11. Subjects will be 
given a subject HAE attack diary, and instructed how to record details of any angioedema attacks 
that occur (Section 11.2.2). Subjects will be asked to complete the diary once each day starting at 
the screening visit. 
If a subject does not initiate treatment within the 21 day screening window, all or part of the 
screening procedures may be repeated if the subject’s medical condition has changed, at the 
discretion of the Investigator, following discussion with the Sponsor. 
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 with the Sponsor. Any 
screening ECGs may be repeated if the results suggest operator or machine error. Retesting of 
specific laboratory tests within the screening period without entirely rescreening a subject is 
permitted.  
A reason for screen failure will be recorded in the screening eCRF for all subjects that do not 
enter the study. 
10.3.2. 
Baseline (Day 1) 
Subjects that meet all study eligibility criteria, are approved by the Sponsor, and who agree to 
participate will be asked to return for a scheduled Day 1 visit. Inclusion/ Exclusion criteria will 
be reviewed to ensure continued subject eligibility. Subjects should fast overnight for at least 
8 hours prior to the blood draw for the laboratory testing. 
Before any study drug is administered the following assessments will be completed: 
 Review of inclusion and exclusion criteria and prohibited medications 
•
 Review of medical history  
•
 Review and collection of diary entries during screening and further diary instruction 
•
 Review of concomitant medications  
•
 Administration of the AE-QoL and DASS questionnaires  
•
 Weight  
•
 Vital signs (heart rate, blood pressure, and temperature) 
•
 12-lead ECG (in triplicate) 
•
 Targeted physical exam  
•
 Assessment of any AEs that have occurred since the Screening visit 
•
 Urine collection for urinalysis and urine pregnancy test for female subjects of 
•
child-bearing potential 
 Blood collection for clinical chemistry, hematology, and coagulation 
•


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 Blood collection for C3, Troponin I and Troponin T, NGAL, and CK-MB and 
•
HLA typing 
 Optional blood collection for possible exploratory pharmacogenomic analysis (if 
•
consent was signed) 
 Plasma sample for additional PD analyses for possible exploratory analyses used to 
•
elucidate PD properties of BCX7353 
 Blood collection for C1 INH functional level 
•
 Subjects will consume food within 30 minutes prior to first dose (specifications as to 
•
type and amount of food is to be served will be communicated to each site in a 
separate document) 
 Predose blood samples for PK and plasma kallikrein inhibition testing 
•
The first dose of study drug will be administered and the following assessments will then be 
completed: 
 Dispensation of new HAE attack and dosing diaries and diary entry of dosing 
•
administration 
 Dispense study drug for Days 1 through the Day 14 visit 
•
 Review of concomitant medications and AEs 
•
Prior to discharge from the clinic the subject will be reminded to complete the Diary once each 
day for dosing and any HAE attacks that occur.  
If the site is unable to conduct all of the procedures for an individual subject at Baseline on 
Day 1 because of logistical reasons, the following procedures may be conducted on Day −1: 
review of inclusion and exclusion criteria, medical history, diary, and concomitant medications; 
administration of the AE-QoL and DASS questionnaires; weight, vital signs (heart rate, blood 
pressure, and temperature), and a 12-lead ECG (in triplicate) recording; conducting a targeted 
physical exam; assessment of any AEs that have occurred since the Screening visit; urine 
collection for urinalysis and urine pregnancy test for female subjects of child-bearing potential; 
blood collection for clinical chemistry, hematology, coagulation, C3, Troponin I and Troponin T, 
NGAL, CK-MB, and HLA typing; sample for optional possible exploratory pharmacogenomic 
analysis; plasma sample for additional PD analyses (e.g., a sample for possible exploratory 
analyses used to elucidate PD properties of BCX7353) and blood collection for C1 INH levels.  
10.3.3. 
Study Day 7 Visit 
Subjects are required to visit the clinic for the following assessments on Day 7 (± 1 day): 
 Blood collection for liver function tests 
•
 Review of concomitant medications and AEs 
•
 Review of HAE attack and dosing diary completion and study drug compliance 
•
 


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10.3.4. 
Study Day 14 Visit 
Subjects will return to the clinic during Week 2 (Study Day 14 ± 2 days). Subjects will be 
instructed not to take their dose of study medication before the study visit. Subjects should arrive 
in the clinic in a fasted state (8 hours from last ingestion of food). 
The following assessments will be performed: 
 Subject weight  
•
 Targeted physical examination   
•
 Vital signs (blood pressure and heart rate) 
•
 12-lead ECG (including review of QTcF to Baseline value) 
•
 Review of concomitant medications and AEs 
•
 Administration of the DASS questionnaires  
•
 Blood collection for clinical chemistry, hematology and coagulation 
•
 Urine collection for urinalysis and urine pregnancy test for female subjects of 
•
child-bearing potential 
 Blood collection for Troponin I and Troponin T, NGAL, and CK-MB 
•
 Plasma sample for additional PD analyses for possible exploratory analyses used to 
•
elucidate PD properties of BCX7353 
 Subjects will consume food within 30 minutes prior to dosing (specifications as to 
•
what and how much food is to be served [e.g., servings of protein, carbohydrate, 
and/or fat] will be communicated to each site in a separate document) 
 Collection and review of completed HAE attack and dosing diaries 
•
 Predose blood samples for PK (i.e., trough PK sample) and plasma kallikrein 
•
inhibition testing 
The last dose of study drug from the first assigned kit will be administered and the following 
assessments will then be completed: 
 Serial blood samples drawn for PK analysis and for plasma kallikrein inhibition as 
•
outlined in Section 11.1.13 and Section 11.1.14. 
 Dispensation of new HAE attack and dosing diaries 
•
 Recording of study drug dosing time in the diary 
•
 Study drug accountability and new study drug kit dispensing (unless held for Day 15 
•
dispensation) 
 Any further instruction on HAE attack and dosing diary completion and study drug 
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10.3.5. 
Study Day 15 
If the subject underwent serial PK blood draws on Day 14, the subject will return to the clinic to 
have blood drawn for a PK analysis sample and a plasma kallikrein inhibition sample 24 hours 
after the initial dose on Day 14. The subject will be instructed not to take their study drug prior to 
the blood draw. Subjects will consume food within 30 minutes prior to dosing (specifications as 
to what and how much food is to be served [e.g., servings of protein, carbohydrate, and/or fat] 
will be communicated to each site in a separate document). Study drug will be administered 
in-clinic; study drug dosing time will be recorded in the diary for Day 15 while the subject is 
in-clinic. If preferred by the subject and/or site, the new study drug kit assigned on Day 14 may 
be dispensed to the subject after dosing on Day 15. Review of concomitant medications and AEs 
will be performed. Subjects will also be reinstructed on HAE attack and dosing diary completion 
and study drug compliance. Concomitant medication, AE and diary review may take place post-
dose if desired by the site. 
10.3.6. 
Study Day 21 Visit 
Subjects are required to visit the clinic for the following assessments on Day 21 (± 1 day): 
 Blood collection for liver function tests 
•
 Review of concomitant medications and AEs 
•
 Review of HAE attack and dosing diary completion and study drug compliance 
•
10.3.7. 
Study Day 29 Visit 
Subjects who were unable to complete their steady state PK sampling at the Day 14 visit will 
undergo serial PK and PD assessments around the last dose (Day 28) visit with a 24-hour PK 
collection at the scheduled visit on Day 29; blood samples will be obtained as outlined in 
Section 11.1.13 and Section 11.1.14. AEs and conmeds will be collected and diary completion 
will be supervised should this visit occur. 
Subjects will return to the clinic on Day 29 (+ 1 day), timed preferably to capture a trough PK 
sample approximately 24 hours post-last dose. Subjects should arrive in the clinic in a fasted 
state (at least 8 hours from last ingestion of food). 
The following assessments will be performed: 
 Blood samples for PK and plasma kallikrein inhibition testing 
•
 Subject weight  
•
 Targeted physical examination   
•
 Vital signs (blood pressure and heart rate) 
•
 12-lead ECG 
•
 Review of concomitant medications and AEs 
•
 Collection and review of completed HAE attack and dosing diaries and dispensation 
•
of new diaries to be completed during follow-up 
 Administration of AE-QoL and DASS questionnaires  
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 DLCO testing* 
•
 Blood collection for clinical chemistry, hematology and coagulation 
•
 Urine collection for urinalysis and urine pregnancy test for female subjects of 
•
child-bearing potential 
 Blood collection for Troponin I and Troponin T, NGAL, and CK-MB 
•
 Plasma sample for additional PD analyses for possible exploratory analyses used to 
•
elucidate PD properties of BCX7353 
 Blood collection for C1 INH functional level 
•
 Study drug collection and accountability  
•
*Note: If DLCO testing cannot be conducted on site, the Day 29 DLCO test may be assessed any 
time from Day 24 to Day 32.  
10.3.8. 
Follow-up/Early Termination Visits 
Subjects who discontinue treatment early must continue to complete all regularly scheduled 
visits and procedures as outlined in Table 3. As indicated in Section 8.3.1, the only reason for 
withdrawal from the study is a subject’s withdrawal of consent. A subject who withdraws 
consent prior to study completion will be requested to attend a termination visit to complete all 
end-of-study evaluations. 
For all subjects who complete treatment the follow-up visit should be conducted on follow-up 
Day 44 (+ 7 days). Assessments to be performed at this visit are outlined in Table 3 and 
described in Section 11. In the event that there are clinically significant findings from safety 
assessments that are ongoing at follow-up Day 44, the subject will be followed at additional 
study visits until the findings are resolved or stabilized at a new baseline. 
The following assessments will be performed at the follow-up or early termination visit: 
 Subject weight  
•
 Targeted physical examination   
•
 Vital signs (blood pressure and heart rate) 
•
 12-lead ECG 
•
 Review of concomitant medications and AEs 
•
 Blood collection for clinical chemistry, hematology and coagulation 
•
 Urine collection for urinalysis and urine pregnancy test for female subjects of 
•
child-bearing potential 
 Blood collection for Troponin I and Troponin T, NGAL, and CK-MB 
•
 Study drug accountability (for subjects who discontinued treatment early) 
•
 Review and collection of the attack diaries  
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11. 
ASSESSMENTS 
The schedule of procedures/assessments to be conducted is outlined by study day in Table 3 with 
details on the conduct of the procedures/assessments provided below. 
11.1. 
Investigator-Completed Assessments 
Demographic information, including year of birth, sex, race or ethnicity, and medical and 
medication history will be captured for each subject participating in the study at the Screening 
visit. Medical history and review of inclusion and exclusion criteria and prohibited medications 
will also be rechecked before dosing on Day 1. Prior to dosing, laboratory samples should be 
obtained in the fasted state. Once blood samples are obtained, the investigator will need to ensure 
that the subject consumes food within 30 minutes prior to dosing and takes a PK sample where 
indicated within 5 minutes of dosing; all other assessments can occur in any order. After dosing 
PK sampling takes precedence and needs to be obtained at the specified time points as described 
in Section 11.1.13.  
11.1.1. 
Physical Examination 
A full physical examination should be conducted at Screening. All subsequent physical 
examinations may be targeted (ie, symptom-driven). Genitourinary and breast examinations may 
be omitted when not required by normal site practice. 
11.1.2. 
HAE Medical and Medication History 
A HAE medical history questionnaire provided by the Sponsor will be completed at screening. 
All questions should be completed by the Investigator (or designee) from historical source 
documentation when available, with subject input as necessary to complete the remaining 
questions. The completed HAE Medical History Questionnaire will be considered a source 
document and must be entered in the eCRF in full to enable randomization (see Section 9.3.2). 
11.1.3. 
Weight/Body Mass Index 
For determination of height and weight, subjects should be dressed, without shoes. Body mass 
index should be calculated using the following formula: 
 
BMI = weight (kg)/height (m)2 
11.1.4. 
12-lead Electrocardiograms 
A standard bedside 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 must rest 
quietly in a supine position for at least 10 minutes. 
Qualified site personnel should review the ECGs and automated findings in real-time for gross 
abnormalities and interval measurements of concern (absolute readings and for postdose ECGs, 
change from baseline). For all ECGs, the clinical interpretation of the ECG should be recorded 
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Baseline (predose) ECGs will be obtained in triplicate (i.e., 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.  
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 heart rate should be taken after the subject has rested 
in the supine position for at least 5 minutes. 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 blood pressure or ECG machine.  
Temperature will be obtained only at screening and Day 1 predose.  
11.1.6. 
Clinical Laboratory Assessments 
Blood and urine samples will be obtained per the schedule of events. Individual laboratory tests 
to be performed are provided in Table 4. Subjects should fast overnight for at least 8 hours prior 
to the blood draw for the laboratory testing on Days 1, 14, and 29. An overnight fast is not 
required for the blood draws for laboratory testing on Days 7 and 21. 
All laboratory samples will be analyzed by a centralized laboratory with the exception of urine 
pregnancy tests which will be assessed locally at the site. A laboratory reference manual will be 
provided to the site detailing kit contents, reordering supplies, sample collection, handling, 
storage and shipment instructions. 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 
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Table 4: 
Clinical Laboratory Evaluations 
Chemistry 
Hematology 
• Albumin 
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Bilirubin (total and direct) 
• Blood glucose (fasting) 
• Blood urea nitrogen (BUN) 
• Electrolytes (calcium, sodium, potassium, 
chloride, bicarbonate [CO2], phosphorus)  
• Lipid panel (total cholesterol, triglycerides) 
**Baseline and Day 29 visit only 
• Creatine kinase 
• Creatinine and calculated CLcr 
• Gamma-glutamyltransferase (GGT) 
• Lactate dehydrogenase (LDH) 
• Total serum protein 
• Uric acid 
• Amylase (reflex lipase if amylase > 2 × ULN) 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• MCH 
• MCHC 
• MCV 
• White blood cell count, with differential 
(lymphocytes, monocytes, neutrophils, 
eosinophils, and basophils) 
• Platelets 
Pregnancy Test 
Serum (screening) and urine (other scheduled visits) 
βHCG for women of childbearing potential only  
Drug screen 
• Amphetamines 
• Barbiturates 
• Benzodiazepines 
• Cocaine 
• Opiates 
• Methamphetamine 
• Ecstasy 
Urinalysis 
• Specific gravity 
• Blood  
• Bilirubin 
• Glucose  
• Leukocytes 
• Ketones 
• Nitrates 
• pH 
• Protein 
• Urobilinogen 
• Microalbumin to creatinine ratio 
• Reflex Microscopy if dipstick is abnormal  
Additional Tests 
• FSH for women postmenopausal ≤ 2 years 
• Hepatitis B surface antigen, Hepatitis C antibody, 
HIV antibody; if HCV antibody positive, reflex 
to HCV RNA testing 
• Troponin I 
• Troponin T 
• Neutrophil gelatinase-associated lipocalin 
(NGAL) 
• CK-MB 
• C3 
• HLA typing 
• Sample for possible exploratory 
pharmacogenomic analysis (optional) 
• C1 INH level and function 
Coagulation 
• Prothrombin time (PT) and international 
normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
Liver Function Tests 
• ALP 
• ALT 
• AST 
• Bilirubin (total and direct) 
• GGT 
 


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CLcr will be calculated using the Cockcroft-Gault formula and actual body weight (ABW): 
CLcr (mL/min) = (140 – age in years) × ABW (kg) (× 0.85 for females) 
72 × serum creatinine (in mg/dL) 
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 
Follicle stimulating hormone will be measured at screening in women declaring themselves 
postmenopausal ≤ 2 years to establish childbearing status. 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.  
A serum pregnancy test will be administered to women of childbearing potential or who are 
postmenopausal ≤ 2 years at screening; all other pregnancy tests performed during the study may 
be urine pregnancy tests (for women of childbearing potential only). A serum pregnancy test 
should immediately be drawn and sent for analysis for any positive urine pregnancy test. 
11.1.9. 
 C1 INH Testing 
If laboratory results confirming HAE diagnosis are not historically available, additional testing to 
determine C1 INH levels and function will be performed from a sample drawn at screening. 
C1 INH function will be measured from samples taken on all subjects at Day 1 and Day 29.  
11.1.10. 
Other Laboratory Assessments 
Troponin I, Troponin T, NGAL and CK-MB will be measured in this study at the following time 
points: Day 1, Day 14, Day 29, and follow-up/early termination. C3 level will be taken at 
Baseline only unless required for AE assessment (see Section 12.2.1). 
11.1.11. 
Pulmonary Diffusion 
Pulmonary diffusion testing, which can measure clinically significant thickening of the capillary 
alveolar space, will be required for all subjects. Testing will be conducted at the screening and 
Day 29 visits. If the site cannot perform this procedure onsite, an offsite provider may be used. 
The procedure will be done according to the specific protocol of the pulmonary lab performing 
the assessment. If the site cannot perform the DLCO onsite, the screening assessment can occur 
anytime before baseline, and the Day 29 assessment may be assessed any time between Day 24 
and Day 32. 
Findings from the screening DLCO will not be used to establish study eligibility. However, the 
results should be reviewed (with documentation of review) by the Investigator before dosing to 
ensure no underlying medical conditions, that, in the opinion of the Investigator, would interfere 
with the subject’s safety or ability to participate in the study. 
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11.1.12. 
Rash Assessment 
Because of the potential for a study drug-related rash (see Section 5.3), all sites are required to 
have the ability to obtain high resolution photographs and obtain an appropriate skin biopsy. 
These can be performed by experienced site physicians or a dermatologist on retainer for this 
study.  
Subjects should be medically evaluated within 24 to 36 hours of awareness of any treatment-
emergent rash, regardless of grade or causality and the site must inform the Sponsor medical 
monitor at the time a rash is diagnosed (Section 12.1.5.1). In the event the site is notified of a 
rash on the weekend, the medical evaluation and Sponsor notification can be performed on the 
next working day.  
 
The following assessments must be completed for all subjects with a rash assessed as possibly, 
probably or definitely related to study drug by the Investigator 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 blistering and if present, its 
extent and presence or absence of mucosal involvement and if present, its extent and 
any other associated abnormal physical findings. 
 High resolution photographs taken to provide both detail regarding the rash and 
•
details regarding the extent of the rash. 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. 
 Blood taken for chemistry, hematology including differential, and C3 level 
•
 Urine sent to local laboratory for urine eosinophils (if evaluation is available locally) 
•
 All detailed clinical information regarding the rash, examination, clinical and 
•
laboratory assessments, treatment and interpretation of the event needs to be reported 
on an SAE/Event of Special Interest Report form as per Section 12.1.5.1.  
 Subjects will also be requested to donate a blood sample for peripheral blood 
•
mononuclear cells (PBMCs) for analysis of possible drug-specific immune responses 
and possible drug-responsive T-cells.  This sample should be obtained preferably 
1-3 months after occurrence of the rash. Information on PBMC collection, processing 
and shipment will be communicated to sites prior to sample collection.  
 
In addition, although not mandatory, it is requested that a biopsy of a fresh lesion both for 
diagnostic and scientific purposes be obtained in all subjects with a drug-related rash after 
obtaining specific informed consent for the biopsy. If the study site cannot perform a biopsy or 
any of the above mandatory assessments (i.e., photographs), then subjects should be referred 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, a full written consultation should be 
obtained expeditiously consisting of their exam findings and assessment. Subjects undergoing a 
biopsy will provide appropriate consent for both the procedure and the reporting of the biopsy 


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results to BioCryst. Biopsies should be at least 3 mm minimum diameter and submitted to a local 
pathologist as per the local lab standard practices.  
The time of each assessment described in this section, including any medications administered in 
the treatment of rash, must be denoted in the source records. 
11.1.13. 
Pharmacokinetics 
All plasma samples for determination of BCX7353 concentrations will be analyzed using a 
validated liquid chromatography-mass spectroscopy assay. Instructions for collection, 
processing, storage, and shipment of PK samples will be provided to the clinical site in the 
laboratory manual. Samples may also be analyzed on an exploratory basis for possible 
BCX7353-metabolites.  
On Day 14 serial blood samples will be drawn for PK analysis predose and at the following time 
points: 1, 2, 3, 4, 5, 6, 8, and 24 hours postdose. For the 24 hour postdose samples, subjects will 
return to the clinic and have the blood sample drawn prior to dosing on Day 15. On Day 29, a 
trough PK blood sample will be drawn.  
However, if the subject is unable to provide serial PK samples on Day 14, only the predose 
sample (i.e., trough PK sample) will be obtained on Day 14 and steady state serial PK samples 
will be obtained on Day 28, with a 24-hour PK sample drawn at the scheduled visit on Day 29. 
Within 6 hours postdose, an acceptable window around each PK draw is ± 10 minutes. After 
6 hours, an acceptable window is ± 20 minutes. Predose samples should be drawn within 
5 minutes of the next scheduled dosing time. 
Plasma BCX7353 PK parameters will be calculated as applicable, including the following: 
maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration versus time 
curve (AUC), and 24 hour half-life (t1/2) in plasma.  
Actual date and time of PK sample collection will be recorded in the eCRF. In addition, the site 
should verify that the time of last dose taken at home prior to the visit is documented in the diary. 
The lab performing bioanalytical analysis will be provided the randomization scheme. Two 
samples will ordinarily be analyzed for subjects randomized to placebo: the 4 hour postdose 
sample on Day 14 and the trough at Day 29. 
11.1.14. 
Pharmacodynamics 
On Day 1 and Day 14 a plasma sample for plasma kallikrein analysis will be drawn prior to 
dosing and, on Day 14, at 1, 2, 3, 4, 5, 6, 8, and 24 hours postdose. The Sponsor may waive the 
participation in any or all serial PD sampling on a case by case basis. A sample for plasma 
kallikrein analysis will also be drawn on Day 29. 
A plasma sample for possible exploratory analysis used to elucidate PD properties of BCX7353 
will be drawn on Day 1, Day 14, and Day 29.  
Instructions for collection, processing, storage and shipment of samples will be provided in a 
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11.1.15. 
HLA Typing 
All subjects will have a blood sample drawn at Baseline/Day 1 (or any other time point on study 
if not obtained at Baseline) for HLA-typing. 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. 
11.1.16. 
Possible Exploratory Pharmacogenomics Testing 
All subjects who are willing to participate and sign a separate informed consent will have a blood 
sample drawn at Baseline / Day 1(or any other time point on study if not obtained at Baseline) 
for possible exploratory pharmacogenomics testing. 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.  
11.2. 
Subject-Completed Assessments 
11.2.1. 
Quality of Life Questionnaires 
To assess quality of life, the AE-QoL and DASS questionnaires will be administered once at 
Baseline, Day 14 (DASS only) and at Day 29. 
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.  
11.2.2. 
HAE Attack and Dosing Diaries 
The Sponsor will supply paper diaries to all sites. Sites will dispense diaries to subjects at 
screening, Day 1, Day 14 and Day 29. Diaries will be collected on Day 1, Day 14, Day 29 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 daily, 
recalling whether symptoms of an HAE attack were experienced in the last 24 hours. Subjects 
must fill out the diary daily, regardless of the 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 symptoms of the attack, severity, and treatment(s) administered and times of 
administration. During the treatment period, subjects will also record the time of day study drug 
was taken, and the number of capsules of study drug taken at each dose in the diary on a daily 
basis. Study drug doses administered in the clinic will be entered into the diary on site.  
The Investigator (or designee) will proactively assess completion of the diary, during visits on 
Days 1, 7, 14, 21 and 29. 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/phone call 
based on outstanding questions a subject may have or incorrect assumptions/interpretation of 
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Further training on completing the diary should be provided at each clinic visit or where 
required, during a telephone call.   


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12. 
ASSESSMENT OF SAFETY 
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/ IMP 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 (e.g., requiring unscheduled diagnostic procedures or treatment 
measures, or resulting in withdrawal from the study) are considered to be AEs. 
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 clinical 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 
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, unless they meet the criteria for a SAE. HAE attacks and associated symptoms will be 
recorded in the subject’s diary. The events that may trigger a HAE attack such as an infection or 
trauma are considered AEs and should be reported as such. 
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 


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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. 
Adverse events are designated as “nonserious” or “serious.” 
12.1.1.2. Serious Adverse Event 
A SAE is an adverse event/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 
•
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. 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 any abortions (elective or spontaneous), fetal demise, and still 
birth to be serious adverse events for reporting purposes (see Section 12.1.6).  
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, nonserious treatment-emergent rashes will be considered events of special 
interest. This event in and of itself will not be considered serious unless it meets the criteria 
above. Events of rash regardless of severity or suspected relationship to study drug/IMP must be 
reported to the Sponsor Medical Monitor as described in Section 12.1.5.1. Management of rash 
possibly, probably or definitely suspected to be related to study drug/IMP, is provided in 
Section 12.2.1.  
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. All AEs and SAEs are to be reported on the AE eCRF.  


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AEs should be documented on eCRFs as Investigators become aware of them. AEs are to be 
followed until the event resolves. If an event is ongoing at the last follow-up 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/IMP (see Section 12.1.3 for AE grading). For all Grade 3 and 4 events or events 
deemed possibly, probably or definitely related to use of study drug/IMP, 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 fax or email, 
and entering the event onto the AE eCRF 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 
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 be sent to the Sponsor within 24 hours to ensure that the Sponsor shall have the necessary 
information to continuously assess the benefit-risk profile of the study drug/IMP in clinical trial. 
12.1.3. 
Definition of Severity 
All AEs will be assessed (graded) for severity and classified using the Division of Microbiology 
and Infectious Diseases (DMID) criteria for grading AEs (see Appendix 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. 
 


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12.1.4. 
Definition of Relationship to Study Drug (Investigational Medicinal Product) 
The Investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug/IMP 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/IMP and the event. 
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/IMP 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 study drug/IMP 
administration, abates upon discontinuation of the study drug/IMP, 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/IMP 
administration, follows a known or suspected response pattern to the study drug/IMP, 
is confirmed by improvement upon stopping the study drug/IMP (dechallenge), and 
reappears upon repeated exposure (rechallenge, if rechallenge is medically 
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 or fax using the SAE/Event of Special Interest report form within 24 hours of the 
Investigator’s awareness of the SAE. In addition, all SAEs must be recorded on the AE eCRF 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 addresses or fax numbers: 
Sylvia Dobo, MD, Medical Monitor 
Cell number (24 hours) +1 773-304-8942 
Email: safety@biocryst.com; sdobo@biocryst.com 
Safety Fax: +1 919-226-5888 
 
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/IMP in clinical trial, if the relevant 
information was not already available and provided in the initial report. 


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Investigators or designees at each site are responsible for retaining copies of all SUSAR reports 
(initial and follow-up) and other safety information (e.g., revised IB) in their files. 
BioCryst or its designee will submit all SUSAR reports (initial and follow-up) or other safety 
information (e.g., revised IB) to the IEC and central IRBs. 
BioCryst shall ensure that all relevant information about SUSARs that are fatal or life-
threatening is recorded and reported as soon as possible to all competent authorities, and to the 
IECs, and central IRBs, in any case no later than 7 calendar days after knowledge by BioCryst of 
such a case, and that relevant follow-up information is subsequently communicated within an 
additional 8 days. All other SUSARs shall be reported to the competent authorities concerned 
and to the IECs/IRBs concerned as soon as possible but in no case later than 15 calendar 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 treatment-emergent rash regardless of severity or suspected 
relationship to study drug/IMP must be reported by phone or email to the Sponsor Medical 
Monitor and in writing via email or fax using the SAE/Event of Special interest report form 
within 24 hours of the Investigator’s assessment of the event. 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/Event of Special 
Interest report form should be sent to the following email addresses or fax numbers: 
Sylvia Dobo, MD, Medical Monitor 
Cell number (24 hours) +1 773-304-8942 
Email: safety@biocryst.com; sdobo@biocryst.com 
Safety Fax: +1 919-226-5888 
 
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 event. This also allows the independent DMC to review the emerging 
safety data in real time. In addition, 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.  
The follow-up report should contain information about the clinical course, medical evaluation, 
photographs, biopsy, and laboratory results. 
12.1.6. 
Pregnancy 
Any female subject who becomes pregnant during the course of the study should have study 
drug/IMP discontinued immediately and must be followed through the end of the pregnancy. 
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 study partners will be obtained prior to reporting any 
details of the pregnancy. Information related to the pregnancy must be given on a “Pregnancy 
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pregnancy may be followed and an outcome determined. Any AEs or SAEs experienced by a 
pregnant subject are to be reported as directed 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 
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 
It is the responsibility of the Sponsor to notify the licensing authority of any serious breach 
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/IMP are permissible. Resumption of study drug/IMP administration is also 
permissible upon resolution of the event as assessed by the Investigator and provided 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/IMP 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 eCRF and source documents, including 
the reason for the interruption. 
12.1.9. 
Emergency Procedures 
Access to study drug/IMP assignment will be available if the Investigator deems it necessary to 
break the study blind in the interest of a subject’s medical safety, in case of a medical 
emergency, to meet regulatory reporting obligations, or if warranted during scheduled safety 
reviews. Where medically appropriate, the Investigator will contact the Sponsor Medical 
Monitor to discuss the situation which has arisen and resulted in the need for unblinding of the 
subject. The Sponsor Medical Monitor will not be involved in the decision to unblind. 
Detailed instructions for unblinding will be provided in a separate communication to the sites. 
12.2. 
Toxicity Management 
The Investigator (or qualified designee) will grade clinically significant events and laboratory 
abnormalities (if considered AEs) 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/IMP discontinuation, unless such a delay is not consistent with 
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In the event that 2 subjects experience similar Grade 3 or 4 treatment-emergent laboratory 
abnormalities or AEs that are suspected to be drug related as determined by the Investigator and 
not otherwise physiologically explained, a DMC meeting will be immediately convened by the 
Sponsor. 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  
Management of rash should be based on best medical practice and address the subject’s 
presentation. If a subject experiences a Grade 2 or higher rash suspected to be due to study 
drug/IMP, the subject should have study drug/IMP stopped as per Section 8.3.2.2. 
In the event that 2 subjects experience a rash that is suspected to be study drug/IMP related as 
determined by the Investigator and not otherwise physiologically explained, a DMC meeting will 
be convened by the Sponsor. 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. 
Special evaluation of drug rash is required as per Section 11.1.12 and special reporting is 
described in Section 12.1.5.1.  
12.2.2. 
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 the event that study personnel become aware of an overdose of study drug/IMP (> 3 capsules 
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 
An independent DMC will review safety data. The DMC will meet on a scheduled basis at least 
3 times: once after every 12 enrolled subjects have completed 28 days of dosing through Part 3 
of the study.  The DMC will also be convened at any time upon meeting the criteria listed in 
Section 12.2 or at other times as requested. A separate DMC charter, maintained in the trial 
master file, will describe membership, roles, timing of DMC review, and responsibilities of the 
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13. 
STATISTICS 
13.1. 
Sample Size Considerations 
Given that the BCX7353 response rate is unknown, the sample size was kept flexible to cover a 
range of response options that would achieve 90% power with an alpha of 0.05.  The study 
population is expected to have a mean baseline attack rate of 1 attack/week. The expected mean 
reduction in attack rate of 350 mg BCX7353 QD is at least 70%. The mean reduction in attack 
rate in the placebo group may be as high as 30%. Sample size sensitivity assessments provided in 
Table 5 and Table 6 are based on various BCX7353 and placebo responses and variability.   
Table 5: 
Power assessment based on sample size and on-study attack rate 
Placebo 
BCX7353 
Power 
Mean 
SD 
n 
Mean 
SD 
N 
0.7 
0.45 
12 
0.3 
0.3 
12 
68% 
0.7 
0.45 
12 
0.3 
0.45 
12 
55% 
0.7 
0.45 
18 
0.3 
0.3 
18 
86% 
0.7 
0.45 
18 
0.3 
0.45 
18 
74% 
0.8 
0.45 
12 
0.3 
0.3 
12 
86% 
0.8 
0.45 
12 
0.3 
0.4 
12 
79% 
0.8 
0.45 
12 
0.3 
0.5 
12 
69% 
0.8 
0.45 
18 
0.3 
0.3 
18 
97% 
0.8 
0.45 
18 
0.3 
0.4 
18 
93% 
0.8 
0.45 
18 
0.3 
0.5 
18 
87% 
Note: Calculations were based on a 2-sided test at significance level of 0.05 and rates and SD are expressed in units. 
 
Table 6: 
Power assessment based on sample size and attack free proportion  
Placebo 
BCX7353 
N 
Attack Free 
N 
70% Attack 
Free 
75% Attack 
Free 
80% Attack 
Free 
85% Attack 
Free 
12 
15% 
12 
85% 
91% 
95% 
98% 
12 
20% 
12 
76% 
84% 
91% 
95% 
12 
25% 
12 
67% 
76% 
84% 
91% 
18 
20% 
18 
90% 
95% 
98% 
99% 
18 
25% 
18 
83% 
90% 
95% 
98% 
18 
30% 
18 
73% 
83% 
90% 
95% 
Note: Calculations were based on a 2-sided test at significance level of 0.05. 


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13.2. 
Statistical Methods 
Subjects will be randomized in Part 1 in a 1:1 ratio to the 350mg BCX7353 QD and placebo QD 
treatment groups, in a 3:3:1 ratio to the 125 mg QD, 250 mg QD and placebo QD treatment 
groups in Part 2in a 3:3:3:1 ratio to the 62.5 mg QD, 125 mg QD, 250 mg QD and placebo QD 
treatment groups in Part 3. Part 4, if conducted and if excluding a 62.5 mg dose, will have 
subjects randomized in a 1:6 ratio to the placebo QD and 175 mg QD treatment groups. Part 4, if 
conducted and if including a 62.5 mg dose, will have subjects randomized in a 1:6:3 ratio to the 
placebo QD, 175 mg QD, and 62.5 mg QD treatment groups. , Subjects randomized to the same 
treatment will be pooled across all study parts and Treatment Group 4 (62.5mg QD) will be 
pooled with Part 3 and 4, if conducted, for the final analyses of efficacy, safety, PD and PK/PD 
where applicable. 
A detailed statistical analysis plan (SAP) will be developed and finalized prior to database lock 
at the conclusion of the study. The SAP will describe the methods of analyses/summaries, 
including all endpoints, time points, populations, missing data, etc. Any deviation from the 
analyses outlined in the SAP will be described in the final clinical study report. 
13.2.1. 
Interim Analyses 
There will be one planned administrative interim in Part 1 of the study, after 24 subjects 
complete through the Day 28 dose. Sponsor employees not interacting with the site will receive 
unblinded primary and secondary efficacy tables and statistical output, at a minimum. Ad hoc 
analyses to enable discernment of treatment differences between the study drugs may be 
requested. At the conclusion of the interim analysis, a decision will be made to either continue 
enrollment into Part 1 or to close Part 1 and initiate Part 2 (dose ranging). A continuation of 
Part 1 may include up to 12 additional subjects for a total of up to 36 subjects completing Part 1 
of the study. Additional administrative interim analyses will be conducted after completion of 
Parts 2 and 3 to support decision making for future development of the drug. 
13.2.2. 
Analysis Populations 
The analysis populations are defined below.   
13.2.2.1. Full Analysis Set  
The FAS population will include all subjects who are randomized, receive at least 1 dose of 
study drug, and have post baseline HAE diary data recorded. Subjects will be analyzed according 
to the randomized treatment. The FAS population will be the population for efficacy analyses. 
13.2.2.2. Safety Population 
The safety population will include all subjects who received at least 1 capsule of study drug. 
Subjects will be analyzed according to the treatment received. This population will be used for 
all analyses of accountability, demographics, BCX7353 drug concentrations, and safety. 
13.2.2.3. Pharmacokinetic Population 
The PK population will include all subjects for whom PK parameters can be estimated. The PK 
population will be the primary population for the PK analysis. 


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13.2.2.4. Pharmacodynamic Populations 
13.2.2.4.1. Plasma Kallikrein Inhibition 
The PD population for plasma kallikrein inhibition will include all subjects for whom at least 
1 pre- and postdose plasma kallikrein inhibition result can be estimated. This population will be 
used for all analyses of plasma kallikrein inhibition and for correlation with PK or BCX7353 
concentrations. 
13.2.2.4.2. C1 INH  
There will be 1 additional PD population, for C1 INH functional levels. This PD population will 
include all subjects with a baseline and at least 1 postdose value and will be the primary 
population for the relevant PD analyses. 
13.2.3. 
Subject Demographic and Disposition Data 
Demographic data and baseline characteristics including age, gender, race or ethnicity, height at 
screening, weight at screening and BMI at screening will be summarized by treatment group 
using descriptive statistics. 
Subject disposition will be presented for all subjects. The number of subjects who completed the 
study and 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 be presented for each treatment group. Treatment adherence, dose modifications 
and reason for dose modifications will be provided as summaries. 
13.2.4. 
Analysis of Efficacy Variables 
As discussed in Section 7.2.1, each subject-reported HAE attack must be confirmed by an 
independent adjudication panel prior to inclusion in any statistical analysis or summary of 
efficacy. 
There are no formal hypotheses planned for the study.  The primary efficacy endpoint is the 
number of confirmed HAE attacks in the FAS population. The number of HAE attacks will be 
analyzed by treatment group using appropriate descriptive statistics as follows:  weekly attack 
rate, counts of attacks, proportion of subjects with no attacks, and number of attack-free days. 
The relative change in attack rate from placebo will also be calculated for each active arm. 
Efficacy analyses will be conducted for HAE attacks reported over the entire dosing interval 
(Days 1 to 28 inclusive) and during the dosing period in which BCX7353 should be at 
steady-state conditions (Days 8 to 28, inclusive). 
Efficacy endpoints will be summarized and listed for each treatment group. Between-treatment 
comparisons (active vs placebo and between active dose groups) for continuous efficacy 
variables will be performed using an analysis of variance (ANOVA) and an analysis of 
covariance (ANCOVA) model. The between treatment comparisons for the proportion of 
subjects who are attack free will be compared using a Fisher’s exact test. A general linear model 
will be used to test the dose response. Additional statistical models may be considered and 
details will be provided in the statistical analysis plan. 


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There will be no adjustments for multiplicity and all statistical tests will be 2-sided with an alpha 
of 0.05. 
Secondary efficacy endpoints including attack severity, location, duration and symptoms of 
attacks, and number of attacks requiring attack medication will be summarized for each 
treatment group. 
13.2.5. 
Analysis of Safety Variables 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any event reported on the subject’s study record 
that occurs on or after the initiation of study drug within a given treatment period is defined as 
treatment emergent. Additionally, it is assumed that an AE that is reported to have started on 
Day 1 without an associated onset time may have occurred after the initiation of study drug. 
Hence, AEs occurring on Day 1 with no associated onset time will be assumed to be treatment 
emergent. The occurrence of treatment-emergent AEs will be summarized by treatment group 
using MedDRA preferred terms, system organ classifications, and severity. Separate summaries 
of treatment-emergent SAEs and AEs considered to be related to study drug will be generated. 
All AEs will be listed for individual subjects showing both verbatim and preferred terms.  
Descriptive summaries of vital signs, weight, ECG parameters, and clinical laboratory results 
will be presented separately for each study visit and treatment group. Laboratory abnormalities 
will be graded according to the DMID Adult Toxicity Table (Publish Date: Draft, November 
2007, see 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 by 
treatment group. Laboratory toxicity shifts from baseline to post baseline assessments will be 
summarized by study visit and treatment group. DLCO results will be presented as change from 
baseline in mL/min. 
Clinically significant abnormal morphological ECG findings will be summarized by study visit. 
Physical examination results will be presented in listings. 
Concomitant medications will be coded using the World Health Organization (WHO) dictionary. 
These data will be summarized by treatment group. 
13.2.6. 
Pharmacokinetic Analysis 
Concentrations of BCX7353 will be determined by validated plasma assays and will be 
summarized by treatment and displayed in figures. Plasma PK parameters for each subject will 
be estimated over the sampling interval using non-compartmental analysis (WinNonlin v 6.3 or 
higher, Pharsight Corp) and summarized by treatment and dose using descriptive statistics.  


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The PK parameters that may be estimated are listed in Table 7. Additional analyses may be 
conducted as appropriate.  
Table 7: 
Pharmacokinetic Parameters 
Pharmacokinetic 
Parameter 
Definition 
AUCtau  
Area under the plasma concentration versus time curve over the dosing interval 
(tau) (i.e., 24 hours for once daily dosing) 
C0 
Observed concentration predose 
Cav,ss  
Average steady-state plasma drug concentration during multiple-dose 
administration 
Cmax 
Maximum observed concentration of drug 
Ctau (steady state only) 
Observed drug concentration at the end of the dosing interval (tau) 
CL/F 
Apparent oral clearance after administration of the drug calculated as Dose/AUCtau  
λz 
Terminal elimination rate constant, estimate by log linear regression of the 
terminal elimination phase of the concentration of drug versus time curve 
Vz/F 
Apparent volume of distribution of the drug 
t1/2 
Estimate of the terminal elimination half-life of the drug 
Tmax 
Time of Cmax 
 
In all derivations of PK parameters, zero will be substituted for concentrations below the 
quantification limit (BQL) of the assay. Samples which are BQL, but are between 2 samples with 
detectable concentrations will be excluded from PK analysis. 
Dose proportionality will be analyzed using a power model and an ANOVA model based on 
dose normalized PK parameters. Additional analyses may be conducted as appropriate. 
13.2.7. 
Pharmacodynamic Analysis 
On–treatment plasma kallikrein inhibition data will be expressed as percent inhibition compared 
to subject baseline activity. Ex vivo plasma kallikrein activity will be listed by subject, treatment, 
day, and time and summarized separately by treatment, day, and time. Descriptive statistics will 
be reported. Mean and individual plasma kallikrein inhibition versus time profiles will be plotted 
by treatment group.   
C1 INH functional levels and absolute change from baseline will be summarized.  
13.2.8. 
Pharmacokinetic/Pharmacodynamic Analyses 
Exposure-response analyses of the relationships between plasma kallikrein inhibition, efficacy 
endpoints and BCX7353 plasma concentrations may be explored using model-based techniques 
as applicable.  


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13.2.9. 
Quality of Life Analyses 
The change from baseline in the domain scores of the AE-QoL (function, fatigue, nutrition & 
fear/shame) and the DASS (depression, anxiety, stress) as well as the composite score of each 
instrument will be compared between the treatment and placebo groups. Individual items will be 
plotted to understand their contribution to the domain sub-scores. 


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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; Good Clinical Practices (GCPs), 
including International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines (ICH E6); EMA regulatory 
requirements; 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 study drug 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. After the protocol has been submitted, any amendment must be agreed 
by the Investigator after discussion with the Sponsor and will be formally documented. All 
substantial amendments will be submitted for an opinion as required by current regulations.  
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. 
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 
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.  


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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. 
If an ICF is updated as a result of a substantial protocol amendment, the new IRB/IEC-approved 
versions will be used to re-consent currently enrolled subjects and must be provided to additional 
subjects prior to their entry into the study.  
The Investigator (or designee) 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 nonenrollment. 
14.1.4. 
Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
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 the eCRF 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 Investigator and their relevant personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
14.3. 
Quality Assurance 
The 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 
Formal stopping rules for individual subjects, parts of the trial or the entire trial, are defined in 
Section 8.3. 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 End of Trial is defined as the completion of the Last Subject’s last scheduled study visit. 
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 eCRFs 
completed to the greatest extent possible. 
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, eCRFs, and medical/hospital records), all original signed ICFs, all eCRFs, 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. 
14.6. 
Confidentiality of Information 
BioCryst affirms the subject’s right to protection against invasion of privacy. 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. 
BioCryst will ensure that the use and disclosure of protected health information obtained during 
a research study complies with the Health Insurance Portability and Accountability Act (HIPAA) 
Privacy Rule, where this rule is applicable. The Rule provides federal protection for the privacy 
of protected health information by implementing standards to protect and guard against the 
misuse of individually identifiable health information of subjects participating in BioCryst-
sponsored clinical trials. "Authorization" is required from each research subject, i.e., specified 
permission granted by an individual to a covered entity for the use or disclosure of an 
individual's protected health information. A valid authorization must meet the implementation 
specifications under the HIPAA Privacy Rule. Authorization may be combined in the ICF 


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(approved by the IRB/IEC) or it may be a separate document, (approved by the IRB/IEC) or 
provided by the Investigator or Sponsor (without IRB/IEC approval). 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 
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. 
Chatman, L. A., D. Morton, T. O. Johnson and S. D. Anway (2009). "A strategy for risk 
management of drug-induced phospholipidosis." Toxicol Pathol 37(7): 997-1005. 
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. 
Cicardi, M. and D. T. Johnston (2012). "Hereditary and acquired complement component 1 
esterase inhibitor deficiency: a review for the hematologist." Acta Haematol 127(4): 208-220. 
Crawford, J. R. and J. D. Henry (2013). "The Depression Anxiety Stress Scales (DASS): 
Normative data and latent structure in a large non-clinical sample." British J Clin Psychol 42: 
111-131. 
Cugno, M., C. E. Hack, J. P. de Boer, A. J. Eerenberg, A. Agostoni and M. Cicardi (1993). 
"Generation of plasmin during acute attacks of hereditary angioedema." J Lab Clin Med 121(1): 
38-43. 
Cugno, M., J. Nussberger, M. Cicardi and A. Agostoni (2003). "Bradykinin and the 
pathophysiology of angioedema." Int Immunopharmacol 3(3): 311-317. 
FDA (2012). "Drug Interaction Studies-Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations." Draft Guidance for Industry. 
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. 
Kaplan, A. P., K. Joseph and M. Silverberg (2002). "Pathways for bradykinin formation and 
inflammatory disease." J Allergy Clin Immunol 109(2): 195-209. 


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Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-481. 
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. 
Martello, J. L., M. R. Woytowish and H. Chambers (2012). "Ecallantide for treatment of acute 
attacks of hereditary angioedema." Am J Health Syst Pharm 69(8): 651-657. 
Maurer, M. and M. Magerl (2011). "Long-term prophylaxis of hereditary angioedema with 
androgen derivates: a critical appraisal and potential alternatives." J Dtsch Dermatol Ges 9(2): 
99-107. 
Nussberger, J., M. Cugno, C. Amstutz, M. Cicardi, A. Pellacani and A. Agostoni (1998). 
"Plasma bradykinin in angio-oedema." Lancet 351(9117): 1693-1697. 
Nussberger, J., M. Cugno and M. Cicardi (2002). "Bradykinin-mediated angioedema." N Engl J 
Med 347(8): 621-622. 
Pappalardo, E., M. Cicardi, C. Duponchel, A. Carugati, S. Choquet, A. Agostoni and M. Tosi 
(2000). "Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with 
angioedema." J Allergy Clin Immunol 106(6): 1147-1154. 
Patston, P. A., P. Gettins, J. Beechem and M. Schapira (1991). "Mechanism of serpin action: 
evidence that C1 inhibitor functions as a suicide substrate." Biochemistry 30(36): 8876-8882. 
Riedl, M. (2012). "Hereditary angioedema therapies in the United States: movement toward an 
international treatment consensus." Clin Ther 34(3): 623-630. 
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. 
STN125267. "CINRYZE [C1 Inhibitor] for routine prophylaxis against HAE attacks." Lev 
Pharmaceuticals Inc, from www.fda.gov. 
Suffritti, C., A. Zanichelli, L. Maggioni, E. Bonanni, M. Cugno and M. Cicardi (2014). "High-
molecular-weight kininogen cleavage correlates with disease states in the bradykinin mediated 
angioedema due to hereditary c1-inhibitor deficiency." Clin Exp Allergy. 
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. 
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. 
Zuraw, B. L, Cicardi, M., Longhurst, H., and Craig, T. (2016). "A randomized trial of 
subcutaneous C1-inhibitor of Hereditary Angioedema Attacks." Oral presentation O002, 


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American College of Allergy, Asthma & Immunology 2016 Annual Scientific Meeting, San 
Francisco, Nov 10-14, 2016 


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16. 
APPENDICES 
16.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) 
 
http://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Documents/dmidadultt
ox.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: 
BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 1 of 59                                                07FEB2017 
 
 
 
 
 
BIOCRYST 
PHARMACEUTICALS, INC. 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
A randomized, double-blind, placebo-controlled, dose-
ranging, parallel-group study to evaluate the efficacy, safety, 
tolerability, pharmacokinetics and pharmacodynamics of 
BCX7353 as a preventative treatment to reduce the 
frequency of attacks in subjects with hereditary angioedema 
 
 
Sponsor 
BioCryst Pharmaceuticals, Inc. 
 
4505 Emperor Blvd., Suite 200 
 
Durham, NC 27703 
Phone: (919) 859-1302 
Fax: (919) 851-1416 
 
 
 
 
Name of Test Drug: 
BCX7353 
 
 
Protocol Number: 
BCX7353-203 
 
 
Phase: 
Phase 2 
 
Analysis Plan Version 
Version 2.0 
 
 
Analysis Plan Date 
07FEB2017 






BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 3 of 59                                                07FEB2017 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.1.1. 
Primary Objective .........................................................................................................9 
2.1.2. 
Secondary Objectives ...................................................................................................9 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary Endpoints ........................................................................................................9 
2.2.2. 
Secondary Endpoints ....................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................11 
4. 
PLANNED ANALYSES ............................................................................................18 
4.1. 
Interim Analyses .........................................................................................................18 
4.2. 
Final Analysis .............................................................................................................18 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................19 
6. 
ANALYSIS POPULATIONS ....................................................................................20 
6.1. 
Randomized Set ..........................................................................................................20 
6.2. 
Safety Population ........................................................................................................20 
6.3. 
Full Analysis Set .........................................................................................................20 
6.4. 
Per Protocol Population ..............................................................................................20 
6.5. 
Pharmacokinetic Population .......................................................................................20 
6.6. 
Pharmacodynamic Populations ...................................................................................20 
6.6.1. 
Plasma Kallikrein Inhibition .......................................................................................20 
6.6.2. 
C1 INH, BMP and Cleaved HK .................................................................................20 
6.7. 
Pharmacokinetic and Pharmacodynamic Population ..................................................21 
7. 
HYPOTHESES AND TREATMENT COMPARISONS ..........................................22 
7.1. 
Hypotheses ..................................................................................................................22 
7.2. 
Comparisons of Interest ..............................................................................................22 
8. 
TREATMENT DESCRIPTIONS FOR DATA DISPLAYS ......................................23 
9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ...................................24 
9.1. 
General Considerations ...............................................................................................24 
9.2. 
Reporting Conventions ...............................................................................................24 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 4 of 59                                                07FEB2017 
 
9.3. 
Covariates and Subgroups ..........................................................................................25 
10. 
DATA HANDLING CONVENTIONS ......................................................................26 
10.1. 
Missing Data and Data Handling Rules......................................................................26 
10.2. 
Pharmacokinetic Concentration Data .........................................................................27 
10.3. 
Baseline Definition .....................................................................................................27 
10.4. 
Change from Baseline .................................................................................................28 
10.5. 
Multiple Measurements at One Time Point ................................................................28 
10.6. 
Treatment Period For Efficacy Analyses ....................................................................28 
10.7. 
Assessment Windows .................................................................................................28 
10.8. 
Derived Attack Endpoints ...........................................................................................28 
10.8.1. 
Rate of Attacks ...........................................................................................................29 
10.8.2. 
Number and Percentage of Subjects Who Are Attack Free .......................................30 
10.8.3. 
Number and Percentage of Attack-Free Days ............................................................30 
10.8.4. 
Attack Duration ..........................................................................................................30 
10.8.5. 
Attack Onset Relative to Prior Dose of Study Drug ...................................................30 
10.8.6. 
Angioedema Activity Score (AAS) ............................................................................30 
10.8.7. 
Attack HAE Medications ............................................................................................31 
10.8.8. 
Attack Symptoms ........................................................................................................31 
10.8.9. 
Attack Triggers ...........................................................................................................31 
10.8.10. 
Attack Location ..........................................................................................................31 
11. 
STUDY POPULATION .............................................................................................32 
11.1. 
Subject Disposition .....................................................................................................32 
11.2. 
Protocol Deviations ....................................................................................................33 
11.3. 
Potential Revisions to the SAP ...................................................................................33 
11.4. 
Demographic and Baseline Characteristics ................................................................33 
11.4.1. 
Demography ...............................................................................................................33 
11.4.2. 
HAE and HAE Medication History ............................................................................33 
11.4.3. 
Medical History ..........................................................................................................33 
11.4.4. 
Physical Examination .................................................................................................34 
11.5. 
Concomitant Medications ...........................................................................................34 
12. 
EFFICACY ANALYSES ...........................................................................................35 
12.1. 
Statistical Analysis Methods.......................................................................................35 
12.1.1. 
Analysis of Primary Efficacy Endpoint ......................................................................35 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 5 of 59                                                07FEB2017 
 
12.1.2. 
Supportive Analyses ...................................................................................................36 
12.1.3. 
Sensitivity analyses .....................................................................................................36 
12.1.4. 
Analysis of Secondary Efficacy Endpoints ................................................................37 
12.1.4.1. 
Angioedema Quality of Life (AE-QoL) .....................................................................38 
12.1.4.2. 
Depression, Anxiety, Stress Scales (DASS) ...............................................................39 
12.2. 
Extent of Exposure .....................................................................................................40 
12.3. 
Treatment Compliance ................................................................................................40 
12.4. 
Adverse Events ...........................................................................................................41 
12.4.1. 
Adverse Event Severity and Toxicity Grading ...........................................................41 
12.4.2. 
Summaries of Adverse Events ....................................................................................41 
12.5. 
Clinical Laboratory Evaluations .................................................................................42 
12.5.1. 
Summaries of Numeric Laboratory Results ...............................................................42 
12.5.2. 
Graded Abnormalities .................................................................................................42 
12.6. 
Vital Signs ..................................................................................................................43 
12.7. 
Electrocardiograms .....................................................................................................43 
12.8. 
Pulmonary Diffusion ..................................................................................................43 
12.9. 
Pregnancy ...................................................................................................................43 
12.10. 
Other Safety data ........................................................................................................43 
13. 
PHARMACOKINETIC ANALYSES ........................................................................44 
13.1. 
Drug Concentration Measures ....................................................................................44 
13.2. 
Deriving and Summarizing Pharmacokinetic Parameters ..........................................44 
14. 
PHARMACODYNAMIC ANALYSES .....................................................................46 
14.1. 
Kallikrein Inhibition, Cleaved HK Fragments, and C1 INH ......................................46 
14.2. 
Correlations of Dose or Drug Exposure with Pharmacodynamic Responses 
and Efficacy Outcomes ...............................................................................................46 
15. 
REFERENCES ...........................................................................................................48 
16. 
TABLES, FIGURES AND LISTINGS ......................................................................49 
 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 6 of 59                                                07FEB2017 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AAS 
Angioedema Activity Score 
AE(s) 
Adverse Event 
AeQoL 
Angioedema Quality of Life questionnaire 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AUCtau 
Area under the plasma concentration versus time curve over the dosing interval (tau)  
BQL 
Below the quantification limit 
BMI 
Body mass index 
BP 
Blood pressure 
Cav,ss  
Average steady-state plasma drug concentration during multiple-dose administration  
C1 INH 
C1 esterase inhibitor 
CI 
Confidence Interval 
CL/F 
Apparent oral clearance 
Cmax 
Maximum plasma concentration 
Ctau 
Observed drug concentration at the end of the dosing interval (tau) 
CV 
Coefficient of Variation 
CVb 
Between-subject coefficient of variation 
DASS 
Depression, Anxiety, Stress Scales 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
HAE 
Hereditary Angioedema 
HR 
Heart rate 
FAS 
Full Analysis Set 
λz  
Terminal elimination rate constant  
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
n 
Number of observations 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
RS 
Randomized subjects  
SD 
Standard Deviation 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 7 of 59                                                07FEB2017 
 
Abbreviation 
Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
t½ 
Half-life 
Tmax 
Time of maximum concentration 
Vz/F  
Apparent volume of distribution of the drug 
WHO 
World Health Organization 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 8 of 59                                                07FEB2017 
 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the interim and final analyses to 
be performed for Study BCX7353-203: A randomized, double-blind, placebo-controlled, dose-
ranging, parallel-group study to evaluate the efficacy, safety, tolerability, pharmacokinetics and 
pharmacodynamics of BCX7353 as a preventative treatment to reduce the frequency of attacks in 
subjects with hereditary angioedema. 
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 9 of 59                                                07FEB2017 
 
2. 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
• 
To evaluate the efficacy of once-daily prophylactic BCX7353 at 4 dose levels, as 
measured by the number of attacks of HAE observed in patients with HAE enrolled 
in each treatment group 
2.1.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of BCX7353 over 28 days in subjects with 
HAE 
• To describe the PK profile of daily BCX7353 in subjects with HAE 
• To characterize the anticipated pharmacodynamic PD effects of BCX7353 in subjects 
with HAE 
• To characterize the dose-response relationship of BCX7353 in subjects with HAE 
• To evaluate effects of BCX7353 on quality of life 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
• Number of confirmed HAE attacks: analyzed by treatment group using appropriate 
descriptive statistics as follows: weekly attack rate, counts of attacks, proportion of 
subjects with no attacks, and number of attack-free days. 
2.2.2. 
Secondary Endpoints 
• Safety and tolerability of BCX7353 as assessed by adverse events (AEs), clinical 
laboratory tests, electrocardiograms (ECG), vital signs, and physical exam findings 
 
• Number of attacks requiring attack medication (Medications recorded on Diary page 
to treat HAE attack include Cinryze, Berinert , Firazyr, Ruconest, Tranexamic acid 
and Kalbitor) 
• Duration of attacks 
• Severity of attacks 
• Attack onset relative to the time of last dose of study drug 
• Discontinuations due to lack of efficacy 
• Symptoms and anatomical locations of attacks 
• Number of emergency room visits and/or hospitalizations 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 10 of 59                                                07FEB2017 
 
• Quality of life scales, as measured by the Angioedema Quality of life (AE-QoL) and 
Depression, Anxiety, Stress Scales (DASS) 
• BCX7353 steady-state pharmacokinetic (PK) parameters including Cmax, Ctau, Tmax, 
AUCtau, AUC0-t, half-life, λ, Vd/F, and CL/F 
• Ex-vivo kallikrein inhibition 
• Cleaved high-molecular-weight kininogen (HK) and C1INH functional level values 
and change from baseline 
 
 
 
 
 
 
 
 
 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 11 of 59                                                07FEB2017 
 
3. 
STUDY DESIGN 
This is a Phase 2, randomized, double-blind, placebo-controlled, 3-part, parallel-group, dose-
response study to evaluate the safety, tolerability, PK, PD, and efficacy of BCX7353 in subjects 
with HAE. HAE patients with a documented recent history of frequent angioedema attacks who 
have provided written informed consent will be evaluated for participation in this study at a 
screening visit. Up to 36 subjects with HAE are planned to be enrolled in Part 1 of the study and 
will be randomized 1:1 (placebo: active) to receive one of the following treatments: 
• Part 1, Treatment Group 1: placebo QD orally for 28 days 
• Part 1, Treatment Group 2: 350 mg BCX7353 QD orally for 28 days 
After 24 subjects have completed through the Day 28 dose, there will be an administrative 
interim analysis of the accrued efficacy data by the Sponsor. Additional administrative analyses 
may be conducted following completion of Part 1 and Part 2. 
If it is desired to more fully characterize the treatment effect of BCX7353 350 mg relative to 
placebo or to verify assumptions made for sizing this proof-of-concept study, additional subjects 
will be enrolled to complete Part 1 (up to 36). Enrollment into Part 1 will continue until either a 
decision is made to halt enrollment in favor of opening Part 2 or enrollment reaches 36 subjects 
in Part 1. Additionally, upon completion of Part 1 (36 subjects dosed), enrollment into Part 2 of 
the study may immediately commence. 
In Part 2, approximately 14 subjects who meet all eligibility criteria are planned to be 
randomized in a 1:3:3 (placebo:active:active) ratio into 1 of the following 3 treatment groups: 
• Part 2, Treatment Group 1: placebo QD orally for 28 days 
• Part 2, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days 
• Part 2, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days 
If tolerability issues prevent full enrollment of Part 1 as described or study drug is poorly 
tolerated due to gastrointestinal effects, future subjects randomized to active study drug in Part 1 
may receive 250 mg orally once daily for 28 days. In this case, any dose level changes warranted 
for Part 2 will be instituted via protocol amendment. 
Following completion of enrolment in Part 2, Part 3 of the study may be initiated: 
In Part 3, approximately 20 subjects with Type 1 or Type 2 HAE who meet all eligibility criteria 
are planned to be randomized in a 1:3:3:3 (placebo: active: active: active) ratio into 1 of the 
following 4 treatment groups:  
• Part 3, Treatment Group 1: placebo QD orally for 28 days 
• Part 3, Treatment Group 2: 125 mg BCX7353 QD orally for 28 days  
• Part 3, Treatment Group 3: 250 mg BCX7353 QD orally for 28 days  
• Part 3, Treatment Group 4: 62.5 mg BCX7353 QD orally for 28 days 
 
The overall study design is presented in Figure 1; Figure 2 depicts the schema for conduct of 
each study part. 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 12 of 59                                                07FEB2017 
 
 Following an up to 21-day screening period, eligible subjects, who have had entry criteria 
confirmed by the Sponsor, will be dosed on Day 1. Subsequent clinic visits will be held on Days 
7, 14, 21 and 29, At the Day 14 visit, subjects will also have serial blood samples drawn 
immediately prior to and after the dose, including a visit on Day 15 for collection of a 24-hour 
postdose PK sample. A follow-up visit will be performed on Day 44. 
Subjects will record the occurrence and details of all angioedema attacks at least once daily 
beginning from the date of screening until the follow-up visit. On Days 1 through 28, subjects 
will also record the time of day the study drug (BCX7353 or placebo) was taken and the number 
of capsules of study drug taken at each dose. Subject-reported study drug administration and 
HAE attacks will be captured in a diary. 
During the study, each subject will continue to use their prescribed acute attack medication to 
treat any attacks, under the medical management plan advised by their physician. All participants 
must have access to effective, approved treatments for attacks of angioedema as part of their 
routine medical care. 
Individual subjects may only participate in one Part of the study. 
 
Figure 1: 
Study BCX7353-203 Study Design 
 
 
 
 
 
 
 
 
Part 1: enrollment/data prior to interim
data through Day 28, n = 24:
n = 12 dosed 350 mg BCX7353 QD
n  = 12 dosed placebo QD
Interim 
administrative 
analysis of efficacy 
by Sponsor
Complete Part 1
n = 36 subjects
n = 18 dosed 350 mg BCX7353 QD x28 days       
n  = 18 dosed placebo QD x28 days
Enrollment in 
Part 1 will 
continue 
through efficacy 
interim analysis
Complete Part 2 dose-ranging
n = approximately 14 subjects
n = 6 dosed 250 mg BCX7353 QD x28 days
n = 6 dosed 125 mg BCX7353 QD x28 days 
n  = 2 dosed placebo QD x28 days
Treatment effect of 
study drug must be 
further defined
Treatment effect of 
BCX7353 and 
placebo differentiated
Treatment effect of 
BCX7353 and 
placebo differentiated
Enrollment in 
Part 2 may 
commence 
immediately 
after completion 
of enrollment of 
Part 1 
Complete Part 3 dose-ranging
n = approximately 20 subjects
n = 6 dosed 250 mg BCX7353 QD x28 days
n = 6 dosed 125 mg BCX7353 QD x28 days
n = 6 dosed 62.5 mg BCX7353 QD x28 days 
n  = 2 dosed placebo QD x28 days
Treatment effect of 
BCX7353 and 
placebo differentiated
Enrollment in 
Part 3 may 
commence 
immediately 
after completion 
of enrollment of 
Part 2 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 13 of 59                                                07FEB2017 
 
Figure 2: 
Study Schema – Parts 1, 2 and 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up
Day 44
                                                              Screening                       Baseline          Day 7             Day 14          Day 2        Day 29          Follow-up
                                                                   visit
   
            visit                visit                 visit               visit             visit                 visit
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 350 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 1
Follow-up
Day 44
                                                              Screening                      Baseline          Day 7              Day 14            Day 21      Day 29          Follow-up
                                                                   visit
   
           visit                 visit                visit                 visit           visit                   visit
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 125 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 3
BCX7353 62.5 mg QD
Follow-up
Day 44
Initial kit 
shipment
Historical HAE Attack 
Documentation Period
Study Drug Dosing 
 Days 1-28 
Placebo QD
BCX7353 250 mg QD
 daily diary recording for all subjects
Screening Period
Up to 21 days
Serial PK
PART 2
BCX7353 125 mg QD
BCX7353 250 mg QD
                                                             Screening                      Baseline          Day 7              Day 14            Day 21      Day 29          Follow-up
                                                                  visit
   
           visit                 visit                visit                 visit           visit                   visit


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
 
Page 14 of 59                                                07FEB 2017 
 
Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Baseline 
Day 1u 
 
Follow-up  
(or Early 
Term [ET]) 
Day  
−21  to −1 
Day 1 
Pre-
Dose 
Day 1 
Post-
dose 
Day 7 
± 1 days 
Day 14 
± 2 days 
Day 15t 
Pre-
dose 
Day 21   
± 1 days 
Day 29 
+ 1 day 
Day 44 
+ 7 days 
Informed consenta 
X 
 
 
 
 
 
 
 
 
Clinic visitb 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/ Exclusion criteria & prohibited 
medications 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
HAE medical and medication history 
X 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
Xd 
 
 
Xd  
 
 
Xd 
Xd 
Drugs of abuse screene 
X 
 
 
 
 
 
 
 
 
HIV/HCV/ HBV serology 
X 
 
 
 
 
 
 
 
 
C1 INH antigenic and/or functional levelf 
X 
X 
 
 
 
 
 
X 
 
Physical examinationg 
X 
Xg 
 
 
Xg 
 
 
Xg 
Xg 
12-lead ECGh 
X 
X 
 
 
X 
 
 
X 
X 
Vital signsi 
X 
X 
 
 
X 
 
 
X 
X 
Pregnancy testj 
X 
X 
 
 
X 
 
 
X 
X 
FSHk 
X 
 
 
 
 
 
 
 
 
DLCO 
X 
 
 
 
 
 
 
Xl 
 
Chemistry, hematology and coagulation 
laboratory evaluationse 
X 
X 
 
 
X 
 
 
X 
X 
Liver Function Teste 
 
 
 
X 
 
 
X 
 
 
Troponin I & Troponin T 
 
X 
 
 
X 
 
 
X 
X 


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Assessment 
Screening 
Baseline 
Day 1u 
 
Follow-up  
(or Early 
Term [ET]) 
Day  
−21  to −1 
Day 1 
Pre-
Dose 
Day 1 
Post-
dose 
Day 7 
± 1 days 
Day 14 
± 2 days 
Day 15t 
Pre-
dose 
Day 21   
± 1 days 
Day 29 
+ 1 day 
Day 44 
+ 7 days 
C3 
 
X 
 
 
 
 
 
 
 
HLA typingm 
 
X 
 
 
 
 
 
 
 
Optional sample for possible exploratory 
pharmacogenomic testingv 
 
X 
 
 
 
 
 
 
 
NGAL 
 
X 
 
 
X 
 
 
X 
X 
CK-MB 
 
X 
 
 
X 
 
 
X 
X 
Urinalysise 
X 
X 
 
 
X 
 
 
X 
X 
Attack frequency confirmation 
X 
 
 
 
 
 
 
 
 
Sponsor approval and randomizationn 
X 
 
 
 
 
 
 
 
 
HAE attack and dosing diary 
instruction/review/collectiono 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary completionp 
 
AE-QoL and DASS 
 
X 
 
 
Xx 
 
 
X 
 
Plasma for PK analysisq 
 
X 
 
 
Xt 
Xt 
 
X 
 
Plasma for kallikrein inhibitionq 
 
X 
 
 
Xt 
Xt 
 
X 
 
Plasma for additional PD analysesr 
 
X 
 
 
X 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
study drug accountability/dispensing 
 
 
X 
 
Xw 
 
 
X 
X (ET) 
study drug dosings 
 
 
 
 
a Signing of the main informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures are 
performed. Subjects will also be asked to sign a separate consent form permitting collection of a blood sample at baseline for possible exploratory 
pharmacogenomic analysis (this consent form may be signed at any time during the study prior to drawing the sample).  


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b Clinic visits are scheduled for screening and Days 1, 7, 14, 21, 29, and 44. Additionally, a Day 15 visit for a 24-hour PK and PD sample post 14 dose will 
occur. If the subject is unable to provide serial PK samples on Day 14, steady state PK samples may be obtained on Day 28, with a 24-hour PK sample drawn at 
the scheduled visit on Day 29.  
 
d Weight only. 
e Analytes to be measured can be found in the protocol. Subjects are required to fast overnight for at least 8 hours prior to blood draw on Days 1, 14, and 29. 
f If no prior laboratory results confirming HAE diagnosis are available at screening, C1 INH level and function will be drawn. At baseline (Day 1) and Day 29, 
all subjects will have a sample for C1 INH function drawn. 
g Physical examinations conducted after the screening visit will be targeted to reported signs and symptoms. A complete physical examination will be performed 
at screening only. 
h Bedside 12-lead ECGs will be conducted in triplicate predose on Day 1; all other ECGs will be captured as single assessments. Any scheduled blood draws 
should occur after obtaining the ECG. Subjects should rest quietly for 10 minutes in a supine position prior to ECGs being performed. 
i Vital signs include measurement of heart rate, blood pressure and temperature. Temperature will be measured only at screening and on Day 1. 
j A serum pregnancy test will be administered to women of childbearing potential or who are postmenopausal ≤ 2 years at screening; all other pregnancy tests 
performed during the study may be urine pregnancy tests (for women of childbearing potential only). 
k  FSH will be measured in women declaring themselves postmenopausal ≤ 2 years.  
L If the site cannot perform DLCO onsite, the Day 29 sample may also be assessed any time from Day 24 to Day 32. 
m A blood sample for HLA-typing will be drawn at the Baseline/Day 1 visit; if a blood sample is not obtained at Baseline, the sample may be drawn at any time  
    during the study. 
n Subjects will be randomized by the Sponsor on or after the screening visit and is contingent upon review of screening visit data entered into the eCRF 
subsequent questions the Sponsor may have. Randomization will trigger shipment of a kit of study drug for the first 14 days and an automatic resupply to arrive 
on-site at approximately study Day 10 after entry into the eCRF system that the subject has had a Day 1 visit. More details on randomization and kit shipment 
will be provided to the site. 
o The Investigator (or designee) will provide a diary for collection of HAE attacks (screening through follow-up) and study drug dosing (Days 1-28) at screening, 
Day 1, Day 14 and Day 29. Diaries will be collected on Day 1 (screening diary), Day 14, Day 29 and follow-up. At each visit and phone call, the Investigator 
(or designee) will review proper recording of attacks and dosing (as applicable) in the diary. 
p At any time the diary is in a subject’s possession, they will enter HAE attacks and relevant details and dosing information (as applicable) at least once per day. 
q On Day 14, a blood sample for plasma PK and plasma kallikrein analysis will be drawn prior to dosing (< 5 min) and at 1, 2, 3, 4, 5, 6, 8, and 24 hours postdose 
(i.e., on Day 15); Day 29 will be trough samples. If the subject is unable to provide serial PK samples on Day 14, steady state PK samples may be obtained on 
Day 28, with a 24-hour PK sample drawn at the scheduled visit on Day 29. In this case, trough PK samples will be drawn on Day 14. If the subject has a Day 
29 visit for the 24-hour PK sampling, concomitant medications and AEs should also be assessed at the visit. Within 6 hours postdose, an acceptable window 
around each PK draw is ± 10 minutes. After 6 hours, an acceptable window is ± 20 minutes. Plasma PK and plasma kallikrein samples will be collected prior to 
in clinic dosing on Day 1 and Day 14. The Day 29 samples will be collected approximately 24 hours post-last dose. 
r Cleaved HK and an additional sample for possible exploratory analysis used to elucidate PD properties of BCX7353 will be drawn. 
s Subjects will take their study drug in the clinic on Day 1, Day 14 and Day 15 (Day 28 if subjects must complete serial PK on the last dose). Subjects will take 
all other doses at home as instructed. The last day of study drug dosing is Day 28. 
t Subjects unable to undergo the serial PK blood draw on study Day 14 will only have a predose or trough blood sample drawn; a steady-state serial PK blood 
collection will then be obtained on Day 28 with a 24-hour blood draw conducted at the scheduled visit on Day 29. In the event the serial PK is not conducted on 
Day 14, the Day 15 visit is not required. 


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u If the site is unable to conduct all procedures for an individual subject at Baseline on Day 1 because of logistical reasons, refer to the protocol for procedures 
that may be conducted on Day −1. 
v A blood sample for possible exploratory pharmacogenomic testing will be drawn at the Baseline/Day 1 sample only if consent is obtained for this optional 
testing; 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.  
w Study drug may be dispensed to the subject on Day 15 after in-clinic dosing in lieu of dispensing on Day 14 if preferred. 
x The AE-QoL questionnaire will not be administered at the Day 14 visit. 
.


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
 
There will be one planned administrative interim in Part 1 of the study, after 24 eligible subjects 
complete through the Day 28 dose. Ad hoc analyses to enable discernment of treatment 
differences between the study drugs may be requested. At the conclusion of the interim analysis, 
a decision will be made to either continue enrollment into Part 1 or to close Part 1 and initiate 
Part 2 (dose ranging). A continuation of Part 1 may include up to 12 additional subjects for a 
total of up to 36 subjects completing Part 1 of the study. Additional administrative interim 
analyses may be conducted after completion of Part 1 (if more than 24 subjects are enrolled) and 
after completion of Part 2 to support decision making for future development of the drug. 
4.2. 
Final Analysis 
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. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Given that the BCX7353 response rate is unknown, the sample size was kept flexible to cover a 
range of response options that would achieve 90% power with an alpha of 0.05. The study 
population is expected to have a mean baseline attack rate of 1 attack/week. The expected mean 
reduction in attack rate of 350 mg BCX7353 QD is at least 70%. The mean reduction in attack 
rate in the placebo group may be as high as 30%. Sample size sensitivity assessments provided in 
Tables 2 and 3 are based on various BCX7353 and placebo responses and variability. 
Table 2: 
Power assessment based on sample size and on-study attack rate 
 
Placebo 
BCX7353 
Power 
Mean 
SD 
n 
Mean 
SD 
N 
0.7 
0.45 
12 
0.3 
0.3 
12 
68% 
0.7 
0.45 
12 
0.3 
0.45 
12 
55% 
0.7 
0.45 
18 
0.3 
0.3 
18 
86% 
0.7 
0.45 
18 
0.3 
0.45 
18 
74% 
0.8 
0.45 
12 
0.3 
0.3 
12 
86% 
0.8 
0.45 
12 
0.3 
0.4 
12 
79% 
0.8 
0.45 
12 
0.3 
0.5 
12 
69% 
0.8 
0.45 
18 
0.3 
0.3 
18 
97% 
0.8 
0.45 
18 
0.3 
0.4 
18 
93% 
0.8 
0.45 
18 
0.3 
0.5 
18 
87% 
Note: Calculations were based on a 2-sided test at significance level of 0.05 and rates and SD are expressed in units. 
 
 
Table 3: 
Power assessment based on sample size and attack free proportion  
Placebo 
BCX7353 
N 
Attack Free 
N 
70% Attack 
Free 
75% Attack 
Free 
80% Attack 
Free  
85% Attack 
Free 
12 
15% 
12 
85% 
91% 
95% 
98% 
12 
20% 
12 
76% 
84% 
91% 
95% 
12 
25% 
12 
67% 
76% 
84% 
91% 
18 
20% 
18 
90% 
95% 
98% 
99% 
18 
25% 
18 
83% 
90% 
95% 
98% 
18 
30% 
18 
73% 
83% 
90% 
95% 
Note: Calculations were based on a 2-sided test at significance level of 0.05. 
 


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6. 
ANALYSIS POPULATIONS 
6.1. 
Randomized Set 
The randomized set will include all subjects who are randomized.   
6.2. 
Safety Population 
The safety population will include all subjects who are randomized and receive at least 1 capsule 
of study drug. Subjects will be analyzed according to the treatment received. This population will 
be used for all analyses of accountability, demographics, BCX7353 drug concentrations, and 
safety. 
6.3. 
Full Analysis Set 
The full analysis set (FAS) population will include all subjects who are randomized, receive at 
least 1 dose of study drug, and have post baseline HAE diary data recorded. Subjects will be 
analyzed according to the randomized treatment. The FAS population will be the population for 
efficacy analyses. 
6.4. 
Per Protocol Population 
The per protocol (PP) population will include all subjects who are randomized, receive at least 
90% of the planned 28-days of study drug, based on drug accountability, have post baseline HAE 
diary data recorded and have no significant protocol violations. Subjects will be analyzed 
according to the actual treatment received. The PP population will be an additional population 
for efficacy analyses. 
6.5. 
Pharmacokinetic Population 
The PK population will include all subjects for whom PK parameters can be estimated. The PK 
population will be the population for the PK analysis.   
6.6. 
Pharmacodynamic Populations 
6.6.1. 
Plasma Kallikrein Inhibition 
The PD population for plasma kallikrein inhibition (KKI) will include all subjects for whom at 
least 1 pre- and post-dose plasma kallikrein inhibition result can be estimated. This population 
will be used for all analyses of plasma kallikrein inhibition. 
6.6.2. 
C1 INH, BMP and Cleaved HK 
 
There will be 3 additional PD populations, one for each of the following PD assessments: C1 
INH functional or C4 levels, BMP and cleaved HK. Each PD population will include all subjects 
with a baseline and at least 1 post-dose value and will be the primary population for the relevant 
PD analyses. 


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6.7. 
Pharmacokinetic and Pharmacodynamic Population 
 
The PK-PD analyses will be based on the subjects with both PK and PD measurements.        
 


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7. 
HYPOTHESES AND TREATMENT COMPARISONS 
7.1. 
Hypotheses 
 
This study is designed to evaluate the efficacy of once-daily prophylactic BCX7353 at 4 dose 
levels, as measured by the number of attacks of HAE observed in patients with HAE.  
 
An estimation approach will be used to evaluate the dose-response relationship for BCX7353 
and the treatment difference vs. placebo. 
7.2. 
Comparisons of Interest 
Comparisons of the following efficacy endpoints will be undertaken between each BCX7353 
dose group and placebo, if data permit: 
• Number of confirmed HAE attacks as weekly attack rate 
• Proportion of subjects attack-free during the treatment period   
• Number and percent of attack-free days 
• Duration of attacks 
• Severity of attacks 
• AAS   
• Attack onset relative to the time of last dose of study drug 
• Symptoms and anatomical locations of attacks 
• Number of Emergency room visits and/or hospitalizations 
• Quality of life scores, as measured by the Angioedema Quality of life (AE-QoL) and 
Depression, Anxiety, Stress Scales (DASS) 
• BCX7353 PK Parameters, Plasma kallikrein inhibition (KKI), PD assessments 
including C1-INH functional levels and cleaved HK level  
 


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8. 
TREATMENT DESCRIPTIONS FOR DATA DISPLAYS 
Data display treatment descriptors with actual treatment dose will be used as shown in Table 4 
below. 
Table 4: 
Data Display Treatment Descriptors 
Study Part 
Treatment Group 
Treatment 
Description 
Final Data Display 
 
 
 
Treatment Description 
Parts 1, 2 and 3 
Combined  
Group 1 
placebo QD orally for 
28 days 
Placebo 
 
Part 1 
Group 2 
350 mg BCX7353 
QD orally for 28 days 
BCX 7353 350 mg 
Part 2 and 3 
Combined 
Group 3 
250 mg BCX7353 
QD orally for 28 days 
BCX7353 250 mg 
 
Group 4 
125 mg BCX7353 
QD orally for 28 days 
BCX7353 125 mg 
Part 3 
Group 5 
62.5 mg BCX7353 
QD orally for 28 days 
BCX7353 62.5 mg 
 


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9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
9.1. 
General Considerations 
Tables and listings will be prepared in accordance with the current International Conference on 
Harmonization (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 output generation 
• 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 a column displaying findings for all subjects by 
treatment group and all subjects active dose combined.   
Version 9.2 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. 
9.2. 
Reporting Conventions 
Data analyses will be performed by, or under the direct supervision of, BioCryst 
Pharmaceuticals, Inc., Durham, NC. 
Listings will be sorted by treatment, subject, and planned assessment time point. Summaries will 
be presented by treatment, study day and planned assessment time point. Unless stated otherwise, 
descriptive summaries will include n, mean, standard deviation, coefficient of variation (CV) or 
Q1, Q3 and 95% CI, median, minimum, and maximum for continuous variables, and n and 
percent for categorical variables. In addition, for log normally distributed parameters, the 
geometric mean with associated 95% CI, between-subject CVs (CVb), and SD of the logs based 
on the geometric mean, will be included. 
The between-subject %CV of the log transformed variable will be calculated as  
%CVb = 100 * √(eSD^2– 1), with SD of the log-transformed data. 
 
 


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For summary tables, the following reporting convention will be used unless otherwise stated:  
Frequencies (safety)  
Counts (n)  
None  
Percentages (%)  
1 decimal place 
Summary statistic 
(safety, number of 
attacks, reported QOL 
and PK)  
n  
None  
Mean  
i + 1 decimal place 
Median  
i decimal places 
SD  
i + 1 decimal place 
Min  
i decimal places 
Max  
i decimal places  
CV%  
none  
Geometric n  
None  
Geometric Mean  
i + 1 decimal place  
Geometric CV%  
none  
Statistical Analyses, 
reporting of derived 
efficacy and QOL 
endpoints 
Derived efficacy end points (%)  
1 decimal place  
Other derived efficacy 
endpoints 
2 decimal places 
p-values  
if <0.001: presented as <0.001 ; 
>0.999, presented as >0.999 
if ≥0.001 and <=0.999: presented to 3 
decimal places  
i refers to the number of decimal places reported in the source workbook or other appropriate source data for the 
original data 
 
Deviations from the analyses in the SAP will be identified in the final Clinical Study Report. 
9.3. 
Covariates and Subgroups  
If data permit, the gender, age and qualifying attack rate(s) will be included as covariates for the 
primary efficacy assessments. Additional demographic and baseline characteristics (i.e., C1 INH 
function and country) may also be included as covariates for the efficacy analysis. 
If data permit, the primary efficacy analysis maybe performed by subgroups based on gender, 
median age, country and covariates that are significantly associated with efficacy response.   
  
 


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10. 
DATA HANDLING CONVENTIONS 
10.1. 
Missing Data and Data Handling Rules 
For subjects who prematurely discontinue the study, all available data will be included in the 
analyses. The planned safety and efficacy analyses will be based on the reported data. Sensitivity 
analyses on the primary efficacy endpoint will consider imputation methods; details are 
discussed in section 12.1.3.  
Incomplete dates for adverse events and medications 
For analysis of AEs and medications, a complete date should be established in order to identify 
AEs or medication as occurring during treatment or not. For the purpose of handling partially 
reported start and stop dates for AEs or medication the following algorithm will be applied: 
• 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 
AE/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 AE/medication, 
then the start date of the event/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. 
 
In subject data listings, start and stop date of AEs or medication will be displayed as reported. 
Missing time of last dose  
In case the time of the last dose is not reported, time of dose will be assigned as the median 
dosing time for the subject. 
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: 
 
• Missing start time but start date present: 
The start time will be set to 12:00PM. 
• Missing start date and time: 


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The start date will be set to the 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 
10.2. 
Pharmacokinetic Concentration Data 
For the creation of individual PK profiles reporting means and medians using the linear scale, all 
PK concentrations below the quantification limit (BQL) will be set to zero except when the 
sampling time of an individual BQL value falls immediately between the sampling times of two 
quantifiable values, in which case it will be set to missing. 
When creating geometric summary statistics or log-linear plots, values that are BQL will be set 
to missing.  No other procedures for replacing or imputing missing data are planned for any 
summarizations.  If a subject has data points missing, that subject will be excluded from the 
analysis for that day and/or time point.  If 24 hour samples that were taken post the next day’s 
dose, those samples will be excluded in the summary statistics for the 24 hour time point. 
10.3. 
Baseline Definition 
Baseline is the last available assessment prior to the time of first dose unless otherwise specified.  
 
The study qualifying attack rate will be used as baseline for the attack rate endpoint and is 
defined as follows:   
Subject Reported Qualifying attack rate: 
Total Number of Qualifying attacks reported ∗7
Duration of Qualifying reporting period in days 
Duration of qualifying attack reporting period is calculated as number of days as the last date of 
the period – the first date of the reporting period +1. 
 
Adjusted Qualifying attack rate: 
Total Number of Adjusted Qualifying attacks reported ∗7
Duration of Qualifying reporting period in days
 
Duration of qualifying attack reporting period is calculated as number of days as the last date of 
the period – the first date of the reporting period +1  
For subject reported historical attacks on consecutive days, these attacks will be counted as a 
single attack in the calculation of the adjusted qualifying attack. 
  


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10.4. 
Change from Baseline 
Change from baseline is calculated as: 
change from baseline value = ‘visit’ value – baseline value 
Percent change from baseline is calculated as 
% change from baseline value = (‘visit’ value – baseline value)*100/Baseline Value 
The change and % change from baseline will be indicated as missing, if either the baseline or 
post-dose value is missing. Baseline is the last assessment prior to the date of first dose.   
10.5. 
Multiple Measurements at One Time Point 
Where multiple measurements are recorded for a particular time point, the mean of the 
measurements will be calculated and used in any derivation of summary statistics.  All available 
data will be listed. 
10.6. 
Treatment Period For Efficacy Analyses 
There are 2 treatment periods for efficacy analyses. 
1. The entire dosing interval (Days 1 to 28 inclusive) is the date of first dose to the last dose on 
day 28+24hours, or 24 hour post last dose of the study drug, whichever is earlier. 
2. The steady-state or effective dosing interval (Days 8 to 28 inclusive) is the date of first dose 
+7 days to the last dose on day 28+24hours, or 24 hour post last dose of the study drug, 
whichever is earlier. 
HAE attacks that occur during the treatment period will be included in all relevant efficacy data 
summaries.  
HAE attacks that occur prior to or after the treatment period will also be summarized for the 
following periods: Qualification Period, screening to baseline Period and the follow-up period. 
 
10.7. 
Assessment Windows 
Nominal times will be used for the descriptive summaries and plots of summary measures.  
Actual times will be used in the listings, individual concentration-time profiles, and in the 
calculation of PK parameters.  
10.8. 
Derived Attack Endpoints 
Subject-reported attacks will be adjudicated by the independent Clinical Endpoint Adjudication 
Panel (CEAP). The attacks that have been confirmed by the adjudication committee will be 
included in efficacy analyses. The details of adjudication are provided in the CEAP charter. 
The attack endpoints described in this section are based on confirmed attacks by the CEAP, 
however the rate of attacks will also be calculated for all subject reported attacks. Efficacy 
analyses will be conducted for HAE attacks reported over the entire dosing period (Days 1 to 28 


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inclusive), during the dosing period in which BCX7353 should be at steady-state conditions 
(Days 8 to 28, inclusive), and during the entire study period (Day 1 to the last HAE diary in the 
follow-up period). 
The efficacy analyses will be calculated for 3 treatment periods: 
• Entire Dosing Period  
Duration (days) = 28 or (Date of last dose –date of first dose+1), whichever is earlier 
• Effective Dosing Period 
Duration (days) = 21 or (Date of last dose –date of first dose-6), whichever is earlier 
• Entire Study Period   
Duration (days) = Date of last HAE Attack Diary collection during the follow-up –date of  
first dose 
All efficacy analyses will also be run by treatment period and population (FAS or PP). 
10.8.1. 
Rate of Attacks 
The primary endpoint, confirmed attack rate, is the total number of (count) confirmed attacks 
during the treatment period and standardized to an appropriate denominator, e.g. 7 days for a 
weekly attack rate. The weekly attack rate will be calculated for each subject: 
𝑊𝑒𝑒𝑘𝑙𝑦 𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒=  Number of Attacks ∗7
Duration (days)
 
 
Number of attacks is total count of attacks reported during the respective dosing period 
(“Duration (days)”  in the above equation]. The primary endpoint will be calculated for the entire 
dosing period and for the effective dosing period. The weekly attack rate will also be derived for 
all subject reported attacks and for confirmed attacks requiring treatment. 
 
The attack rates will also be calculated for pre and post treatment periods: 
 
Attack Rate from Screening to Baseline: 
 
=
Total Number of  attacks reported ∗7
Duration of the reporting period in days 
Attacks with a start date after screening and before the date of first dose will be included and the 
duration of the reporting period is date of first dose – date of screening visit+1.  
Attack Rate from date of day 29 to the last follow-up on study: 
Total Number of  attacks reported ∗7
Duration of the reporting period period in days 
  


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Attacks that start greater than 24 hours after the last dose will be included. The duration of the 
reporting period is from the date of last dose+24 hours to the date of last follow-up. 
 
10.8.2. 
Number and Percentage of Subjects Who Are Attack Free 
The following attack free endpoints will be derived for each treatment period (the entire dosing 
period, and the effective dosing period ): 
• The number and percentage of subjects who report no attacks during the treatment period 
for the FAS set and PP population. Subjects who report no attacks and discontinued 
before the end of the planned treatment period (day 28) are considered attack free.  
• The number and percentage of subjects who report no attacks during the treatment period 
for the FAS set and PP population excluding subjects who discontinue before the planned 
treatment period (day 28). 
• The number and percentage of subjects who report no attacks during the treatment period 
for the FAS set and PP population. Subjects who discontinue before the planned 
treatment period (day 28) are considered not attack free. 
The above attack free endpoints will also be derived for the entire study period. 
10.8.3. 
Number and Percentage of Attack-Free Days 
The number of attack-free days is the sum of the days during the dosing period for which a 
subject reported no attacks.   
The percentage of attack-free days is derived as the total number of days during the dosing 
period for which subjects reported no attacks divided by the duration of the treatment.   
10.8.4. 
Attack Duration 
The duration of each confirmed attack will be calculated in hours, based on the start and stop 
date and time of the attack. For a confirmed 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. 
10.8.5. 
Attack Onset Relative to Prior Dose of Study Drug 
For each confirmed attack, the time to attack onset from the time of the prior dose of study drug 
reported in the subject CRF page will be calculated. If there is no dosing time reported for the 
dose taken prior to the attack, the attack will not be included in the attack onset analyses. 
10.8.6. 
Angioedema Activity Score (AAS) 
The basis of Angioedema Activity Score (AAS) (Weller, Groffik et al. 2013) consists of 5 
questions to be answered for each day during which a subject experiences an HAE attack. 
However, in this study, the answers to the following 4 questions will be collected for each attack: 
1. How severe was the physical discomfort caused by this attack, swelling episode or HAE 
symptom? 


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2. Were you able to perform your daily activities  during this attack, swelling episode, or 
HAE symptoms 
3. Did you feel your appearance was adversely affected by this attack, swelling episode, or 
HAE symptoms 
4. How would you rate the overall severity of this attack, swelling episode, or HAE 
symptoms 
A score between 0 and 3 (inclusive) will be assigned to the responses for each question, and the 
total score for each confirmed attack will be derived as the sum of the 4 question scores.  If more 
than 2 patient reported attacks are combined as 1 confirmed attack, the most severe response to 
each individual AAS question will be used for the confirmed attack. 
 
10.8.7. 
Attack HAE Medications 
All HAE medications reported taken for a confirmed attack will be included in the analyses. 
10.8.8. 
Attack Symptoms 
All symptoms reported for a confirmed attack will be included in the analyses.   
10.8.9. 
Attack Triggers 
All attack triggers for a confirmed attack will be included in the analyses.   
10.8.10. 
Attack Location 
All anatomical locations of swelling reported for a confirmed attack will be included in the 
analyses. 
 


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11. 
STUDY POPULATION 
11.1. 
Subject Disposition 
A summary table will be generated to provide the following: 
• Number of subjects screened 
• Number and percentage of screening failures 
• Reason for screening failure 
• Number and percentage (based on subjects randomized) of subjects in the RS 
population 
• Number of subject randomized and not treated 
• Number and percentage (based on subjects randomized) of subjects in the Safety 
population 
• Number and percentage (based on subjects randomized) of subjects in the FAS 
population 
• Number and percentage (based on subjects randomized) of subjects in the PP 
population 
• Number and percentage (based on subjects randomized) of subjects in the PK 
population 
• Number and percentage (based on subjects randomized) of subjects in each PD 
population 
Subject status at study completion will be listed and summarized.  The listing will include 
whether subjects discontinued from the study drug and 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 study.  A summary table will be 
generated to show: 
• Number and percentage of subjects in the Safety population who completed the study 
• Number and percentage of subjects in the Safety population who discontinued the 
study 
• Number and percentage of subjects in the Safety population who completed the study 
drug 
• Number and percentage of subjects in the Safety population who discontinued the 
study drug 
• Reason for discontinuation of study drug 
• Reason for discontinuation of study 
A CONSORT diagram will be created based on the summary tables for the study report. 


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11.2. 
Protocol Deviations 
Subjects who were randomized but did not satisfy all inclusion and exclusion criteria will be 
listed.  A listing of subjects for whom the treatment blind was broken during the study will also 
be provided, if appropriate. Subjects with dosing compliance <80% will be considered to have a 
major protocol deviation. Additional protocol deviations will be reviewed in a data review 
meeting to classify protocol deviations based on BioCryst Classification of protocol deviation 
Memo, and to discuss any statistical analysis issues.  
11.3. 
Potential Revisions to the SAP 
 
Potential revisions to the SAP include the refinement of the following: computational algorithms, 
rules for handling missing or otherwise unclear data, population definitions, and protocol 
deviations. Statistical methods may be modified if the underlying assumptions of intended 
methods are violated upon inspection at or before the Data Review Meeting.  All revisions will 
be reported in the study report.  
 
11.4. 
Demographic and Baseline Characteristics 
11.4.1. 
Demography 
The Safety, FAS and PP populations will be the primary populations for analyses of 
demographics. Demographics, including age, gender, race, ethnicity, weight, height, and body 
mass index (BMI) will be listed and summarized. 
Body mass index (kg/m2) will be calculated using the standard formula:   
BMI (kg/m2) = Weight (kg)/[Height (m)]2 
11.4.2. 
HAE and HAE 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  
All HAE medical and medication history collected on the CRF will be listed. 
11.4.3. 
Medical History 
Medical history will be listed.  
 


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11.4.4. 
Physical Examination 
Physical examination will be listed.  
11.5. 
Concomitant Medications 
Medications received 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 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. 
Medication verbatim text will be coded using the World Health Organization (WHO) Drug 
Dictionary.  Use of non-study medications will be summarized (number and percentage of 
subjects) by treatment and WHO preferred name. Multiple drug use (by preferred name) will be 
counted once only per subject. No inferential statistics will be provided. 
Medications that were used for HAE related indications will be summarized separately (plasma-
derived C1-INH Berinert, Cinryze will be combined together).  Medication data will be listed. 


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12. 
EFFICACY ANALYSES 
The efficacy data will be summarized descriptively using the FAS and PP populations. Placebo 
subjects will be pooled across study parts for the final analyses. An overall summary by 
treatment group will be provided for each dosing period (i.e., entire and effective) defined in 
section 10.8 to show: 
• Number and percentage of subjects who reported at least 1 attack (non-adjudicated), 
and total number of subject reported attacks 
• Number of and percentage of subjects who reported at least 1 confirmed attack , and 
total  number of confirmed attacks 
• Number of and percentage of subjects who reported at least 1 confirmed attack that 
required treatment, and total  number and percentage of confirmed attacks that 
required treatment 
• Number of and percentage of subjects who reported at least 1 confirmed attack that 
did not require treatment, and total number and percentage of confirmed attacks that 
did not require treatment 
Inferential comparisons of the efficacy endpoints will be performed for each BCX7353 dose vs. 
Placebo and for pairwise dose groups. The FAS and PP populations will be used for the 
comparisons of efficacy endpoints. All efficacy data collected on CRF will be listed. A separate 
listing will be provided for the derived efficacy endpoints. 
 
12.1. 
Statistical Analysis Methods 
12.1.1. 
Analysis of Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the number of confirmed HAE attacks in the FAS and PP 
populations. The number of HAE attacks will be analyzed by treatment group using appropriate 
descriptive statistics for the weekly attack rate, change and percentage change from baseline in 
attack rate, proportion of subjects with no attacks, and number of attack-free days. Efficacy 
analyses will be conducted for HAE attacks reported over the entire dosing interval (Days 1 to 28 
inclusive) and during the effective dosing period in which BCX7353 should be at steady-state 
conditions (Days 8 to 28, inclusive). Efficacy endpoints will be summarized and listed for each 
treatment group.  
 
Between-treatment comparisons (active vs. placebo and between active dose groups) for the 
weekly attack rate will be performed using an analysis of variance model and an analysis of 
covariance (ANCOVA) model.  The adjusted qualifying attack rate will be included as a 
covariate in the ANCOVA model. The LSM for each treatment arm and the relative difference 
and associated 95% confidence intervals in attack rate between placebo and each active arm will 
also be calculated.  If the difference between the 350mg and placebo is statistically significant, 


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additional dose response assessments will be analyzed based on the Tukey, Ciminera, and Heyse 
trend test.   
 
The between treatment comparisons for the proportion of subjects who are attack free will be 
compared using a Fisher’s exact test. If data warrant, a general linear model (Logistic regression) 
will also be used to test the dose response.    
There will be no adjustments for multiplicity or previous interim analyses, if conducted,  and all 
statistical tests will be 2-sided with an alpha of 0.05. 
12.1.2. 
Supportive Analyses 
The distribution of the HAE attacks will be examined. Cumulative distribution function of the 
confirmed attack rate will be produced by treatment group. A supportive analysis will be 
performed using a Poisson-regression model based on the number of confirmed attacks. The 
model will include Treatment and weekly interval as fixed effects. 
The difference between the on treatment attack rate and the adjusted qualifying attack rate will 
be derived and summarized in tabular and graphical formats.  Scatter plots of the adjusted 
qualifying attack vs. the confirmed attack rate and change from the adjusted qualifying attack 
rate will be presented. The individual attack rate over time will plotted.  
12.1.3. 
Sensitivity analyses  
Missing data may have impact on the interpretation of the study results. To examine the nature of 
missing data, subjects who do not have HAE attack diary data completed for 28 days since the 
date of first dose will be listed. The number and percentage of subjects with missing data, the 
missing data pattern and total number of days with missing HAE attack diary data will be 
presented in tabular or graphical format. 
Sensitivity analyses will be performed using the same ANCOVA model including the fixed term 
for treatment group and the adjusted qualifying attack rate(s), and for the following attack-rate 
scenarios: 
1. Attack Rate based on available Diary data 
The attack rate will be derived as the total number (count) of confirmed attacks during the 
treatment period divided by the number of days HAE attack diary was completed. The attack rate 
will be calculated for each subject:   
𝑊𝑒𝑒𝑘𝑙𝑦 𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒=
 Number of Attacks ∗7
Number of days HAE Diary was completed 
 
2. Attack Rate based on Baseline observation carried forward (BOCF) 
For randomized and treated subjects who have missing HAE diary data during the 28 days of 
planed treatment period data due to any reason, their qualifying attack rate will be carried 
forward (BOCF) to derive the on treatment attack rate. The attack rate will be calculated for each 
subject:   


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𝑊𝑒𝑒𝑘𝑙𝑦 𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒=  (Number of Attacks Reported + Number of attacks imputed) ∗7
28
 
 
Number of attacks imputed is derived based on the adjusted qualifying attack rate for the days 
HAE attack diary were not completed.  
Number of attacks imputed =  Number of days missed ∗Qualifying attack rate
 7
 
3. Sensitivity analyses based on subject reported attacks will be performed using the similar 
ANCOVA model including the fixed term for treatment group and the subject reported 
qualifying attack rate(s) as a covariate. 
 
12.1.4. 
Analysis of Secondary Efficacy Endpoints 
 
The number and percentage of attack-free days will be analyzed similarly to the attack rate 
endpoint.  The secondary efficacy endpoints including attack location, duration, symptoms of 
attacks, and number and percent of attacks requiring attack medication will be summarized for 
each treatment group.  
 
The between-treatment comparisons for the weekly attack rate will be also be performed 
separately by attack location (peripheral or abdominal) using the ANCOVA model as described 
for the primary endpoint.  
 
The attack onset relative to the time of last dose of study drug, discontinuations due to lack of 
efficacy and number of emergency room visits and/or hospitalizations will also be reported by 
treatment group. 
 
AAS will be summarized descriptively by treatment group for each AAS question at attack level 
and at subject level.  The most severe response from all confirmed attacks will be used at subject 
level summary. The between treatment group comparisons for the total AAS score and individual 
AAS question scores will be performed using an ANCOVA model. The adjusted qualifying 
attack rate will be included as a covariate. 
 
The following additional efficacy analyses will also be performed: 
 
• The attack rate in the pre and post treatment periods 
• Time intervals between attacks 
 
Time intervals between attacks will be derived as follows: 
 
Subjects with no attack:               Interval = duration of treatment or 28 
Subjects with 1 attack:                 Interval = the Max of the duration of (the first dose to start of 
the attack) or (stop of attack to the end of the dose ) 


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Subjects with >1 attack:               Interval = the duration between the stop of the first attack and 
start of the next attack (subjects with N attacks will have n-1 intervals) 
 
• Time to first attack after the study medication   
 
The time to first attack after the first study medication will be summarized descriptively and 
graphically using Kaplan-Meier method.  The Kaplan-Meier (KM) estimate for the median, and 
the first and third quartiles will be determined along with approximate 95% confidence intervals.  
Brookmeyer-Crowley method will be used for the confidence interval calculation.  Subjects who 
do not have an attack will be censored at the date of last dose for the KM analysis. 
 
• Time to first attack after the last dose  
 
The time to first attack after the last dose will be summarized descriptively and graphically using 
Kaplan-Meier method.  The Kaplan-Meier (KM) estimate for the median, and the first and third 
quartiles will be determined along with approximate 95% confidence intervals.  Brookmeyer-
Crowley method will be used for the confidence interval calculation.  Subjects who do not have 
an attack will be censored at the date of last follow-up assessment for the KM analysis. 
  
• Time to treatment  
The time to treatment defined as the time from the start of an attack to the use of the first HAE 
medication reported in the diary will be derived for each attack and summarized by treatment, by 
country and site at attack level. 
 
The time to first HAE medication will also summarized graphically using KM method. The KM 
estimate for the median and the first and third quartiles will be determined along with 
approximate 95% confidence intervals.  Brookmeyer-Crowley method will be used for the 
confidence interval calculation.  Subjects who do not take medication will be censored at end of 
the attack.    
  
12.1.4.1. Angioedema Quality of Life (AE-QoL) 
The AE-QoL (Weller, Groffik et al. 2012) consists of four domains and a total score. 
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 


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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 
 
The AE-QoL domain  scores and the AE-QoL total score are calculated using the following 
formula: 
(Σ items – min Σ items )/( max Σ items – min Σ items) x 100 
where 
Σ items= Sum of reported item scores per CRF 
min Σ items= Sum of the Minimum possible score for each domain 
max Σ items= Sum of the Maximum possible score for each domain 
The calculated AE-QoL ranges from 0 (best) to 100 (worst).  
The actual and change from baseline scores by domain and total will be summarized by visit and 
treatment. The AE-QoL change from baseline will be analyzed using an ANCOVA model. The 
estimated treatment difference for each BCX7353 dose– Placebo at each visit (ie, Baseline, and 
Day 29) will be displayed together with the 95% confidence interval and the associated p-value. 
Least Squares Means (LS Means) for each visit will also be presented with the standard error and 
the number of subjects contributing to the LS Means. The responses to the individual AE-QoL 
questions will also be listed. 
12.1.4.2. Depression, Anxiety, Stress Scales (DASS) 
 
The DASS (Crawford and Henry 2013) is a set of three self-report scales designed to measure 
the negative emotional states of depression, anxiety and stress. Each of the three DASS scales 
contains 14 items, divided into subscales of 2-5 items with similar content. The Depression scale 
assesses dysphoria, hopelessness, devaluation of life, self-deprecation, lack of 
interest/involvement, anhedonia, and inertia. The Anxiety scale assesses autonomic arousal, 
skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The 
Stress scale is sensitive to levels of chronic non-specific arousal. It assesses difficulty relaxing, 
nervous arousal, and being easily upset/agitated, irritable/over-reactive and impatient. Subjects 
are asked to use 4-point severity/frequency scales to rate the extent to which they have 
experienced each state over the past week. Scores for Depression, Anxiety and Stress are 
calculated by summing the scores for the relevant items. 
The rating scale is as follows: 
0  Did not apply to me at all 


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1  Applied to me to some degree, or some of the time 
2  Applied to me to a considerable degree, or a good part of time 
3  Applied to me very much, or most of the time 
 
Scores of Depression, Anxiety and Stress are calculated by summing the scores for the 
relevant items.  
 
The depression scale items are 3, 5, 10, 13, 16, 17, 21, 24, 26, 31, 34, 37, 38, 42.  
The anxiety scale items are 2, 4, 7, 9, 15, 19, 20, 23, 25, 28, 30, 36, 40, 41.  
The stress scale items are 1, 6, 8, 11, 12, 14, 18, 22, 27, 29, 32, 33, 35, 39. 
 
The score for each of the subjects over each of the sub-scales, are then evaluated as per the 
severity-rating index below. 
 
 
Depression 
Anxiety 
Stress 
Normal 
0-9 
0-7 
0-14 
Mild 
10-13 
8-9 
15-18 
Moderate 
14-20 
10-14 
19-25 
Severe 
21-27 
15-19 
26-33 
Extremely Severe 
28+ 
20+ 
34+ 
 
A total DASS score will be derived as the sum of three scales.  DASS (total and individual scale 
score) will be analyzed similarly as AE-QOL.  The actual and change from baseline scores by 
domain and total will be summarized by visit and treatment. The DASS change from baseline 
will be analyzed using an ANCOVA mixed model. The estimated treatment difference for each 
BCX7353 dose– Placebo at each visit (ie, Baseline, and Day 29) will be displayed together with 
the 95% confidence interval and the associated p-value. Least Squares Means (LS Means) for 
each visit will also be presented with the standard error and the number of subjects contributing 
to the LS Means.  
 
The number and percentage of subjects in the severity-rating index categories will also be 
summarized by treatment and visit.  The responses to the individual DASS questions will also be 
listed. 
The relationship among the AE-QOL, DASS domains and confirmed weekly HAE attack rate 
will be provided descriptively and graphically using Pearson or Spearman correlation coefficient 
statistics and scatter plots.  
12.2. 
Extent of Exposure 
The number of subjects exposed to study drug and the duration of treatment will be summarized 
by treatment group. 
12.3. 
Treatment Compliance 
Treatment compliance will be computed by determining the number of capsules taken relative to 
the number of capsules that should have been administered. Treatment compliance based on the 


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drug accountability page and dosing diary will be calculated separately using the same formula 
below. 
For compliance (%) based on the dosing diary: 
compliance (%)= (number of capsules taken)/(number of capsules expected)*100 
For compliance (%) based on the drug accountability page: 
number of capsules taken= the number of capsules dispensed – the number of capsules 
returned 
number of capsules expected= (date of the last dose-date of the first dose+1)*3 
Summary of treatment compliance will be presented by treatment group and method. The 
number and percentage for compliance expressed as a categorical variable (<80%, ≥80%) will be 
also presented by treatment group and method. 
12.4. 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 18.1).  
System organ class (SOC), high level group term, high level term, preferred term, and lower 
level term will be attached to the clinical database. A table showing the mappings of AE 
verbatim text to the coded terms will be provided. 
Adverse events with an onset date and time prior to the first dose of study drug for the study will 
be assigned as a pre-dose AE for the listing and will not be included in the summaries.  
Treatment-emergent AEs are defined as AEs that occurred on or after date of first dose of study 
drug and up to +30 days after the last dose. Investigators are not required to contact subjects after 
the last follow-up if it occurs prior to 30 days from last dose.  
12.4.1. 
Adverse Event Severity and Toxicity Grading 
Adverse events are graded by the Investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), or Grade 4 (life-threatening) according to DMID Adult Toxicity Table (Draft, publish 
date : November 2007). 
 
12.4.2. 
Summaries of Adverse Events 
Summaries of treatment emergent AEs will be provided for the Safety Population.  No inferential 
statistics will be provided.  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), drug related SAE, or 9) died.  Drug-related events are defined as 
those AEs in which the Investigator believes were possibly, probably, or definitely related to the 
study drug. 
AEs will be summarized by treatment group. For each SOC and preferred term, 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 


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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. 
The following summary tables (number and percentage of subjects) of treatment-emergent AEs 
(by SOC and preferred term) will be provided by treatment group: 
• Overall summary of Treatment-Emergent adverse events 
• Summary of treatment-emergent adverse events 
• Summary of drug-related, treatment-emergent adverse events 
• Summary of treatment-emergent adverse events by severity 
• Summary of treatment-emergent Grade 3 or Grade 4 adverse events 
• Summary of drug-related, treatment-emergent Grade 3 or Grade 4 adverse events 
• Summary of serious treatment-emergent adverse events 
• Summary of treatment-emergent adverse events leading to permanent discontinuation 
of study drug 
• Summary of treatment-emergent adverse events leading to interruption of study drug 
• Summary of drug-related, treatment-emergent serious adverse events 
• Summary of Treatment-Emergent Rashes Considered Related to Study Drug 
 
Data listings will be provided for all AE data.  In addition to listing all AEs, distinct data listings 
will also be provided for 1) Grade 3 or Grade 4 AEs, 2) AEs leading to permanent study 
discontinuation, 3) SAEs and deaths, 4) Rashes. 
 
12.5. 
Clinical Laboratory Evaluations 
Summaries of clinical laboratory data will be provided for subjects in the Safety Population 
based on central lab data. No inferential statistics will be provided. All laboratory assessments 
collected after date of first dose of study drug and up to +30 days after the last dose will be 
included in the summary tables. All laboratory data will be listed. 
12.5.1. 
Summaries of Numeric Laboratory Results 
Quantitative values and change from baseline in quantitative values will be summarized by 
planned nominal time and treatment for each quantitative lab.  Listings of all laboratory results 
and reference ranges will be provided.  Laboratory values that fall outside the reference range 
will be flagged.  
12.5.2. 
Graded Abnormalities 
Clinical laboratory results will be graded according to criteria specified in the protocol using 
DMID Adult Toxicity Table (2007), if applicable.  


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Any graded abnormality that occurs following the initiation of study drug and up to +30 days 
after the last dose, 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 by treatment group. A laboratory shift table will 
be provided to show the baseline grade to the maximum post baseline grade. Laboratory values 
that do not meet the graded laboratory abnormalities are assigned grade 0 in the shift table. 
12.6. 
Vital Signs 
Vital sign data (blood pressure [BP], heart rate [HR], and body weight) will be summarized by 
treatment, visit, and planned time and will be listed by subject, visit, treatment, planned time and 
actual date and time.  Change from baseline for BP, HR, and body weight will also be 
summarized.   
12.7. 
Electrocardiograms 
The ECG data and change from baseline values will be listed and summarized by treatment, visit 
and planned time. The number and proportion of subjects with QTcF >450, >480 or >500 msec; 
or changes of >30 -≤60 msec, or >60 msec will be summarized by treatment over time. 
Clinically significant abnormal ECG findings will also be summarized. 
12.8. 
Pulmonary Diffusion 
Pulmonary diffusion data, including actual and percent change from baseline values will be listed 
and summarized by treatment and visit.      
12.9. 
Pregnancy 
If any female subjects or female partners of male subjects become pregnant during the study, a 
listing will be provided. 
12.10. 
Other Safety data 
Number and percentage of attacks that required additional medical care and type of medical care 
will be summarized by treatment group, if data warrant.  


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13. 
PHARMACOKINETIC ANALYSES 
13.1. 
Drug Concentration Measures 
Plasma concentrations of BCX7353 will be measured by a validated assay. These plasma 
concentrations will be listed for all subjects with a result (including those from placebo-treated 
subjects) and summarized by active treatment and time using the Safety Population. Linear and 
semi-log figures for individual subjects as well as mean and median concentration-time data will 
be generated. 
13.2. 
Deriving and Summarizing Pharmacokinetic Parameters 
Steady-state BCX7353 (metabolites if measured) plasma PK parameters will be estimated over 
the sampling interval for each subject using noncompartmental analysis (Phoenix WinNonlin 
version 6.4 or later, Certara, LP). Steady-state BCX7353 PK parameters collected on Day 14 or 
Day 28 will be combined by treatment group for summary statistics. The PK population will be 
used for the evaluation of PK parameter data. 
The PK parameters that may be estimated are listed below. Additional analyses may be 
conducted as appropriate. 
 
 
For the calculation of individual PK parameters, all PK concentrations that are BQL will be set 
to zero except when an individual BQL value falls immediately between two quantifiable values, 
in which case it will be set to missing. Actual elapsed time from dosing will be used to estimate 
Pharmacokinetic 
Parameter 
Definition 
AUCtau  
Area under the plasma concentration versus time curve over the 
dosing interval (tau) (ie, 8 hours for q8h dosing) 
Cav,ss  
Average steady-state plasma drug concentration during multiple-
dose administration 
Cmax 
Maximum observed concentration of drug 
Ctau 
Observed drug concentration at the end of the dosing interval (tau) 
t1/2 
Estimate of the terminal elimination half-life of the drug, 
calculated as 0.693/λz 
CL/F 
Apparent oral clearance after administration of the drug calculated 
as Dose/AUCtau  
 
λz 
Terminal elimination rate constant, estimate by linear regression of 
the terminal elimination phase  of the natural logarithm of 
concentration of drug versus time curve 
Vz/F 
Apparent volume of distribution of the drug 
Tmax 
Time of Cmax 


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all the individual plasma PK parameters.   
 
The appropriateness of estimation of λz and λz-derived parameter estimates will depend on an 
accurate estimation of the terminal elimination phase of the analyte, based upon inspection of 
individual subject PK profiles. λz and λz -derived parameter estimates that are considered by the 
Clinical Pharmacologist at BioCryst to be unreliable may be excluded from the summary 
statistics. In general, a minimum of three time points in the terminal phase with unadjusted R2 
≥0.7 will be required to report λz.  
 
Plasma PK parameters, except Tmax, will also be summarized based on log transformed data. 
 
Dose proportionality will be analyzed using a power model, and the slope and its 90% 
confidence interval will be estimated. A secondary assessment of dose proportionality will be 
made using log transformed dose normalized AUC and Cmax, which will be analyzed by using an 
analysis of variance including terms for dose effects. Each dose will be compared with the 
125mg dose on a pair-wise basis, with the ratio and its 90% confidence interval estimated . 
 
The trough plasma BCX7353 concentrations obtained pre-dose or 24 hour post-dose on Days 14, 
15, 28 and 29 (as applicable) will be plotted and summarized by treatment group.  Achievement 
of steady-state will be assessed by calculating the 90% CI of the slope of the linear regression of 
Days 14-29 trough concentration versus Day for each treatment group. 
 
The number and proportion of subjects with average plasma BCX7353 trough concentrations 
(Ctau) above 4x and 8x kallikrein inhibition EC50 values (35.8 ng/mL and 71.6 ng/mL will be 
summarized by treatment group.   
 
For each subject, the percent of plasma BCX7353 trough concentrations (Ctau) above 4x and 8x 
kallikrein inhibition EC50 will be derived and summarized by treatment group.  


BioCryst, Inc. Protocol No. BCX7353-203 
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CONFIDENTIAL 
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14. 
PHARMACODYNAMIC ANALYSES 
14.1. 
Kallikrein Inhibition, Cleaved HK Fragments, and C1 INH 
On–treatment plasma kallikrein inhibition data (assessed with and without stimulation by ellagic 
acid) will be expressed as percent inhibition compared to subject baseline activity. Ex vivo 
plasma kallikrein activity will be listed by subject, treatment, day, and time and summarized 
separately by treatment, day, and time. Descriptive statistics will be reported. Mean and 
individual plasma kallikrein inhibition versus time profiles will be plotted by treatment group.  
Plasma kallikrein inhibition data from Day 14 or Day 28 will be combined by treatment group 
for analysis. The difference between each active treatment group vs placebo and between active 
doses in plasma kallikrein inhibition will be analyzed using a repeated measures analysis of 
variance with time, treatment and time by treatment as fixed effects.  Subject will be fitted as a 
random effect in the model. The point estimates and corresponding 95% confidence interval (CI) 
for treatment differences will be calculated at each time point. 
Cleaved HK fragments and C1 INH functional levels and absolute change from baseline will be 
summarized by treatment group.  The HK end of treatment /Baseline ratio will also be listed and 
summarized by treatment group.  The difference between each active treatment group and 
placebo and the pairwise difference between active doses in C1inh Change from baseline, 
cleaved HK change from baseline and HK end of treatment /Baseline ratio will be analyzed 
using ANOVA with treatment as fixed effects. Baseline value will be included as a covariate.  
The point estimates and corresponding 95% confidence interval (CI) for treatment differences 
will be calculated for each comparison.   
 
14.2. 
Correlations of Dose or Drug Exposure with Pharmacodynamic 
Responses and Efficacy Outcomes 
The following dose-response and exposure-response analyses of the relationships between 
pharmacokinetic, pharmacodynamic and efficacy measures will be explored using descriptive 
statistics, correlation assessment and model-based techniques as data permit: 
  
• Correlation and exposure-response between plasma kallikrein inhibition and 
BCX7353 plasma concentrations 
 
• Correlation and exposure-response between BCX7353 PK Parameters (Cmax, AUCtau, 
mean Ctau) and confirmed weekly HAE attack Rate 
 
• Correlation between BCX7353 PK Parameters (Cmax, AUCtau, mean Ctau) and cleaved 
HK Change from baseline to the end of study and HK Follow-up/Baseline Ratio 
 
• Correlation between the percent of plasma BCX7353 trough concentrations (Ctau) 
above 4x and 8x kallikrein inhibition EC50 and confirmed attack rate  
 


BioCryst, Inc. Protocol No. BCX7353-203 
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The correlation and exposure-response assessments will be presented graphically using a scatter 
plot along with the fitted regression line. Person correlation coefficient and p-value will be 
included on the plot.  
 
• Plasma BCX7353 concentration, PK Parameters (Cmax, AUCtau, mean Ctau), and PD 
(HK, C1INH) data will be presented by attack free status 
 
The PK and PD parameter will be summarized by subgroup based on attack free status for the 
subjects received the active BCX7353 dose. The between group difference will be estimate based 
on an ANCOVA model including fixed effect of subgroup. The qualifying attack rate will be 
included as a covariate. 
 
• Comparison of confirmed attack rate between subgroup based on average plasma 
BCX7353 trough concentrations (Ctau) above 4x and 8x kallikrein inhibition EC50 
values 
 
The confirmed attack rate will be summarized by subgroup based on the average plasma 
BCX7353 trough concentrations (Ctau) for subjects received the active BCX7353 doses. The 
between group difference will be estimate based on an ANCOVA model including fixed effect of 
subgroup. The qualifying attack rate will be included as a covariate. 
  
Additional PK-PD analysis may be explored as data permit. 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 48 of 59                                                07FEB 2017 
 
 
15. 
REFERENCES 
SAS Institute Inc., SAS® Version 9.1 Software, Cary, North Carolina, USA. 
Weller, K., A. Groffik, et al. (2012). “Development and construct validation of the angioedema 
quality of life questionnaire.” Allergy 67(10): 1289-1298. 
Weller, K., A. Groffik, et al. (2013). “Development, Validation and initial Results for the 
Angioedema Activity Score (AAS).” Allergy 68(9): 1185-92. 
Crawford, J. R. and J. D. Henry (2013). “The Depression Anxiety Stress Scales (DASS): 
Normative data and latent structure in a large non-clinical sample.” British J Clin Psychol 42: 
111-131. 


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16. 
TABLES, FIGURES AND LISTINGS 
Tables  
Title 
 Population 
Study Population 
14.1.1 
Summary of Study Disposition 
All Subjects 
14.1.2 
Summary of Study Disposition by Country and Site  
Safety 
14.1.2 
Summary of Study Completion 
Safety 
14.1.3.1 
Summary of Demography 
FAS 
14.1.3.2 
Summary of Demography 
PP 
14.1.3.3 
Summary of Demography  
Safety 
14.1.3.4 
Summary of Sub-groups 
Safety 
14.1.3.5 
Summary of Medical History   
Safety 
14.1.4.1 
Summary of Concomitant Medications 
Safety 
14.1.4.2 
Summary of Concomitant Medications for HAE 
Safety 
14.1.5.1 
HAE Demography – HAE History  
Safety 
14.1.5.2 
HAE Demography – Past on-Demand Treatments of HAE 
Safety 
14.1.5.3 
HAE Demography – Current on-Demand Treatments of HAE 
Safety 
14.1.5.4 
HAE Demography – Past Prophylactic Treatments of HAE 
Safety 
14.1.5.5 
Summary of Pretreatment Attack Rate (include Subject reported qualifying 
rate, adjusted qualifying rate,  Screening attack rate) 
Safety 
14.1.5.6 
Summary of Attack Confirmation  
Safety 
14.1.6.1 
Summary of Inclusion/Exclusion Criteria Deviations 
Safety 
14.1.6.2 
Summary of Protocol Deviation 
Safety 
 
 
 
Efficacy Tables for Entire Dosing Period and Entire Study Period  
All tables will be repeated for the PP population 
Table Numbering: FAS tables will end as .1; PP tables will end as .2   
14.2.1.1.1 
Overall Attack Summary during Entire Dosing Period 
FAS  
14.2.1.1.2 
Overall Attack Summary during Entire Dosing Period 
PP  
14.2.1.1.3 
Overall Attack Summary during Entire Study Period 
FAS  
14.2.1.1.4 
Overall Attack Summary during Entire Study Period 
PP  
14.2.1.2 
Summary of Rate of Confirmed Attacks during Entire Dosing Period  
(include the difference from the adjusted qualifying rate on the same table) 
FAS/PP     
14.2.1.2.3 
Summary of Rate of Confirmed Attacks during Entire Study Period  
(include the difference from the adjusted qualifying rate on the same table)  
FAS 
14.2.1.2.4 
Summary of Rate of Confirmed Attacks during Entire Study Period   
(include the difference from the adjusted qualifying rate on the same table) 
PP 
14.2.1.3 
Summary of Number of Confirmed Attacks by Week during Entire Dosing 
Period 
FAS/PP   
14.2.1.4 
Summary of Rate of Confirmed Attacks Requiring Treatment during Entire 
Dosing Period 
FAS/PP 
14.2.1.5 
Summary of Rate of Confirmed Abdominal Attacks during Entire Dosing 
Period 
FAS/PP 
14.2.1.6 
Summary of Rate of Confirmed Peripheral Attacks during Entire Dosing 
FAS/PP   


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Tables  
Title 
 Population 
Period 
14.2.1.7 
Summary of Rate of Subject-Reported Attacks during Entire Dosing Period 
FAS/PP 
14.2.1.8 
Statistical Analysis of Rate of Confirmed Attacks during Entire Dosing 
Period 
FAS/PP   
14.2.1.8.3 
Statistical Analysis of Rate of Confirmed Attacks during Entire Study 
Period 
FAS  
14.2.1.8.4 
Statistical Analysis of Rate of Confirmed Attacks during Entire Study 
Period 
PP   
14.2.1.9 
Statistical Analysis of Rate of Confirmed Attacks during Entire Dosing 
Period -  Poisson-regression Model   
FAS/PP 
14.2.1.10 
Statistical Analysis of Rate of Confirmed Attacks Requiring Treatment 
during Entire Dosing Period  
FAS/PP   
14.2.1.11 
Sensitivity Statistical Analysis of Rate of Confirmed Attacks Excluding 
Missing Diary Days during Entire Dosing Period  
FAS/PP   
14.2.1.12 
Sensitivity Statistical Analysis of Rate of Confirmed Attacks during Entire 
Dosing Period (BOCF) 
FAS/PP   
14.2.1.13 
Statistical Analysis of Rate of Confirmed Abdominal Attacks during Entire 
Dosing Period 
FAS/PP   
14.2.1.14 
Statistical Analysis of Rate of Confirmed Peripheral Attacks during Entire 
Dosing Period 
FAS/PP   
14.2.1.15 
Statistical Analysis of Rate of Subject-Reported Attacks during Entire 
Dosing Period (subject reported qualifying rate will be used as covariate) 
FAS/PP   
14.2.1.16 
Summary of Proportion of Subjects who are Attack-free during Entire 
Dosing Period (include sensitivity analyses of missing=failure; 
missing=excluded )  
FAS/PP   
14.2.1.16.3 
Summary of Proportion of Subjects who are Attack-free during Entire Study 
Period (include sensitivity analyses of missing=failure; missing=excluded )  
FAS 
14.2.1.16.4 
Summary of Proportion of Subjects who are Attack-free during Entire Study 
Period (include sensitivity analyses of missing=failure; missing=excluded )  
PP 
14.2.1.17 
Summary of Number of Attack-free days during Entire Dosing Period 
FAS/PP   
14.2.1.18 
Summary of Percent of Attack-free days during Entire Dosing Period 
FAS/PP 
14.2.1.19 
Statistical Analysis of Number of Attack-free days during Entire Dosing 
Period 
FAS/PP   
14.2.1.20 
Statistical Analysis of Percent of Attack-free days during Entire Dosing 
Period 
FAS/PP   
14.2.1.21 
Assessment of Dose Response - Entire Dosing Period 
FAS/PP 
Efficacy Tables for Effective Dosing Period 
All tables will be repeated for the PP population 
Table Numbering: FAS tables will end as .1; PP tables will end as .2   
14.2.2.1 
Overall Attack Summary during Effective Dosing Period 
FAS/PP   
14.2.2.2 
Summary of Rate of Confirmed Attacks during Effective Dosing Period 
(include the difference from qualifying on the same table) 
FAS/PP 
14.2.2.3 
Summary of Number of Confirmed Attacks by Week during Effective 
Dosing Period 
FAS/PP   
14.2.2.4 
Summary of Rate of Confirmed Attacks Requiring Treatment during 
Effective Dosing Period 
FAS/PP 
14.2.2.5 
Summary of Rate of Confirmed Abdominal Attacks during Effective Dosing 
FAS/PP   


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Tables  
Title 
 Population 
Period 
14.2.2.6 
Summary of Rate of Confirmed Peripheral Attacks during Effective Dosing 
Period 
FAS/PP 
14.2.2.7 
Summary of Rate of Subject-Reported Attacks during Effective Dosing 
Period 
FAS/PP   
14.2.2.8 
Statistical Analysis of Rate of Confirmed Attacks during Effective Dosing 
Period 
FAS/PP 
14.2.2.9 
Statistical Analysis of Rate of Confirmed Attacks during Effective Dosing 
Period -  Poisson-regression Model     
FAS/PP   
14.2.2.10 
Statistical Analysis of Rate of Confirmed Attacks Requiring Treatment 
during Effective Dosing Period  
FAS/PP 
14.2.2.11 
Sensitivity Statistical Analysis of Rate of Confirmed Attacks Excluding 
Missing Diary Days during Effective Dosing Period  
FAS/PP   
14.2.2.12 
Sensitivity Statistical Analysis of Rate of Confirmed Attacks during 
Effective Dosing Period (BOCF) 
FAS/PP   
14.2.2.13 
Statistical Analysis of Rate of Confirmed Abdominal Attacks during 
Effective Dosing Period 
FAS/PP 
14.2.2.14 
Statistical Analysis of Rate of Confirmed Peripheral Attacks during 
Effective Dosing Period 
FAS/PP   
14.2.2.15 
Statistical Analysis of Rate of Subject-Reported Attacks during Effective 
Dosing Period (subject reported qualifying rate will be used as covariate) 
FAS/PP 
14.2.2.16 
Summary of Proportion of Subjects who are Attack-free during Effective 
Dosing Period (include sensitivity analyses of missing=failure; 
missing=excluded ) 
FAS/PP   
14.2.2.17 
Summary of Number of Attack-free days during Effective Dosing Period 
FAS/PP 
14.2.2.18 
Summary of Percent of Attack-free days during Effective Dosing Period 
FAS/PP   
14.2.2.19 
Statistical Analysis of Number of Attack-free days during Effective Dosing 
Period 
FAS/PP 
14.2.2.20 
Statistical Analysis of Percent of Attack-free days during Effective Dosing 
Period 
FAS/PP   
14.2.2.21 
Assessment of Dose Response - Effective Dosing Period 
FAS/PP 
The following will be provided for the Entire Dosing Period 
All tables will be repeated for the PP population 
Table Numbering: FAS tables will end as .1; PP tables will end as .2   
  
14.2.3.1.1 
Summary of Time intervals between Attacks  
FAS/PP   
14.2.3.2 
Summary of AAS Categorical Response -Attack level  
FAS/PP 
14.2.3.3 
Summary of AAS Categorical Response -Subject level  (worst response for 
each AAS question) 
FAS/PP   
14.2.3.4 
Summary of AAS Total Score (include AAS total and Domain Total Score)  
FAS/PP 
14.2.3.5 
Statistical Analysis of AAS Total Score (include AAS total and Domain 
Total Score)  
FAS/PP   
14.2.3.6 
Summary of Attack Duration at Subject Level – Confirmed Attacks  
FAS/PP 
14.2.3.7 
Summary of Attack Duration of All Confirmed Attacks  
FAS/PP   
14.2.3.8 
Summary of Attack Triggers – Confirmed Attacks 
FAS/PP 
14.2.3.9 
Summary of Attack Symptoms – Confirmed Attacks 
FAS/PP   
14.2.3.10 
Summary of Number of Symptoms – Confirmed Attacks 
FAS/PP 


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Tables  
Title 
 Population 
14.2.3.11 
Summary of Attack Location – Confirmed Attacks  
FAS/PP   
14.2.3.12 
Summary of Attack Onset time from the last dose– Confirmed Attacks 
FAS/PP 
14.2.3.13 
Summary of Administrations of Acute HAE Medications – Confirmed 
Attacks 
FAS/PP   
14.2.3.14 
Number and Percentage of Attacks Requiring Additional Medical Care 
FAS/PP 
14.2.3.15 
Summary of time to treatment –Confirmed Attacks  (overall, by country and 
by site ) 
FAS/PP   
14.2.3.16 
Time to Treatment  (KM estimates) 
FAS/PP 
14.2.3.17 
Summary of Qualifying, Screening Attack and Post Treatment HAE attack 
Rate   
FAS/PP   
14.2.3.18 
Statistical Analysis of Post Treatment HAE attack Rate   
FAS/PP 
14.2.3.19 
Time of First Attack after the First Dose (KM estimates) 
FAS/PP   
14.2.3.20 
Time of First Attack after Last Dose (KM estimates) 
FAS/PP 
14.2.4.1 
Summary of AeQoL scores 
FAS/PP   
14.2.4.2 
Statistical Analysis of AeQoL Scores   
FAS/PP 
14.2.4.3 
Correlation among AeQoL and Attack Rate 
FAS/PP   
14.2.4.4 
Summary of DASS Severity-Rating Index Categories 
FAS/PP 
14.2.4.5 
Summary of DASS scores 
FAS/PP   
14.2.4.6 
Correlation among DASS Domains and Attack Rate 
FAS/PP 
14.2.4.7 
Correlation between AeQoL and DASS Domains 
FAS/PP   
14.2.5.1 
Statistical Analysis of DASS Scores   
FAS/PP 
Pharmacokinetic Analysis 
14.2.5.2 
Summary of Plasma BCX7353 Concentration  
PK 
14.2.5.3 
Summary of Derived Plasma BCX7353 Pharmacokinetic Parameters 
PK 
14.2.5.4 
Summary of Trough BCX7353 Concentration 
PK 
14.2.5.5 
Assessment of Dose Proportionality based on Power Model  
PK 
14.2.5.6 
Assessment of Dose Proportionality based on ANOVA  
PK 
14.2.5.7 
Assessment of Steady State  
PK 
14.2.5.8 
Number and Percent of Average Ctrough above 4xEC50 and 4xEC80 
PK 
14.2.5.9 
Summary of Percent of Ctrough above 8xEC50 and 8xEC80 
PK 
Pharmacodynamic Analysis 
14.2.6.1 
Summary of Plasma Kallikrein Inhibition 
KKI PD 
14.2.6.2 
Summary of Plasma Kallikrein Inhibition without Ellagic Acid Stimulation  
KKI PD 
14.2.6.3 
Statistical Analysis of Plasma Kallikrein Inhibition 
KKI PD 
14.2.6.4 
Statistical Analysis of Plasma Kallikrein Inhibition without Ellagic Acid 
Stimulation  
KKI PD 
14.2.6.5 
Summary of C1INH Functional and C4 Levels 
C1INH PD 
14.2.6.6 
Summary of Cleaved HK Fragments 
Cleaved HK 
PD 
14.2.6.7 
Statistical Analysis of Cleaved HK Fragments 
Cleaved HK 
PD 
14.2.6.8 
Summary of BMP Levels  
BMP PD 


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Tables  
Title 
 Population 
PKPD/Efficacy Analysis (PK-PD include subjects with measurements for both PK-PD/Efficacy 
data)  
14.2.7.1 
Summary of Plasma Kallikrein Inhibition by Attack Free Response 
KKI PD   
14.2.7.2 
Summary of Plasma BCX7353 Concentration by Attack Free Response 
PK   
14.2.7.3 
Summary of Trough BCX7353 Concentration by Attack Free Response 
PK   
14.2.7.4 
Summary of Derived Plasma BCX7353 Pharmacokinetic Parameters by 
Attack Free Response 
PK   
14.2.7.5 
Summary of cleaved HK levels by Attack Free Response 
HK PD     
14.2.7.6 
Summary of C1INH and C4 levels by Attack Free Response 
C1INH PD   
Additional PKPD and Efficacy analyses maybe performed if data permit.   
Safety 
14.3.1.1.1 
Summary of Treatment Exposure 
Safety 
14.3.1.1.2 
Summary of Study Drug Compliance – Drug Accountability   
Safety 
14.3.1.2 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
14.3.1.3 
Summary of Treatment-Emergent Adverse Events 
Safety 
14.3.1.4 
Summary of Drug-related Treatment-Emergent Adverse Event 
Safety 
14.3.1.5 
Summary of Treatment-Emergent Adverse Events by severity 
Safety 
14.3.1.6 
Summary of Treatment-Emergent Grade 3 or Grade 4 Adverse Events 
Safety 
 
Summary of Drug-related Treatment-Emergent Grade 3 or Grade 4 Adverse 
Events 
Safety 
14.3.1.7 
Summary of Treatment-Emergent Serious Adverse Events 
Safety 
14.3.1.8 
Summary of Treatment-Emergent Adverse Events leading to Permanent 
Discontinuation of Study Drug 
Safety 
14.3.1.9 
Summary of Treatment-Emergent Adverse Events leading to Interruption of 
Study Drug 
Safety 
14.3.1.10 
Summary of Drug-related Treatment-Emergent Serious Adverse Event 
Safety 
14.3.1.11 
Summary of Treatment-Emergent Rashes Considered Related to Study Drug 
Safety 
14.3.5.1 
Summary of Laboratory Values by Visit – Hematology 
Safety 
14.3.5.2 
Summary of Laboratory Values by Visit – Chemistry 
Safety 
14.3.5.3 
Summary of Laboratory Values by Visit – Urinalysis 
Safety 
14.3.5.4 
Summary of Graded Shift in Laboratory Abnormalities - Hematology 
Safety 
14.3.5.5 
Summary of Graded Shift in Laboratory Abnormalities – Chemistry 
Safety 
14.3.5.6 
Summary of Treatment-Emergent Laboratory Abnormalities 
Safety 
14.3.5.7 
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities 
Safety 
14.3.5.8 
Summary of Lab Toxicity Grade Increase from Baseline 
Safety 
14.3.6.1 
Summary of Vital Signs by Visit 
Safety 
14.3.6.2 
Summary of Body Weight by Visit 
Safety 
14.3.6.3 
Summary of QTcF Categorical Findings by Visit 
Safety 
14.3.6.4 
Summary of 12-lead Electrocardiograms Parameters by Visit 
Safety 
14.3.6.5 
Summary of 12-lead Electrocardiograms Assessment by Visit 
Safety 
14.3.6.6 
Summary of Pulmonary Diffusion data by Visit 
Safety 
14.3.6.7.1 
Summary of Fold x ULN for Liver Function Tests 
Safety 


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Tables  
Title 
 Population 
14.3.6.7.2 
Summary of Fold x ULN for Liver Function Tests –Subjects with Prior 
Androgen Use 
Safety 
14.3.6.7.3 
Summary of Fold x ULN for Liver Function Tests –Subjects without Prior 
Androgen Use 
Safety 
14.3.6.8.1 
Summary of Fold x from Baseline for Liver Function Tests   
Safety 
14.3.6.8.2 
Summary of Fold x from Baseline for Liver Function Tests  –Subjects with  
Prior Androgen Use 
Safety 
14.3.6.8.3 
Summary of Fold x from Baseline for Liver Function Tests –Subjects 
without Prior Androgen Use  
Safety 
14.3.6.9.1 
Summary of Number of Subjects with Elevations in Post Baseline Liver 
Function Tests   
Safety 
14.3.6.9.2 
Summary of Number of Subjects with Elevations in Post Baseline Liver 
Function Tests  –Subjects with Prior Androgen Use 
Safety 
14.3.6.9.3 
Summary of Number of Subjects with Elevations in Post Baseline Liver 
Function Tests  –Subjects without Prior Androgen Use 
Safety 


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Figures 
Title 
Population 
Study population 
14.1.1 
Consort Diagram 
All subjects 
14.1.2 
Time to study drug discontinuation    
RS 
Efficacy 
All Efficacy Figure will be repeated for the PP population 
Table Numbering: FAS tables will end as .1; PP tables will end as .2   
14.2.1.1 
Plot of Estimated Treatment Effect (If data permit, Forest plot to show 
estimated between treatment difference and 95%CI, for overall and by each 
subgroup) 
FAS  
14.2.1.2 
Plot of Individual Attack Rate by Treatment –Confirmed Attack 
FAS 
14.2.1.3 
Cumulative Distribution Function of the Confirmed Attack Rate 
FAS 
14.2.1.4 
Plot of Individual Attack Rate by Treatment – Subject Reported Attack 
FAS 
14.2.1.5 
Plot of Confirmed Attack and Acute HAE Medications 
FAS 
14.2.1.6 
Plot of Qualifying Attack Rate (Histogram Plot)   
FAS 
14.2.1.7 
Plot of Individual Attack Rate Overtime (Line plot for each subject)   
FAS 
14.2.1.8 
Plot of On-study Confirmed Attack Rate vs Qualifying Attack Rate 
FAS 
14.2.1.9 
Plot of Difference between On-study Confirmed Attack Rate and Qualifying  
Attack Rate vs Qualifying Attack Rate  
FAS 
14.2.1.10 
Plot of Percentage of Difference between On-study Confirmed Attack Rate 
and Qualifying Attack Rate vs Qualifying Attack Rate 
FAS 
14.2.1.11 
KM Plot of Time to First Attack after Last Dose 
FAS 
14.2.1.12 
KM Plot of Time to First Attack after First Dose 
FAS 
14.2.1.13 
KM Plot of Time to Treatment   
FAS 
14.2.1.XX 
Correlation Plots of AE-Qol, DASS and Confirmed Attack endpoints 
(will plot the domains with significant correlation at P<0.10)  
FAS 
 
   
 
Pharmacokinetic Analysis 
14.2.2.1 
Mean Plasma BCX7353 Concentration-time plot –linear Scale   
PK 
14.2.2.2 
Mean Plasma BCX7353 Concentration-time plot – semi-logarithmic scale 
PK 
14.2.2.3 
Median Plasma BCX7353 Concentration-time plot –linear Scale   
PK 
14.2.2.4 
Median Plasma BCX7353 Concentration-time plot – semi-logarithmic scale 
PK 
14.2.2.5 
Individual Plasma BCX7353 Concentration-time plot –linear Scale   
PK 
14.2.2.6 
Individual Plasma BCX7353 Concentration-time plot  - semi-logarithmic 
scale 
PK 
14.2.2.7 
Mean Trough Plasma BCX7353 Concentration-time plot –linear Scale   
PK 
14.2.2.8 
Median Trough Plasma BCX7353 Concentration-time plot –linear Scale   
PK 
14.2.2.8 
Individual Trough Plasma BCX7353 Concentration-time plot (line plot) 
PK 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 56 of 59                                                07FEB 2017 
 
 
Figures 
Title 
Population 
Pharmacodynamic Analyses 
14.2.3.1 
Plot of Mean Ex-vivo Kallikrein Inhibition - Time Profile by Treatment 
PD 
14.2.3.2 
Plot of Individual Ex-vivo Kallikrein Inhibition - Time Profile by Treatment 
PD 
14.2.3.3 
Plot of Least Squares Mean of Treatment Differences from Placebo in Ex-
vivo Kallikrein Inhibition 
PD 
 
 
 
Pharmacokinetic/Pharmacodynamic Analyses (PK-PD include subjects with measurements for both PK-
PD) 
14.2.4.1 
Plot of Plasma Kallikrein Inhibition and Plasma BCX7353 Concentration  
KKI PD   
14.2.4.2 
Exposure-response Analysis of Ex-vivo Kallikrein Inhibition  
KKI PD 
14.2.4.3 
Plot of Plasma Kallikrein Inhibition by Attack Free Status  
KKI PD 
14.2.4.4 
Plot of Percent of plasma BCX7353 trough concentrations (Ctau) above 4x 
kallikrein inhibition EC50 (35.8 ng/mL) and confirmed attack rate 
PK 
14.2.4.5 
Plot of Percent of plasma BCX7353 trough concentrations (Ctau) above 8x 
kallikrein inhibition EC50 (71.6 ng/mL) and confirmed attack rate 
PK 
14.2.4.6 
Plot of Average Plasma BCX7353 trough concentrations (Ctau) and confirmed 
attack rate 
PK 
14.2.4.7 
Plot of Plasma BCX7353 Concentration by Attack Free Status  
PK 
14.2.4.8 
Plot of Selected Plasma BCX7353 PK Parameters by Attack Free Status 
PK 
14.2.4.9 
Plot of Rate of Attack vs. Plasma BCX7353 PK Parameters (one plot for each 
PK parameter of interest) 
PK 
14.2.4.10 
Plot of Plasma BCX7353 PK Parameters VS HK parameters 
PK and 
Cleaved HK 
PD 
14.2.4.11 
Plot of Cleaved HK Concentration by Attack Free Status 
Cleaved HK 
PD 
14.2.4.12 
Plot of C1INH Concentration by Attack Free Status 
C1 INH PD 
The PKPD/Efficacy plots will be performed as data permit, additional figures may also be added.   
Safety Figures 
14.3.1.1 
Time course of AST in individuals with treatment-emergent AST 
abnormalities (spaghetti plot, 1 line for each subject and page by treatment,)   
Safety 
14.3.1.2 
Time course of ALT in individuals with treatment-emergent ALT 
abnormalities  
Safety 
14.3.1.3 
Time course of ALP in individuals with treatment-emergent ALP 
abnormalities  
Safety 
14.3.1.4 
Time course of GGT in individuals with treatment-emergent GGT 
abnormalities  
Safety 
14.3.1.5 
Time course of Direct Bilirubin in individuals with treatment-emergent Direct 
Bilirubin abnormalities  
Safety 
14.3.1.6 
Time course of Total Bilirubin in individuals with treatment-emergent Total 
Bilirubin abnormalities  
Safety 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 57 of 59                                                07FEB 2017 
 
 
Figures 
Title 
Population 
14.3.1.7 
Peak ALT: Placebo versus BCX7353 subjects 
Safety 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 58 of 59                                                07FEB 2017 
 
 
 
Listings 
Title 
Population 
Study Population  
16.2.1.1 
Subject Randomization 
Safety 
16.2.1.2 
End of Study Record 
Safety 
16.2.2.1 
Inclusion/Exclusion Criteria not Met 
Safety 
16.2.2.2 
Protocol Deviations 
Safety 
16.2.2.3 
Subjects for Whom the Treatment Blind Was Broken 
Safety 
16.2.4.1.1 
Demography 
Safety 
16.2.4.1.2 
HAE Demography – HAE History 
Safety 
16.2.4.2.1 
HAE Demography – Past on-Demand Treatments of HAE 
Safety 
16.2.4.2.2 
HAE Demography – Current on-Demand Treatments of HAE 
Safety 
16.2.4.2.3 
HAE Demography – Past Prophylactic Treatments of HAE 
Safety 
16.2.4.3 
Medical History 
Safety 
16.2.4.4 
Prior Medications 
Safety 
16.2.4.5 
Concomitant Medications 
Safety 
16.2.4.6 
Concomitant Medications for indication related to HAE 
Safety 
Efficacy  
16.2.6.1 
Attack Diary (include multiple listings) 
Safety 
16.2.6.2 
Attack Diary Results Adjudicated by the Independent Clinical Endpoint 
Adjudication Panel (CEAP) 
Safety 
16.2.6.3 
Efficacy Endpoints 
FAS 
16.2.6.4 
Efficacy Endpoints 
PP 
16.2.6.5 
Pretreatment and Post Treatment Attack Rate 
Safety 
16.2.6.6 
Angioedema Quality of Life 
Safety 
16.2.6.7 
DASS 
Safety 
 
 
 
Pharmacokinetic  
16.2.6.5 
Plasma BCX7353 Concentration Data 
Safety 
16.2.6.6 
Plasma BCX7353 PK Parameter Data 
PK 
  
  
  
Pharmacodynamic   
16.2.6.7 
Ex-vivo Kallikrein Inhibition Data 
Safety 
16.2.6.8 
C1INH Data 
Safety 
16.2.6.9 
Cleaved HK Data 
Safety 
16.2.6.10 
BMP data 
Safety 
Safety 
16.2.5.1 
Dosing Record 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.7.1 
Adverse Events 
Safety 


BioCryst, Inc. Protocol No. BCX7353-203 
Statistical Analysis Plan Version 2.0 
 
CONFIDENTIAL 
Page 59 of 59                                                07FEB 2017 
 
 
Listings 
Title 
Population 
16.2.7.2 
Adverse Events Grade 3 or Grade 4 
Safety 
16.2.7.3 
Adverse Events Leading to Permanent Discontinuation from Study/Study 
Drug 
Safety 
16.2.7.4 
Serious Adverse Events   
Safety 
16.2.7.5 
Adverse Events - Rash 
Safety 
16.2.7.6 
Death (please provide a blank table if no death reported) 
Safety 
16.2.8.1 
Clinical Chemistry 
Safety 
16.2.8.2 
Clinical Hematology 
Safety 
16.2.8.4 
Other Lab tests 
Safety 
16.2.8.5 
Serum Pregnancy 
Safety 
16.2.8.6 
Urine Pregnancy 
Safety 
16.2.8.7 
Graded laboratory abnormalities 
Safety 
16.2.8.8 
Grade 3 or Grade 4 laboratory abnormalities 
Safety 
16.2.8.9 
Pregnancy  (List female subjects or female partners of male subjects become 
pregnant) 
Safety 
16.2.9.1 
Vital Signs 
Safety 
16.2.9.2 
Twelve-lead Electrocardiograms 
Safety 
16.2.9.3 
Physical Exam 
Safety 
16.2.9.4 
Pulmonary Diffusion 
Safety 
16.2.9.5 
Liver Function Tests 
Safety 
16.2.9.6 
Listing of all LFT Test Results in x ULN for Subjects with any Abnormal 
LFT Finding   
Safety 
16.2.9.7 
Listing of LFT Fold Change From Baseline for Subjects with any Abnormal 
LFT Finding 
Safety 
16.2.9.8 
Elevation of ALT in Temporal Association with Nausea, Vomiting, 
Anorexia, Abdominal Pain, or Fatigue 
Safety