A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Study to Evaluate the Efficacy, Safety and Tolerability of Single Doses of BCX7353 as an Acute Attack Treatment in Subjects With Hereditary Angioedema
Phase: PHASE2
Conditions: Hereditary Angioedema (HAE)
Sponsor: BioCryst Pharmaceuticals

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
1 
1. 
TITLE PAGE 
BIOCRYST 
PHARMACEUTICALS, INC. 
 
 
Protocol No. BCX7353-202 
 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, DOSE-RANGING STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY 
OF SINGLE DOSES OF BCX7353 AS AN ACUTE ATTACK 
TREATMENT IN SUBJECTS WITH HEREDITARY 
ANGIOEDEMA  
 
EudraCT Number: 2016-001424-55 
 
Version 4.0: 16 March 2018 
 
 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703, USA 
Phone: +1 (919) 859-1302 
Fax: +1 (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. 
 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
2 
CONFIDENTIAL 
Protocol Number: 
BCX7353-202 
Study Title: 
A randomized, double-blind, placebo-controlled, dose-ranging, study to 
evaluate the efficacy, safety and tolerability of single doses of BCX7353 as an 
acute attack treatment in subjects with hereditary angioedema 
IND Number: 
N/A 
EudraCT No. 
2016-001424-55 
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: +1 (919) 226-5860 
Cell: +1 (773) 304-8942 
Email: sdobo@biocryst.com 
Principal Investigator: 
Dr Hilary Longhurst 
 
Email: hlonghurst@doctors.org.uk  
Sponsor Project Manager: Sharon VanDyke 
BioCryst Pharmaceuticals 
Office: +1 (919) 859-7914 
Cell: +1 (919) 830-8019 
Email:sdyke@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: 16 December 2016 
Version 2.0: 24 February 2017 
Version 3.0: 02 August 2017 
Version 4.0: 16 March 2018 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
4 
1.2. 
Clinical Study Protocol Agreement 
 
Protocol No:       BCX7353-202 
Protocol Title: A randomized, double-blind, placebo-controlled, dose-ranging, study to 
evaluate the efficacy, safety, and tolerability of single doses of BCX7353 as an 
acute attack treatment in subjects with hereditary angioedema 
Date: 
 
Version 4.0:  16 March 2018 
 
 
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) 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
5 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. 
Name of Investigational Product: 
BCX7353 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-
fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 
Title of Study:  
A randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy, safety and 
tolerability of single doses of BCX7353 as an acute attack treatment in subjects with hereditary 
angioedema 
Study centers: Study centers in Europe and Israel 
Principal Investigator: Dr Hilary Longhurst 
Studied period (years):  
Estimated date first patient enrolled: July 2017 
Estimated date last patient completed: September 2018 
Phase of development:  
2 
Objectives:  
Primary: 
• To evaluate the efficacy of single oral doses of BCX7353 in treating acute attacks in subjects 
with hereditary angioedema (HAE)  
Secondary: 
• To evaluate the safety and tolerability of single oral doses of BCX7353 in subjects with HAE 
• To evaluate the relationship of BCX7353 dose with clinical responses 
• To evaluate subject satisfaction with BCX7353 treatment 
• Substudy: to describe the natural history and temporal pattern of symptoms of untreated 
attacks and those treated with commercially available attack medications 
 
Efficacy Endpoints:   
• 
Proportion of subject attacks with an improved or stable 3-symptom composite visual analogue 
scale (VAS) score at 4 hours post-dose. The 3-symptom composite will be calculated as the 
average of the VAS scores for abdominal pain, skin pain and skin swelling. A subject is 
considered improved or stable if the change from baseline (time of drug administration) in VAS 
is less than or equal to 0.  
• Proportion of subject attacks with a patient global assessment of improved or stable symptoms at 
4 hours post-dose   
• Proportion of subject attacks with no symptoms or mild symptoms of an HAE attack at 4 hours 
post-dose 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
6 
• Proportion of subject attacks requiring standard of care attack treatment through 24 hours post-
dose 
• Time to use of standard of care acute attack treatment through 24 hours 
• Time to stable or improved symptoms by composite VAS score through 24 hours post-dose 
• Time to symptom relief (first documented time point when a subject experiences a 50% 
reduction in the 3-symptom composite VAS score from the pretreatment composite score) 
• Time to almost complete symptom relief (first documented time point when a subject records a 
VAS score < 10 mm in the 3-symptom composite VAS score) 
• Time to initial symptom relief (time from ingestion of study medication to report that the worst 
symptoms of the attack are over) 
• Time to complete symptom relief (time from ingestion of study medication to no HAE attack 
symptoms) 
Methodology:  
This is a 3-part, Phase 2, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy 
and safety of single oral doses of a liquid formulation of BCX7353 in the treatment of acute HAE 
attacks. All subjects enrolled will receive both active and placebo blinded study drug in a randomized 
sequence. Part 1 of the study will evaluate single doses of 750 mg BCX7353; Part 2 will evaluate single 
doses of 500 mg BCX7353 and Part 3 will evaluate single doses of 250 mg BCX7353. 
Randomization 
Up to 36 subjects with Type 1 or 2 HAE with a documented history of HAE attacks will be sequentially 
enrolled into Part 1 of the study and randomized to receive a treatment sequence containing one of the 
following: 
Treatment A1: Single oral dose of BCX7353, 750 mg (Part 1)  
Treatment B: Single oral dose of placebo 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single oral doses 
of BCX7353 500 mg in Part 2; or Treatment A3 = single oral doses of BCX7353 250 mg in Part 3.  
Initially, in Part 1,12 subjects will be randomized to one of 3 treatment sequences (n = 4 per sequence): 
Sequence 1:  ABA 
Sequence 2:  BAA 
Sequence 3:  AAB 
If required, additional subjects will be enrolled into Part 1 (as outlined below) using the same 1:1:1 ratio 
for the 3 sequences, with a maximum total number of 36 subjects for Part 1. 
Part 2 will evaluate a dose of 500 mg (Treatment A2) and placebo (Treatment B). A maximum of 12 
subjects will be enrolled, using the same 1:1:1 ratio for the 3 sequences. Part 3 will evaluate a dose of 
250 mg (Treatment A3) and will enroll a maximum of 12 subjects in a 1:1:1 ratio for each of the 3 
sequences. 
If tolerability issues prevent enrollment of Part 1 as described, additional subjects in Part 1 may be dosed 
with active study drug at a dose of 500 mg. If the dose in Part 1 is reduced and at least 12 subjects are 
treated with an active study drug dose of 500 mg, a 250 mg active dose may be assessed in Part 2. Any 
further dose level changes warranted for Part 2 and Part 3 will be instituted via protocol amendment. 
Enrollment and Analyses 
Up to 36 subjects will be enrolled in Part 1. Upon full enrollment, enrollment into Part 2 of the study 
(maximum of 12 subjects) may immediately commence. Part 3 (n = up to 12) may 
immediately commence upon enrollment of Part 2. 
Following the 12th subject completing Part 1, the treatment effect may be estimated. The predefined 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
7 
endpoint, determined by the Haybittle-Peto method, is the proportion of subjects with a stable or 
improved composite VAS at 4 hours post-dose. A Haybittle-Peto boundary of p < 0.001 is considered 
clinically significant. 
If the Haybittle-Peto analysis is run and the boundary is not crossed with 12 subjects, the treatment 
effect may be estimated with cumulative data after each treated attack in accordance with the fully 
sequential analysis method assessing the estimate of treatment effect using the Haybittle-Peto boundary 
(p < 0.001).  
Alternatively, if the boundary is not crossed with 24 subjects or the Heybittle-Peto analyses are not 
performed, treatment differences may be assessed using available data in Parts 1, 2 and 3 in order to plan 
subsequent studies.  
Study Conduct Overview 
At the Screening visit, subjects will be provided a diary and receive instruction on the correct 
completion of the diary in real-time to record attack symptoms and severity and any medication usage 
during an acute attack. During the 35-day screening period, subjects will be required to: 1) phone the 
Investigator at the onset of pain or swelling associated with an HAE attack; 2) complete diary details in 
real time of this HAE attack; and 3) phone the Investigator at the 4 hour post-call timepoint.  Completion 
of these procedures will confirm that the subject is able and competent to perform on-study requirements 
in early identification of an attack and treating and documenting an appropriate attack with study drug.  
Eligible subjects will return to the clinic to attend a Baseline visit. At the conclusion of the baseline visit, 
subjects will receive their first randomized dose of study drug for treatment of attacks by self-
administration. The investigational medicinal product (IMP; BCX7353 or placebo) is supplied as a 
powder form drug product, presented in a bottle, that will require reconstitution to a liquid formulation 
with vehicle by the subject prior to administration. 
At the Baseline visit, all subjects will be instructed on how to prepare and use study drug to treat a 
protocol-qualified acute HAE attack and will receive further instruction on the correct completion of a 
diary in real-time immediately prior to and after study drug administration.  
Subjects will be instructed to contact the on-call Investigator (or designee) at the first symptom of 
swelling or pain associated with a potentially protocol-qualified HAE attack.  
Protocol-qualified attacks approved for study drug treatment must meet all of the following: 
• 
have pain and/or swelling associated with an HAE attack reported as a symptom 
• 
subject has contacted Investigator within approximately 1 hour of onset time of HAE pain 
and/or swelling not involve pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, icatibant) 
without delay. 
• 
not be an abdominal attack that has already resulted in vomiting. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, icatibant). 
• 
have an identifiable onset time, with the exception that abdominal attacks with an onset 
during sleep may be permitted for study drug treatment. Onset time for abdominal attacks 
will be time the subject woke up with symptoms. Peripheral attacks starting with an onset 
during sleep will not be approvable for study drug treatment. 
• 
occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor antagonist (i.e. 
Firazyr) OR treated with human recombinant C1 INH (i.e. Ruconest) OR any non-

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
8 
targeted therapy (i.e. pain medication, anti-spasmodic, anti-emetic, tranexamic acid) 
OR was not treated with any medication: new attack can be treated with IMP if has 
been 48 hours since the complete resolution of all symptoms of the previous HAE 
attack AND the Investigator believes it is a new (de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH (i.e. 
Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent detergent 
plasma): new attack can be treated with IMP if it has been 96 hours since the 
complete resolution of all symptoms of the previous HAE attack 
• 
occur at least 96 hours after complete recovery from a procedure or injury  
• 
occur at least 14 days from a previous dose of study drug 
After approval of the attack for study drug administration, subjects will reconstitute and take study drug 
preferably within one hour of the onset of symptoms. Subjects will complete the diary questionnaire, 
record any additional medications taken, and a 3-component VAS on a 100 mm scale for abdominal 
pain, cutaneous pain, and cutaneous swelling at the time of administration and 1, 2, 3, 4, approximately 
8 and at 24 hours after study drug administration. Subjects will then phone the on-call Investigator (or 
designee) at approximately 4 hours after study medication to review their response to study drug and 
diary completion.  
At each visit following treatment of an attack with study drug, the completed diary will be reviewed and 
any re-education required to ensure correct diary completion will be performed. Safety assessments will 
be completed and the next randomized dose of study drug will be dispensed to the subject.  
Each subject will continue on study to treat 3 attacks with study drug. Clinic visits will be scheduled 10 
to 14 days after each attack that is treated with study drug.  Any additional attacks that occur in the 
intervening periods between study visits may be treated according to standard of care for the subject. 
Subjects will also be asked to track the start and stop times of any attacks not treated with study drug 
that occur after the baseline visit through the last study visit (Post-Attack 3 visit). 
Optional Observational Substudy 
Subjects will be asked to participate in an optional observational substudy to obtain diary data on all 
HAE attacks, through 12 weeks commencing from the last study visit.  Consenting subjects will receive 
a diary and instruction for completion at the Post-Attack 3 visit. For the next 12 weeks, subjects will 
complete their diaries, with periodic subject contact (telephone) to ensure diary adherence. 
A schedule of assessments is presented in Table 4.  
Number of subjects (planned):  
Up to 36 evaluable subjects with Type 1 or 2 HAE are planned to be enrolled in Part 1, up to 12 
evaluable subjects in Part 2 and up to 12 evaluable subjects in Part 3. An evaluable subject is one who 
treats 3 attacks with study drug and for which there is diary information recorded.  
Subjects who complete Part 1 will not be eligible to participate in Parts 2 or 3. Subjects completing Part 
2 will not be eligible to participate in Part 3 of the study. 
Criteria for inclusion: 
1. Able to provide written, informed consent. 
2. Males and non-pregnant, non-lactating females age 18 to 70 years. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
9 
3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined having a C1 INH 
functional level below 50% of normal and a C4 level below the lower limit of the normal 
reference range, as assessed at the Screening visit. 
4. Access to and ability to use standard of care acute attack treatment. Standard of care acute attack 
treatment is defined as a medication approved by the relevant competent authority for the 
treatment of attacks of HAE (e.g. icatibant, ecallantide, plasma-derived C1INH, recombinant 
C1INH). 
5. Female and male subjects must agree to the contraception requirements and must meet the 
inclusion criteria regarding contraception, and contraception of female partners (as applicable), 
as outlined in Section 8.2. 
6. Any regularly administered concomitant medication recorded at the Screening visit and 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 (screening through follow-up). 
7. In the opinion of the Investigator, the subject is expected to adequately comply with all required 
study procedures for the duration of the study. To be dispensed study drug at baseline, the 
subject must demonstrate adequate compliance with all study procedures required from the 
Screening visit through randomization, including phoning the Investigator and diary recording 
of at least one HAE attack during the screening period. 
8.  Must have a documented HAE attack rate of at least 1 unique attack per month for 3 months (up 
to 93 days) within the 4 months prior to the Screening visit. 
Criteria for exclusion: 
1. No HAE attack reported to the on-call Investigator (or designee) through the 35 days of the 
Screening period. 
2. 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 increase the risk of participation for that subject.  
3. 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. 
4. Clinically significant abnormal electrocardiogram (ECG) at the Screening visit. This includes, 
but is not limited to, a QTcF > 470 msec for women, a QTcF > 450 msec for men, a PR > 220 
msec (both sexes), or ventricular and/or atrial premature contractions that are more frequent than 
occasional, and/or as couplets or higher in grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant 
cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other clinically 
significant cardiovascular abnormality such as poorly controlled hypertension.  
6. Known family history of sudden cardiac death. Family history of sudden death from HAE is not 
exclusionary. 
7. History of or current implanted defibrillator or pacemaker. 
8. Any laboratory parameter at screening that, in the opinion of the Investigator, is clinically 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
10 
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). 
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, which was associated with a non-
HAE related swelling, a severe rash requiring treatment/hospitalization, or anaphylaxis. 
15. Hypersensitivity reaction to BCX7353. 
16. Use of tranexamic acid, androgens or C1 INH for prophylaxis of HAE attacks within the 7 days 
prior to the Screening visit or initiation during the study. Use of a C1 INH therapy for treatment 
of attacks is not excluded at any time, nor is C1 INH for pre-procedure prophylaxis. 
17. Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, and 
CYP3A4 and have a narrow therapeutic range, within 7 days of the Baseline visit or planned 
initiation during the study.  
18. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or planned 
initiation during the study.  
19. Use of a medication that is clinically known to prolong the QT interval and is metabolized by 
CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to baseline or initiation during the 
study. 
20. Current participation in any other investigational drug study or received another investigational 
drug within 30 days of the Screening visit. 
21. An immediate family relationship to either Sponsor employees, the Investigator or employees of 
the study site named on the delegation log. 
Investigational product, dosage and mode of administration:  
BCX7353 powder for reconstitution at doses of 750 mg, 500 mg, and 250 mg.  BCX7353 powder in 
bottle will require reconstitution with vehicle by the subject prior to oral administration. 
All clinical doses of BCX7353 provided in this protocol are in reference to the hydrochloride (HCl) salt. 
Duration of treatment:  
Participating subjects will receive 3 single oral doses of study drug to treat an HAE attack approved for 
study drug treatment: 2 doses of BCX7353 and 1 dose of placebo.  
Reference therapy, dosage and mode of administration:  
Matched placebo powder for reconstitution. Placebo will be lactose monohydrate powder in a bottle that 
will require reconstitution with vehicle by the subject prior to oral administration.  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
11 
Criteria for evaluation: 
Efficacy: 3-symptom composite VAS score, patient global assessment of symptoms, qualitative 
symptom severity, use of standard of care treatment. 
Safety: adverse events (AEs), laboratory analyses [clinical chemistry, hematology, coagulation, 
urinalysis, creatine kinase-MB (CK-MB), troponin I and T], vital signs, ECGs, and physical 
examinations. 
Subject satisfaction:  Treatment Satisfaction Questionnaire for Medication (TSQM)  
Statistical methods: 
Due to the exploratory nature of this study, no formal power or sample size calculations were used to 
determine sample size. Descriptive statistics for disposition, demographics, and baseline characteristics 
will be presented by treatment sequence.  All analyses of efficacy and safety will be attributed to the 
treatment assignment at the time of the assessment. 
Efficacy Analyses: 
Resolution of attacks will be analyzed by treatment arm. The endpoint that may be assessed using a 
Heybittle-Peto boundary for significance is the proportion of subject treated attacks with improved or 
stable composite VAS at 4 hours post-dose in the full analysis set (i.e., all subject treated attacks). The 
number and proportion of subject treated attacks that stabilize or improve at 4 hours will be summarized 
by treatment group. Attacks that require standard of care acute attack treatment prior to the 4-hour time 
point will be considered as failure (i.e., not having a stable or improved VAS at 4 hours). To assess 
treatment differences, a logistic mixed effect model including treatment, period and sequence as fixed 
effects, and subject within sequence as a random effect will be utilized. Other binary endpoints will be 
analyzed in a similar manner.  
The 3-symptom composite VAS and its associated changes from baseline will be summarized by attack, 
time point and treatment group. Treatment differences in the change from baseline values at each time 
point will be assessed with a mixed effect linear model with factors for treatment, period, sequence, and 
baseline value as fixed effects, and subject within sequence as a random effect. Analyses of other 
continuous variables will be analyzed in a similar manner. 
The time to use of standard of care acute attack treatment will be estimated using the Kaplan-Meier 
method.  Subjects who do not use standard of care acute attack treatment will be censored at the end of 
the attack observation period (i.e., 24 hours).  Treatment differences will be assessed using an 
appropriate proportional hazards model. 
Safety Analyses: 
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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
12 
treatment group. Laboratory toxicity shifts from baseline to post-baseline assessments will be 
summarized by study visit and treatment group.  
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. 
Subject Satisfaction: 
A TSQM global satisfaction score will be calculated as validated. Data on the global score as well as 
relevant subscales will be listed, summarized, and appropriately tested for differences between active 
treatment and placebo and between active and current acute therapy utilized at baseline.  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
13 
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 ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background .................................................................................................................23 
5.2. 
Nonclinical Findings for BCX7353 ............................................................................25 
5.3. 
Clinical Findings for BCX7353 ..................................................................................26 
5.3.1. 
Study BCX7353-101 ..................................................................................................26 
5.3.2. 
Study BCX7353-102 ..................................................................................................27 
5.3.3. 
Study BCX7353-203 ..................................................................................................28 
5.3.4. 
Study BCX7353-109 ..................................................................................................28 
5.4. 
Rationale for Study .....................................................................................................29 
5.4.1. 
Rationale for Study Drug Doses .................................................................................29 
5.4.1.1. 
Rationale for Achievement and Maintenance of Target Concentrations 
Proposed as Efficacious ..............................................................................................29 
5.4.1.2. 
Rationale for Proposed Doses .....................................................................................30 
5.4.2. 
Rationale for Study Design .........................................................................................32 
5.4.3. 
Study Population Rationale ........................................................................................33 
5.4.3.1. 
Rationale for Use of Standard of Care Attack Medication .........................................33 
5.4.4. 
BCX7353 Risk/Benefit Analysis ................................................................................34 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions ............................................................34 
5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 ....................................................35 
5.4.5. 
Benefits of Trial Participation ....................................................................................39 
5.4.6. 
Overall Benefit-Risk Assessment ...............................................................................39 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................40 
6.1. 
Objectives ...................................................................................................................40 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
14 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.1.1. 
Enrollment and Analyses ............................................................................................42 
7.1.2. 
Study Conduct Overview ............................................................................................42 
7.2. 
Endpoints ....................................................................................................................45 
7.2.1. 
Efficacy Endpoints ......................................................................................................45 
7.2.2. 
Safety Endpoints .........................................................................................................45 
7.2.3. 
Other Secondary Endpoints ........................................................................................46 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................47 
8.1. 
Number of Subjects ....................................................................................................47 
8.2. 
Subject Selection ........................................................................................................47 
8.2.1. 
Inclusion Criteria ........................................................................................................47 
8.2.2. 
Exclusion Criteria .......................................................................................................49 
8.3. 
Subject Withdrawal Criteria .......................................................................................51 
8.3.1. 
Subject Discontinuation from Study ...........................................................................51 
8.3.2. 
Subject Discontinuation from Study Drug .................................................................51 
8.3.2.1. 
Discontinuation Due to QT Prolongation ...................................................................51 
8.3.2.2. 
Discontinuation Due to Rash ......................................................................................52 
8.3.2.3. 
End of Trial Definition ...............................................................................................52 
9. 
TREATMENT OF SUBJECTS ..................................................................................53 
9.1. 
Description of Study Drug ..........................................................................................53 
9.2. 
Description of Study Drug Packaging, Labeling and Storage ....................................53 
9.3. 
Blinding and Randomization ......................................................................................54 
9.3.1. 
Blinding ......................................................................................................................54 
9.3.2. 
Randomization ............................................................................................................54 
9.4. 
Study Drug (Investigational Medicinal Product) Reconstitution and 
Administration ............................................................................................................55 
9.5. 
Study Drug Dose Modification ...................................................................................55 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability ...............................55 
9.7. 
Concomitant Medications and Other Restrictions ......................................................56 
9.7.1. 
Prohibited Medications/Restrictions ...........................................................................56 
10. 
STUDY CONDUCT ...................................................................................................58 
10.1. 
Overview .....................................................................................................................58 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
15 
10.2. 
Schedule of Assessments ............................................................................................58 
10.3. 
Study Visits .................................................................................................................62 
10.3.1. 
Screening ....................................................................................................................62 
10.3.2. 
Baseline .......................................................................................................................63 
10.3.3. 
Telephone Contacts ....................................................................................................64 
10.3.4. 
Clinic Visits Following Study Drug Administration ..................................................65 
10.3.5. 
Early Termination Visits .............................................................................................66 
10.3.6. 
Optional Observational Substudy ...............................................................................66 
11. 
ASSESSMENTS.........................................................................................................67 
11.1. 
Investigator-Completed Assessments .........................................................................67 
11.1.1. 
HAE Medical and Medication History .......................................................................67 
11.1.2. 
Physical Examination .................................................................................................67 
11.1.3. 
Weight/Body Mass Index ...........................................................................................67 
11.1.4. 
12-lead Electrocardiograms ........................................................................................67 
11.1.5. 
Vital Signs ..................................................................................................................68 
11.1.6. 
Clinical Laboratory Assessments ...............................................................................68 
11.1.8. 
Pregnancy Testing ......................................................................................................70 
11.1.9. 
C1 INH Testing ...........................................................................................................70 
11.1.10. 
Other Laboratory Assessments ...................................................................................70 
11.1.11. 
Rash Assessment ........................................................................................................70 
11.2. 
Subject-Completed Assessments ................................................................................71 
11.2.1. 
Treatment Satisfaction Questionnaire .........................................................................71 
11.2.2. 
HAE Attack Diaries and Phone Calls .........................................................................71 
11.2.2.1. 
Screening through Post-Attack 3 Visit .......................................................................71 
11.2.2.2. 
Optional Observational Substudy ...............................................................................75 
12. 
ASSESSMENT OF SAFETY .....................................................................................76 
12.1. 
Adverse Events ...........................................................................................................76 
12.1.1. 
Definitions ..................................................................................................................76 
12.1.1.1. 
Adverse Event .............................................................................................................76 
12.1.1.2. 
Serious Adverse Event ................................................................................................77 
12.1.1.3. 
Adverse Events of Special Interest .............................................................................77 
12.1.3. 
Definition of Severity .................................................................................................78 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
16 
12.1.4. 
Definition of Relationship to Study Drug (Investigational Medicinal 
Product) .......................................................................................................................79 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................80 
12.1.5.1. 
Reporting Events of Special Interest ..........................................................................81 
12.1.6. 
Pregnancy ...................................................................................................................81 
12.1.7. 
Serious Breaches .........................................................................................................81 
12.1.8. 
Emergency Procedures ...............................................................................................82 
12.2. 
Toxicity Management .................................................................................................82 
12.2.1. 
Rash ............................................................................................................................82 
12.2.2. 
Overdose .....................................................................................................................82 
12.3. 
Data Monitoring Committee .......................................................................................83 
13. 
STATISTICS ..............................................................................................................84 
13.1. 
Sample Size Considerations .......................................................................................84 
13.2. 
Hypothesis Testing .....................................................................................................84 
13.3. 
Statistical Methods ......................................................................................................84 
13.3.1. 
Analysis Populations ..................................................................................................84 
13.3.1.1. 
Full Analysis Set .........................................................................................................84 
13.3.1.2. 
Safety Population ........................................................................................................84 
13.3.2. 
Subject Demographic and Disposition Data ...............................................................84 
13.3.3. 
Analysis of Efficacy Variables ...................................................................................85 
13.3.4. 
Analysis of Safety Variables ......................................................................................85 
13.3.5. 
Subject Satisfaction Analyses .....................................................................................86 
13.3.6. 
Interim Monitoring and Statistical Stopping Rules ....................................................86 
14. 
STUDY ADMINISTRATION ...................................................................................87 
14.1. 
Regulatory and Ethical Considerations ......................................................................87 
14.1.1. 
Regulatory Authority Approvals ................................................................................87 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals ...................................87 
14.1.3. 
Subject Informed Consent ..........................................................................................87 
14.1.4. 
Payment to Subjects ....................................................................................................88 
14.1.5. 
Investigator Reporting Requirements .........................................................................88 
14.2. 
Study Monitoring ........................................................................................................88 
14.3. 
Quality Assurance .......................................................................................................88 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
17 
14.4. 
Study Termination and Site Closure ...........................................................................89 
14.5. 
Records Retention .......................................................................................................89 
14.6. 
Confidentiality of Information ....................................................................................90 
14.7. 
Study Publication ........................................................................................................90 
15. 
REFERENCES ...........................................................................................................91 
APPENDICES ...............................................................................................................................94 
15.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) .........................94 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
18 
LIST OF TABLES 
Table 1. 
Abbreviations and specialist terms .............................................................................19 
Table 2. 
Simulated first time postdose to achieve BCX7353 concentration ≥71 ng/mL 
following single dose administration of 250, 500, and 750 mg BCX7353 ................32 
Table 3. 
Simulated duration of BCX7353 concentrations exceeding target 
concentration of 71ng/mL following single dose administration of 250, 500, 
and 750 mg BCX7353 ................................................................................................32 
Table 4. 
Schedule of Assessments for Study BCX7353-202 ...................................................59 
Table 5. 
Schedule of Assessments for Optional Observational Substudy ................................62 
Table 6. 
Clinical Laboratory Evaluations .................................................................................68 
 
 
LIST OF FIGURES 
Figure 1. 
Simulated Mean Exposure of BCX7353 over Target Concentration .........................31 
Figure 2.  Study Design Through Follow-up (Post-Attack 3 Visit) ............................................42 
 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
19 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1. 
Abbreviations and specialist terms 
Abbreviation  
Explanation 
AAS 
angioedema activity score 
ABW 
actual body weight 
AE 
adverse event 
ALT 
alanine aminotransferase 
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 
Bis(mono)acylglycerol phosphate 
C1 INH 
C1 esterase inhibitor 
Clast 
last measurable concentration of drug 
CK-MB 
creatine kinase-MB 
CLcr 
creatinine clearance 
CLr 
renal clearance of unchanged drug in a specific interval (CLr[interval]) or 
cumulatively over all collection intervals 
Cmax 
maximum plasma concentration of the drug 
CPK 
creatine phosphokinase 
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) 
CYP 
cytochrome P450 
DMC 
Data monitoring committee 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
20 
Abbreviation  
Explanation 
DMID 
Division of Microbiology and Infectious Diseases 
% Doseexcreted 
percentage of given dose excreted in the urine as unchanged drug 
eCRF 
Electronic case report form 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQoL five-dimensional, 5-level questionnaire 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulation hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HAE 
hereditary angioedema 
HBV 
hepatitis B virus 
HCl 
hydrochloride 
HDPE 
High density polyethylene 
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 
IB 
Investigator’s brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IMPD 
investigational medicinal product dossier 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
21 
Abbreviation  
Explanation 
IUS 
intrauterine system 
IV 
intravenous 
Ka 
absorption rate constant 
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 
MCH 
mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NGAL 
neutrophil gelatinase–associated lipocalin 
P-gp 
p-glycoprotein 
PBMC 
Peripheral blood mononuclear cell 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PKK 
prekallikrein 
PLD 
phospholipidosis 
PO 
oral 
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 
SAE 
serious adverse event 
SAP 
statistical analysis plan 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
22 
Abbreviation  
Explanation 
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 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
Vz/F 
apparent volume of distribution of the drug 
WHO 
World Health Organization 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
23 
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 acute 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 (FXIIa) 
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).  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
24 
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 acute HAE attacks in the European Union (EU). In the United States (US), 
Berinert® and Ruconest® are licensed for this indication. Kalbitor® (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). In addition, Firazyr® 
(icatibant) is a bradykinin B2 receptor antagonist and is licensed in the EU and the US for 
treatment of acute attacks of HAE by subcutaneous injection.  
The goal of acute treatment is to resolve angioedema symptoms as quickly as possible. There are 
no comparative (head-to-head) studies of therapies to treat an acute attack. Double-blind, 
randomized placebo-controlled trials have demonstrated superiority of Berinert, Cinryze 
Ruconest, Firazyr, and Kalbitor over placebo. These data are briefly described below. 
Data from both the Berinert and the Cinryze trials suggest that higher doses (i.e., 20 U/kg 
Berinert, and more than 1 dose of Cinryze 1000 U) have a shorter median time to onset of relief 
with secondary outcomes consistently supported by the efficacy of the higher doses (Craig, Levy 
et al. 2009, Zuraw, Busse et al. 2010, Wasserman, Levy et al. 2011). With C1 INH, serious 
arterial and venous thromboembolic events have been reported at the recommended dose of 
C1 INH products. A general concern over transmission of blood-borne infections is inevitable 
when using human plasma–derived products. Hypersensitivity and allergic/pseudo-allergic 
systemic reactions have also been reported in a few patients. Berinert is approved in Europe for 
self-administration to treat all acute attacks and in the US to treat facial, laryngeal and abdominal 
attacks. Cinryze is approved in Europe to treat all acute attacks. 
Ruconest also demonstrated a treatment effect and the time to minimal symptoms was 
significantly shorter in patients receiving rhC1 INH compared to placebo with no subject in the 
rhC1 INH treatment group experiencing therapeutic failure (Zuraw, Cicardi et al. 2010). 
Hypersensitivity, including anaphylaxis in a single healthy volunteer with an undisclosed rabbit 
allergy, has been reported with the use of Ruconest. Ruconest is approved in Europe for 
treatment for all acute attacks and the US package insert has a limitation of use clause in the 
indication statement that states effectiveness was not established in HAE patients with laryngeal 
attacks. 
Icatibant (Firazyr) is also an acute 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 3 published 
multicenter clinical trials (FAST 1, 2, and 3) patients were randomized to icatibant or comparator 
(placebo or tranexamic acid). Time to almost complete resolution was shorter with icatibant than 
with the comparator in all 3 trials and was statistically significant in the FAST 2 and FAST 3 
trials (Cicardi, Levy et al. 2010, Lumry, Li et al. 2011). Open label studies have shown the 
benefit of different treatments for attacks at all sites. However, approximately 10% of patients 
require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial 
treatment (Longhurst 2010). Icatibant was generally well tolerated and is approved for the 
treatment of all HAE attacks. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
25 
Kalbitor (ecallantide) demonstrated a significantly higher improvement over placebo by using 
2 measures of patient-reported outcomes and demonstrated efficacy at all attack locations (Riedl, 
Campion et al. 2010). The open-label extension phase of the studies suggested that the majority 
of patients benefited from a single dose of ecallantide, although in 29% of attacks a second dose 
was necessary due to incomplete efficacy (Levy, Lumry et al. 2010). Hypersensitivity (including 
anaphylaxis) is a known risk of ecallantide treatment for acute HAE attacks and is a black box 
warning label in the prescribing information, with a 4% incidence in treated patients. Ecallantide 
is approved for the treatment of all acute attacks of HAE. 
BCX7353 is a potent, synthetic, second-generation small molecule inhibitor of plasma kallikrein 
discovered at BioCryst. In contrast to the parenterally administered options outlined above, 
inhibition of kallikrein with an orally bioavailable small molecule such as BCX7353 may offer 
the advantage of oral administration in the rapid and successful treatment of acute HAE attacks.  
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). 
BCX7353 is a potent and highly specific inhibitor of human plasma kallikrein activity with a 
50% inhibitory concentration (IC50) of BCX7353 against plasma kallikrein of 0.88 nM.  
In activated plasma from subjects with HAE, the mean half-maximal effective concentration 
(EC50) value was 15.9 ± 0.57 nM.  
Safety pharmacology studies were negative except for a positive human ether-à-go-go-related 
gene (hERG) signal. Doses > 30 mg/kg increased the duration of ECG intervals including the 
QTc interval, but these effects were not considered adverse as the maximum increase was 10% 
versus the pretest group mean.  
In nonclinical species, orally dosed BCX7353 is recovered in the bile, feces, and urine, and the 
terminal half-life is long. In the rat and monkey, BCX7353 is metabolized by oxidative 
deamination, oxidation, and/or conjugation of cyclopropanecarboxylic acid.  
In vitro, BCX7353 inhibits cytochrome P450 (CYP) 2C9 and CYP2C19, CYP2D6 and CYP3A. 
The time-dependent inhibition screen with BCX7353 suggests it may irreversibly inhibit 
CYP3A, but not CYP2C9 or CYP2C19. BCX7353 is also an inhibitor of the transport protein p-
glycoprotein (P-gp) and also breast cancer resistance protein (BCRP), MATE1, and MATE2-K 
at micromolar concentrations. BCX7353 is a substrate of P-gp and BCRP.  
BCX7353 has a low concern for genotoxicity and has no phototoxic potential. 
In rats and cynomolgus monkeys, the effects of repeated, daily oral doses for durations of 28 
days and 13 weeks have been investigated, in accordance with the OECD Test Guidelines and 
Principles of Good Laboratory Practice (GLP). Twenty-eight day 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; a different drug lot than used in the 28-day studies was utilized) there were no significant 
adverse effects noted. In monkeys administered the highest dose (20 mg/kg/day) for 13 weeks, 
there were no adverse effects noted. In rats dosed at this same dose level, bile duct hypertrophy, 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
26 
hyperplasia and vacuolated macrophages in the liver were noted but not considered adverse.  
Further details can be found in the IB. 
Single oral dose non-GLP studies have also been conducted in rats and monkeys. Doses of 150, 
250 and 450 mg/kg administered to rats were well tolerated; there were no deaths and no clinical 
observations. At the highest dose of 750 mg/kg mortality and clinical signs were noted, mainly in 
females. At the highest tolerated single dose of 450 mg/kg, the mean plasma exposures (Cmax and 
AUC0-24) were 560 ng/mL and 11,900 ng•hr/mL, respectively. A single oral dose of BCX7353 to 
one male and one female cynomolgus monkey was evaluated at 75, 150, 300, 500 and 
700 mg/kg. BCX7353 was tolerated at all dose levels but vomiting was noted at 300 mg/kg and 
higher which may have limited the systemic exposure and hence the toxicity. At 300 mg/kg, the 
mean plasma exposures (Cmax and AUC0-24) were 1,030 ng/mL and 14,400 ng•hr/mL, 
respectively. Exposures were lower at higher doses.  
Definitive embryo-fetal development studies were conducted in pregnant Sprague Dawley rats 
and New Zealand White rabbits. In rats and rabbits there was no evidence of embryo-fetal 
mortality, fetotoxicity, or dysmorphogenesis at any dose level. There was no evidence of adverse 
maternal toxicity at 25 mg/kg/day in rats and at 50 mg/kg/day in rabbits. 
5.3. 
Clinical Findings for BCX7353 
Two studies in human subjects have completed (Study BCX7353-101 and Study BCX7353-102) 
and 2 studies are currently ongoing (Studies BCX7353-203 and BCX7353-109). Brief 
summaries are provided below.  
5.3.1. 
Study BCX7353-101 
Study BCX7353-101 was a first-in human, 3-part, Phase 1, double-blind, placebo-controlled 
dose-ranging study of BCX7353 (solid dosage form) conducted in 96 healthy subjects. Part 1 and 
Part 2 of the study assessed the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of a 
single ascending dose of BCX7353 (10 mg–1000 mg) or multiple ascending doses of BCX7353 
given to healthy Western subjects over 7 to 14 days (125mg–500 mg once daily [QD]), 
respectively. 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.  
BCX7353 was generally safe and well tolerated with no treatment-emergent serious adverse 
events (TESAEs) or Grade 4 treatment emergent adverse events (TEAEs). Most TEAEs were 
Grade 1 in severity. In the multiple dose portion (Part 2), one subject (500-mg group) 
experienced a Grade 3 TEAE. The TEAE was a diffuse, cutaneous maculo-papular rash with no 
mucosal involvement, no desquamation, or constitutional symptoms or laboratory abnormalities 
that was diagnosed after the subject completed 7 days of treatment. This event was consistent 
with a Type IV hypersensitivity reaction, and resolved following treatment with oral and topical 
steroids. The event was assessed as probably related to BCX7353. In addition, a Japanese subject 
treated with BCX7353 250 mg for 7 days experienced a Grade 2 maculo-papular rash after 
completing treatment; the subject had no mucosal involvement, no desquamation, or 
constitutional symptoms or clinically significant laboratory abnormalities. The event resolved 
following treatment with antihistamine and was assessed as probably related to BCX7353. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
27 
Overall, 2 subjects (both enrolled in Part 2) discontinued treatment due to Grade 2 TEAEs upper 
abdominal pain and diarrhea in 1 subject (500-mg group) and upper abdominal pain in 1 subject 
(350-mg group).  
There was no apparent dose response regarding any individual AE; however, more 
gastrointestinal AEs were reported in the higher dose cohorts. Across all parts of the study, there 
were no trends in laboratory abnormalities.  
Electrocardiograms extracted from the 12-lead Holter monitoring data provided evidence of a 
dose-dependent increase in mean QTcF occurring after multiple doses of BCX7353 at dose 
levels of 350 mg QD and higher (250 mg QD in Japanese subjects). This was not seen in the 
single dose cohorts. 
Following single and multiple oral doses of BCX7353, Cmax was reached approximately 2 to 
6 hours after dosing. There was approximately 3- to 5-fold accumulation in BCX7353 plasma 
exposure with 7 or 14 days of BCX7353 dosing, which is consistent with the observed long 
half-lives ranging from 67 to 79 hours. Analysis of trough values indicated that steady-state 
conditions were achieved from 6 to 12 days post first dose. 
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 while reasonable 
dose-proportionality between 250 mg and 500 mg for Cmax was observed. There was a slightly 
greater than dose proportional increase in exposure (AUCtau and Cmax) following multiple dose 
exposure over the 125-mg to 500-mg dose range.  
After a high-fat breakfast, AUC0-last and AUC0-inf appeared to be modestly increased although the 
90% CIs were wide. No significant changes were observed in the geometric mean Cmax values.  
The effect of BCX7353 on plasma kallikrein activity was generally dose dependent. Higher 
doses of BCX7353 (≥ 250 mg QD) provided more potent inhibition that was more consistently 
sustained through a dosing interval, achieving approximately 90% inhibition across an interval 
on average. Exposure-response analyses demonstrated a high correlation between ex-vivo 
kallikrein inhibition activity and plasma concentrations of BCX7353 (r = 0.921). The BCX7353 
concentration and kallikrein inhibition relationship was well described by a sigmoidal Emax 
model with predicted EC50 value of 9.71 ng/mL. 
There were no clinically relevant safety, PK, or PD differences and/or trends observed between 
Western and Japanese subjects following dosing with BCX7353. 
5.3.2. 
Study BCX7353-102 
Study BCX7353-102 evaluated the effect of multiple oral doses of BCX7353 (solid dosage form) 
on hepatic and intestinal metabolism by CYP3A4 (as assessed by pharmacokinetics of 
intravenous [IV] and oral [PO] midazolam, respectively), CYP2C9 (tolbutamide), CYP2C19 
(omeprazole) and CYP2D6 (dextromethorphan) enzyme activity using probe substrate drugs in 
healthy subjects. Study BCX7353-102 has completed dosing.  
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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
28 
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 were increased, indicating that metabolism was inhibited. Based 
on the draft US Food and Drug Administration (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 
Study BCX7353-203 is an ongoing Phase 2, randomized, double-blind, placebo-controlled, 
2-part, parallel-group, dose- response study to evaluate the safety, tolerability, PK, PD, and 
efficacy of BCX7353 (solid dosage form) in subjects with HAE. Up to 36 eligible subjects are to 
be randomized in Part 1 of the study to BCX 7353 350 mg QD or placebo QD orally for 28 days. 
In Part 2, approximately 14 eligible subjects will be randomized into 1 of the following 
3 treatment groups: 1) placebo QD orally for 28 days, 2) BCX7353 125 mg QD orally for 
28 days, and 3) BCX7353 250 mg QD orally for 28 days. 
As of 16 December 2016, 29 subjects have been randomized and treated in Part 1 of the study. 
Fifteen subjects have completed through 28 days of dosing and 2 subjects have discontinued 
study drug prematurely due to TEAEs, one due to a concurrent illness and one due to a TEAE. 
The first subject discontinued due to persistently elevated liver enzyme levels that were present 
at baseline and assessed as not related to study drug by the investigator. The other subject 
discontinued due to elevated liver enzymes that occurred in the setting of gastroenteritis. To date, 
no SAEs have been reported.  
5.3.4. 
Study BCX7353-109 
Study BCX7353-109, is an ongoing, open-label study in subjects with Type 1 or 2 HAE to 
evaluate the single dose pharmacokinetics and pharmacodynamics of BCX7353.  A single dose 
of BCX7353 is administered with 2 dose regimens tested. Subjects may participate in one or 
more of the regimens, although it is preferred to have a subject participate in both regimens. Six 
subjects will be enrolled in each regimen to receive the following treatments, separated by at 
least a 14-day washout period:   
Regimen A: Single oral dose of BCX7353 350 mg in capsule formulation 
Regimen B: Single oral dose of BCX7353 750 mg in capsule formulation 
Regimen C: Single oral dose of BCX7353 750 mg in liquid dose formulation 
Three subjects have currently screened for enrollment. Regimen B (750 mg capsules) will be 
administered first given ready availability of IMP for this dosing level. One subject has received 
Regimen B. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
29 
5.4. 
Rationale for Study 
BCX7353 is a second-generation small molecule developed as an orally administered inhibitor of 
plasma kallikrein that is being evaluated for the treatment of acute angioedema attacks in adult 
patients with HAE. 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 acute HAE 
attacks, and C1 INH treatments also target kallikrein. BCX7353 has activity at low nM 
concentrations against plasma kallikrein (see Section 5.4.1).  Phase I PK data describe a plasma 
concentration profile that supports treatment of acute attacks: following oral administration, 
BCX7353 is rapidly absorbed and has a long terminal elimination half-life.  
Study BCX7353-202 is an initial proof-of-concept study of BCX7353 in the oral treatment of 
acute attacks in adult subjects with HAE. Administration of a liquid formulation of BCX7353 
was chosen for this study to eliminate the time required for disintegration of capsules and 
dissolution of powdered drug substance, in order to optimize the time to effective drug levels in 
the systemic circulation after oral dosing.  
This study is designed to evaluate the treatment effect of BCX7353 750 mg on the resolution of 
acute attacks. Up to 2 additional doses of BCX7353 (500 mg and 250 mg) will be evaluated in 
the dose-ranging parts of the study.  
5.4.1. 
Rationale for Study Drug Doses  
5.4.1.1. 
Rationale for Achievement and Maintenance of 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, achieving BCX7353 concentrations 
at or above an appropriate target level is hypothesized to effectively treat attacks in HAE 
subjects with little or no functional C1 INH, the endogenous inhibitor of kallikrein and 
ultimately, bradykinin production.  Moreover, maintaining these concentrations over the target 
level for a duration of time to prevent recurrence of an attack will be required.  
Selection of appropriate target plasma level of BCX7353 
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 approximately 1680 nM; therefore, the LLN 
for C1 INH corresponds to a BCX7353 concentration of approximately 125 nM, or 71 ng/mL. It 
would be expected that BCX7353 concentrations above approximately 71 ng/mL, would restore 
phenotypically normal total plasma kallikrein inhibitory activity.   
Selection of duration that BCX7353 concentrations must exceed the target plasma level 
To abate an attack, it is desirable to exceed the target plasma concentrations of BCX7353 as 
quickly as possible after a dose. HAE attacks typically follow a predictable time course. Swelling 
classically worsens slowly but relentlessly over the first 24 hours, and gradually subsides over 
the subsequent 48 to 72 hours. Following administration of a single dose formulated in a capsule 
in Study BCX7353-101, BCX7353 was rapidly absorbed. Mean plasma concentrations exceeded 
71 ng/mL by 0.5 to 1 hour postdose at doses ranging from 250 to 1000 mg. Administration of a 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
30 
liquid formulation in the current study is expected to achieve target levels earlier. In summary, 
target concentrations of BCX7353 are achievable early in the development of an HAE attack. 
Current treatments for acute attacks of angioedema in HAE patients are administered 
parenterally, and sometimes retreatment is required after a period to time due to a lack of 
symptom relief. The label for Firazyr (icatibant) specifies that patients should administer 
additional doses every 6 hours if symptoms have not improved, and analysis of the open-label 
extension period of FAST-1 showed that 11.8% of treated attacks required more than one 
injection of Firazyr (icatibant) (Malbran, Riedl et al. 2014). The need for redosing could indicate 
that adequate plasma concentrations of icatibant are not of a sufficient duration to alleviate the 
symptoms of the attack or that a rebound effect is occurring. For an acute treatment, it would be 
advantageous to rapidly achieve plasma concentrations of BCX7353 at levels that lead to potent 
inhibition of plasma kallikrein, and maintain these concentrations above this level for longer than 
6 hours.  
Given that BCX7353 is rapidly absorbed from the gastrointestinal tract and has a long half-life 
(approximately 50 hours after a single dose), it is expected that BCX7353 plasma concentrations 
could be maintained above the target of 71 ng/mL for up to 24 hours with an appropriate dose. 
Following administration of a single 250-mg dose in Study BCX7353-101, BCX7353 was 
rapidly absorbed, and mean plasma concentrations exceeded 71 ng/mL by 1 hour postdose and 
fell below target by 8 hours. After administration of a 500-mg dose, mean BCX7353 plasma 
concentrations exceeded 71 ng/mL after 0.5 hours postdose and remained above that 
concentration through 12 hours. Mean plasma concentrations were above 71 ng/mL at 1 hour 
postdose and remained above this level until the 24-hour time point following administration of 
the 1000-mg dose. In addition, rapid inhibition of plasma kallikrein was observed following a 
single dose of BCX7353 at doses of 250 mg or higher. At doses of 500 and 1000 mg, maximal 
inhibition of plasma kallikrein was sustained through 24 hours postdose.  
The rapid onset and maintenance of kallikrein inhibition with a single dose gives support that 
BCX7353 could be a potent oral option for treatment of acute HAE attacks.  
5.4.1.2. 
Rationale for Proposed Doses 
This study will evaluate the safety and efficacy of a single dose treatment of BCX7353 for an 
acute HAE attack at doses of 750 mg, 500 mg, and 250 mg compared to placebo. The rationale 
for selection of these doses is based upon the safety observed in Study BCX7353-101 and the 
achievement and maintenance of potentially efficacious BCX7353 plasma concentrations. Single 
doses of up to 1000 mg were generally safe and well-tolerated in healthy subjects. 
Gastrointestinal effects were reported more frequently at higher dose levels, although these 
events were predominantly mild. No other dose-related safety concerns were noted, and the 
maximum tolerated dose was not reached in Study BCX7353-101, supporting selection of single 
doses up to 750 mg for clinical evaluation in the current study.  Assuming linear exposure 
between a single 500 mg dose and a 1000 mg dose administered in Study BCX7353-101, the 
AUC0-24  for a single 750 mg dose is predicted to be approximately 4219 ng*h/mL with a Cmax of 
approximately 330 ng/mL. This exposure is expected to be less than the steady-state exposure at 
a 350 mg and 500 mg daily dose as measured in the first in human study (517 ng/mL [Cmax] and 
8230 ng*h/mL [AUCtau] for a 500 mg dose administered for 7 days and 363 ng/mL [Cmax] and 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
31 
5720 ng*h/mL [AUCtau] for a 350 mg dose administered for 14 days). As previously mentioned, 
the doses of BCX7353 imparting this exposure were well-tolerated. 
 
Simulation of plasma drug levels over a range of doses of BCX7353 after single dose 
administration 
Superposition with linear extrapolation was first used to simulate individual plasma 
concentration-time profiles of BCX7353 following single dose administration at dose levels 
ranging from 250 to 750 mg using available pharmacokinetic data from Study BCX7353-101. 
The main purpose of this simulation was to obtain more concentration-time points of BCX7353 
at early times following the dose administration. Simulated mean concentrations (Figure 1) 
facilitated determination of the percentage of theoretical subjects predicted to have 
concentrations over a target concentration of 71 ng/mL at various timepoints postdose (SAS 
Version 9.2 [SAS, USA)], assuming a normal distribution, with 1000 simulations performed at 
each time point for each dose level). These data are presented in Table 2. Following 
administration of a capsule-formulated dose of 750 mg, plasma concentrations are predicted to 
exceed the target concentration of 71 ng/mL within 1.2 hours of dosing in approximately 90% of 
subjects. At this dose, plasma concentrations are predicted to be sustained above 71 ng/mL for 
24 hours, which also provide sustained levels of kallikrein inhibition (Table 3).   
Figure 1. 
Simulated Mean Exposure of BCX7353 over Target Concentration 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
32 
Table 2. 
Simulated first time postdose to achieve BCX7353 concentration ≥71 ng/mL 
following single dose administration of 250, 500, and 750 mg BCX7353 
Dose 
(mg) 
Mean time 
(hr) to first 
achieving 
target 
BCX7353 
concentration  
(≥71 ng/mL) 
Estimated percentiles (1st percentile to 99th percentile) of simulated subjects 
(1,000 at each dose level) for time (hr) to first achieving target drug 
concentration (≥71 ng/mL), based on plasma concentrations observed in study 
BCX7353-101 after dosing solid dosage form (powder in capsule) 
p1 
p5 
p10 
p25 
p50 
p75 
p90 
p95 
p99 
250 
1.56 
0.00 
0.20 
0.36 
0.87 
1.56 
2.22 
2.75 
2.99 
3.66 
500 
0.92 
0.00 
0.12 
0.30 
0.59 
0.91 
1.25 
1.56 
1.70 
2.18 
750 
0.76 
0.00 
0.17 
0.29 
0.53 
0.76 
1.02 
1.23 
1.36 
1.56 
 
Table 3. 
Simulated duration of BCX7353 concentrations exceeding target 
concentration of 71ng/mL following single dose administration of 250, 500, 
and 750 mg BCX7353 
Dose 
(mg) 
Mean duration 
(hr) of 
BCX7353 
concentration  
≥ target (71 
ng/mL)  
Estimated percentiles (1st percentile to 99th percentile) of simulated subjects 
(1,000 at each dose level) for duration (hr) at or above the target drug 
concentration (≥71 ng/mL), based on plasma concentrations observed in study 
BCX7353-101 after dosing solid dosage form (powder in capsule) 
p1 
p5 
p10 
p25 
p50 
p75 
p90 
p95 
p99 
250 
4.0 
0.0 
0.2 
1.1 
2.4 
4.1 
5.6 
6.9 
8.0 
9.6 
500 
17.7 
6.3 
9.5 
11.1 
14.2 
17.6 
21.0 
24.0 
24.0 
24.0 
750 
21.2 
12.6 
15.0 
16.5 
18.5 
21.2 
23.8 
24.0 
24.0 
24.0 
 
5.4.2. 
Rationale for Study Design 
This is a Phase 2 study designed to assess the efficacy and safety of single oral doses of 
BCX7353 for the treatment of acute attacks in subjects with Type 1 or Type 2 HAE.  
A dose-ranging design that incorporates sequential testing was chosen to ensure that a treatment 
effect could be demonstrated while allowing exploration of the potential utility of a range of 
doses. Further, evaluating a total of 3 attacks for each subject (1 of which is treated with placebo) 
enhances the ability to detect a treatment effect at each dose. The study allows for initial 
evaluation of the treatment effect during Part 1, the highest planned dose level (750 mg), and 
employs a Haybittle-Peto boundary for detection of drug effect. Treatment effect will be 
measured by comparing BCX7353-treated and placebo-treated attacks, using the proportion of 
subjects with a stable or improved composite visual analogue scale (VAS) of HAE attack 
symptoms at 4 hours postdose. If conducted, a convincing treatment effect will be demonstrated 
if the p value for the comparison crosses the Haybittle-Peto boundary of < 0.001. This treatment 
effect may be estimated beginning when 12 subjects completing the study at the 750-mg dose 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
33 
level and. If the boundary is not crossed, the treatment effect may be re-estimated based on 
cumulative data after data on each additional attack on study are available.  
Given the Cmax levels achieved with the BCX7353 doses proposed in this study and its long 
terminal half-life, a washout period of at least 14 days between treatments is necessary to 
minimize carryover of a previously administered active dose.  
Risk mitigation built into the protocol includes medical assessment of suitability of the attack, 
prohibiting treatment with study drug of any attack involving the throat or mouth, or any 
abdominal attack that has already resulted in vomiting. Lastly, subjects are allowed to self-treat 
with a standard of care attack medication 4 hours after dosing with study drug or sooner if the 
subject feels that the attack is progressing rapidly after administration of study drug.  
A 3-month optional substudy, commencing at the conclusion of the study drug phase of the 
study, is included with the goal to learn more about the progression of untreated attacks and 
those treated with commercially available attack medications. 
5.4.3. 
Study Population Rationale 
The current study is limited to adults of both sexes with HAE. Adolescents and children are 
excluded from participation since the long term benefit/risk profile has not been sufficiently 
characterized in adults. 
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 efficacy differences. 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. 
Although there is no evidence of embryofetal developmental toxicity with BCX7353 in 
reproductive toxicology studies, appropriate precautions are still warranted with respect to 
administering BCX7353 to women of reproductive age, in accordance with International 
Conference on Harmonization) ICH guidelines. Women of childbearing potential may be 
enrolled in this trial provided they meet the contraceptive requirements and have negative 
pregnancy tests prior to receiving each dose of study drug. 
As BCX7353 is early in clinical development, the benefit/risk profile has not been sufficiently 
characterized to allow pregnant women to receive BCX7353, therefore pregnant women will be 
excluded from participation. Additionally, any female subject who becomes pregnant on study 
will be required to immediately discontinue study drug, and will be followed through the end of 
the pregnancy. 
5.4.3.1. 
Rationale for Use of Standard of Care Attack Medication 
In the current study, all participants must have access to effective, approved treatments for acute 
attacks of angioedema as part of their routine medical care. Each subject will continue to use 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
34 
their prescribed acute attack medication to treat any acute attacks that do not meet the eligibility 
requirements for treatment in this study. For the protection of the safety of the subjects, subjects 
will not utilize study drug to treat any HAE attack with the symptoms of pain or swelling 
involving the throat or mouth; for these attacks, subjects will be instructed to use their standard 
of care acute attack treatment. Abdominal attacks that have resulted in vomiting may be expected 
to reduce or abrogate absorption of an orally administered drug, and are therefore also restricted 
from study drug treatment. For these attacks, subjects will be instructed to use their standard of 
care acute attack treatment. Lastly, subjects who experience progression or do not experience 
improvement of the HAE attack will also be instructed to use their acute attack treatment per 
their standard of care.  
Subjects will be requested to treat early with study drug (within approximately 1 hour of 
symptom onset) and use standard of care, if necessary, no sooner than 4 hours post-study drug 
administration. Requesting a delay in administration of standard of care for 4 hours after 
administration of study drug and maximally 5 hours after the onset of known symptoms is 
necessary for demonstration of a treatment effect of BCX7353 versus placebo and is a reasonable 
request of subjects as part of the protocol for the following reasons: 
1. An HAE attack develops with a worsening of swelling over the first 24 hours with a 
resorption of the edema over the subsequent 48-72 hours. Therefore, four to five hours 
from the onset of symptoms to administration of standard of care attack treatment is 
within a symptom-modifiable timeframe based upon the development of symptoms of 
HAE. 
2. A four to five hour timeframe from the onset of symptoms to administration of standard 
of care attack treatment in the current study is less than the delay in treatment observed in 
pivotal studies of acute attack medications in which treatments were found to be 
efficacious. For instance, in the FAST-3 study of icatibant, the mean (SD) time from 
onset of symptoms to blinded study drug treatment in 43 subjects was 7.07 (3.17) hours; 
in FAST-3, icatibant-treated attacks had a median time to onset of symptom relief of 
2 hours (Lumry, Li et al. 2011).   
 
3. After administration of study drug, subjects may treat an attack with their standard of 
care attack medication before 4 hours post administration of study drug, if they feel that 
the attack symptoms warrant earlier treatment.  
Exclusion of approved kallikrein inhibitor attack prophylaxis with C1 INH is required to clearly 
demonstrate proof of concept of BCX7353. Additionally, use of androgens is prohibited due to 
possible interference of androgen metabolism by CYP3A4 from the inhibitory effect of 
BCX7353, resulting in higher androgen concentrations (see Section 9.7.1).  
5.4.4. 
BCX7353 Risk/Benefit Analysis 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions 
BCX7353 is a small molecule kallikrein inhibitor and given the previous experience with this 
class of agents in man, there is an acceptably low risk of severe adverse reactions, especially 
with two single active doses separated by at least 14 days. Potential risks are outlined below. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
35 
5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 
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, and for 13 weeks, there were no adverse effects noted. In rats dosed at 
20 mg/kg/day, 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 with single doses, particularly at higher doses. 
With multiple days of dosing, similar gastrointestinal effects were seen as well as a delayed 
hypersensitivity drug rash, both occurring in the higher dose cohorts. In addition, at multiple 
dosing with 350 mg and higher, QT prolongation was seen. While the mechanisms of delayed 
hypersensitivity drug rash and QT prolongation following multiple dosing with BCX7353 have 
not yet been elucidated, it is currently considered unlikely that either of these findings will occur 
following administration of single doses of study drug. 
Liver: At 20 mg/kg/day of BCX7353 dosed to rats for 13 weeks, liver bile duct hypertrophy, 
hyperplasia, and vacuolated macrophages were present in the liver with evidence of 
phospholipidosis (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, hepatocyte necrosis, and hepatocellular vacuolation that 
correlated to increased aspartate aminotransferase (AST) and alanine aminotransferase (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 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 completed and unblinded Phase 1 studies. In the 68 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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
36 
Liver function will be monitored after each dose administered in this study, although no toxicity is 
anticipated from single doses of study drug, separated by 14 days at a minimum. 
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 noted in the 28-day monkey 
study. 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 trials, no clinically significant abnormalities of renal function, as measured by 
serum creatinine and creatinine clearance 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 and urine microalbumin will be assessed after each dose 
of study drug administered in this study, although no toxicity is anticipated from single doses of 
study drug, separated by 14 days at a minimum.  
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 trials neither AST nor creatine phosphokinase (CPK) demonstrated any clinically 
significant elevations. All CPK changes were associated with muscular exertions. In addition, no 
subjects have experienced any AEs of potential muscular injury. 
Given the preclinical data, AST and CPK will be monitored after each dose of study drug 
administered in this study, although no toxicity is anticipated from single doses of study drug, 
separated by 14 days at a minimum. 
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 was 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.  
In addition to cardiac muscle changes and physiologic changes in heart rate and blood pressure, 
it should be noted that there is a small risk of hERG channel inhibition, although the cardiac 
action potential was not prolonged.  
In the Phase 1 study BCX7353-101 study, no single ECG in subjects dosed with BCX7353 had a 
clinically significant abnormality. All QRS intervals were < 120 msec. There was a small but 
discernible QT prolongation seen only with multiple day dosing at doses higher than 250 mg; no 
QT prolongations were noted following single doses of BCX7353 up to 1000 mg. After multiple 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
37 
daily doses, there was a dose-dependent increase in QTcF evident at 350 mg QD and higher in 
Western subjects and at 250 mg QD in Japanese subjects, and a concentration-dependent 
increase that was not predicted by analysis of QTcF data for single high doses that produced 
overlapping BCX7353 concentrations. No subject dosed in this study had an absolute QTcF 
value > 448 msec or change from baseline > 37 msec. There were 9 subjects in the entire trial 
with 21 events of QTcF change from baseline > 30 msec. The majority (16/21) of events 
occurred in 4 subjects after 7 days of dosing with 500 mg. The rest of the events occurred in 
5 subjects at lower doses at a single timepoint. In summary, these data indicate that the change 
observed with multiple doses is not likely to be clinically significant in any population with 
normal QTcF and no underlying cardiac conductivity issues, even at a supratherapeutic daily 
doses such as 500 mg QD. 
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 
(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 CK-MB 
elevations, and had no ECG evidence of ischemia.  
Six subjects treated with BCX7353 in the Phase 1 study BCX7353-101 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 5 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 sequestration was 
complete. 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. No significant ECG or laboratory 
changes were seen in BXC7353-102 study. 
As a precaution, this study will exclude subjects with evidence of cardiac disease as indicated by 
medical history, family history of sudden death or abnormal screening ECG. ECGs, troponin and 
CK-MB will be regularly monitored in this study. No cardiac toxicity or QT prolongation is 
anticipated from single doses of study drug, separated by 14 days at a minimum.  
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 studies, no clinically significant changes in any hematologic parameter or 
lymphoid tissue were noted. No organomegaly and no lymphadnopathy were noted on physical 
exam.  
In this study, complete blood counts and general physical examinations will be monitored after 
each dose of study drug administered. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
38 
Presumed Phospholipidosis (PLD):  
In the 28 day studies in both rats and monkeys, foamy macrophages and vacuolated infiltrates 
were found in multiple organs and various tissues, and presumed to be signs of PLD. PLD can 
only be confirmed with electron microscopy which was not done in the 28 day study. In most 
tissues, these infiltrates did not appear to be adverse and there were no clinical or blood 
chemistry findings that correlated. Importantly, the infiltrates were 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 13-week study there were no 
microscopic abnormalities, and no foamy macrophages or vacuolated cellular infiltrates were 
observed. Increased urinary levels of di-docosahexaenoyl (22:6)-Bis(mono)acylglycerol 
phosphate (BMP), an investigational biomarker for PLD, were demonstrated in both rats and 
monkeys dosed with BCX7353 for 13 weeks. This increase was dose related and reversible upon 
cessation of BCX7353 in both species. These data suggest that the urinary BMP changes induced 
by BCX7353 in both rats and monkeys may not be associated with PLD, given the differences 
seen microscopically between the two species.   
PLD is not adverse in and of itself and there are many approved products that cause this 
phenomenon without any unmanageable toxicities. Since PLD requires accumulation of drug, it 
is highly unlikely that subjects are at any risk of this phenomenon with individual doses of study 
drug, separated by at least 14 days at a minimum. 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.  Since phospholipidosis is not toxic in and of itself, organ health 
including function and signs of inflammation will be monitored. Monitoring of renal, liver, 
cardiac, and muscle health will be achieved with routine safety assessments, including ECGs.  
Gastrointestinal (GI) symptoms: Gastrointestinal symptoms, all mild, were noted in half of the 
subjects receiving a single 1000 mg single dose in the Phase 1 BCX7353-101 study. The events 
were both upper GI (nausea, dyspepsia, and vomiting) and lower GI (diarrhea). The events 
resolved without treatment. No pertinent GI events occurred in the 500 mg single dose cohort but 
2 subjects reported GI symptoms at 100 mg.  During multiple day dosing (part 2), all cohorts 
experienced GI symptoms 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 study drug, 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. The Phase 1 study 
demonstrated no adverse impact on the extent of drug exposure from taking BCX7353 with food 
in 6 subjects who received a dose of BCX7353 (250 mg) under fed and fasting conditions. 
However, the time to achieve maximal blood concentrations was delayed when BCX7353 was 
administered with food (median Tmax increased from 2 to 5 hours, with 4 of 6 subjects 
experiencing a delay in Tmax with food relative to fasting). Therefore, since food may materially 
delay achievement of effective blood levels and the gastrointestinal effects to date have been a 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
39 
tolerability issue but not a safety issue, BCX7353 is recommended to be taken without food and 
to delay food at least one hour (to allow for gastric emptying). However, due to the 
unpredictability of onset and location of HAE attacks, recent food intake will not necessarily 
prohibit an attack from being approved for treatment with study drug in this study. The time of 
the last meal prior to the attack will be captured to assess whether recent food ingestion prior to 
an attack may affect efficacy.  
Subject well-being with respect to possible gastrointestinal symptoms will be monitored through 
adverse event reporting and laboratory assessment. 
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. The management of rash is 
specifically addressed in Section 11.1.11. It is unknown if repeat exposure of single doses will 
result in hypersensitivity. 
5.4.5. 
Benefits of Trial Participation 
Study subjects will receive regular medical care for the duration of the study. Subjects may 
experience a resolution in their acute attacks after receiving active study drug; however, subjects 
will be blinded to their treatment sequence so they will not know if they are receiving BCX7353 
or placebo for any given treated attack.  
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. Although there may be no direct benefit to any individual 
subject, the information obtained from this study will support the development of BCX7353 for 
treatment of acute attacks in patients with HAE, a life-threatening disease. The overall risk 
benefit balance is therefore considered to be acceptable. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
40 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Objectives 
The primary objective of this study is as follows:  
• To evaluate the efficacy of single oral doses of BCX7353 in treating acute attacks in 
subjects with HAE  
The secondary objectives of this study are as follows:  
• To evaluate the safety and tolerability of single oral doses of BCX7353 in subjects 
with HAE 
• To evaluate the relationship of BCX7353 dose with clinical responses 
• To evaluate subject satisfaction with BCX7353 treatment 
• Substudy: to describe the natural history and temporal pattern of symptoms of 
untreated attacks and those treated with commercially available attack medications 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
41 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design  
This is a 3-part, Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to 
evaluate the efficacy and safety of single oral doses of a liquid formulation of BCX7353 in the 
treatment of acute HAE attacks. All subjects enrolled will receive both active and placebo 
blinded study drug in a randomized sequence. Part 1 of the study will evaluate single doses of 
BCX7353 750 mg; Part 2 will evaluate single doses of BCX7353 500 mg and Part 3 will 
evaluate single doses of BCX7353 250 mg.  
HAE patients with a documented recent history of 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 Type 1 or 2 HAE with a documented history of HAE attacks will be 
sequentially enrolled into Part 1 of the study and randomized to a treatment sequence containing 
the following: 
• Treatment A1: Single oral dose of BCX7353 750 mg  
• Treatment B: Single oral dose of placebo 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single 
oral doses of BCX7353 500 mg in Part 2; or Treatment A3 = single oral doses of BCX7353 
250 mg in Part 3. 
Initially in Part 1, 12 subjects will be randomized 1:1:1 to 1 of 3 treatment sequences 
(n = 4 subjects per treatment sequence): 
• Sequence 1:  ABA 
• Sequence 2:  BAA 
• Sequence 3:  AAB 
Both subjects and site staff will be blinded to which treatment sequence a subject is randomized 
to receive. 
If required, additional subjects will be enrolled into Part 1 (see below) using the same 1:1:1 ratio 
for the 3 treatment sequences, with a maximum total number of 36 subjects for Part 1. 
Part 2 will evaluate a dose of 500 mg (Treatment A2) and placebo (Treatment B). A maximum of 
12 subjects will be enrolled, using the same 1:1:1 ratio for the 3 sequences. Part 3 will evaluate a 
dose of 250 mg (Treatment A3) and will enroll a maximum of 12 subjects in a 1:1:1 ratio for 
each of the 3 treatment sequences.  
If tolerability issues prevent enrollment of Part 1 as described, additional subjects in Part 1 may 
be dosed with active study drug at a dose of 500 mg. If the Part 1 dose is reduced and at least 
12 subjects are treated with an active study drug dose of 500 mg, a 250 mg active dose may be 
assessed in Part 2. Any further dose level changes warranted for Part 2 and Part 3 will be 
instituted via a protocol amendment. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
42 
The overall study design is presented in Figure 2. 
Figure 2.  
Study Design Through Follow-up (Post-Attack 3 Visit) 
    Screening                          Study Drug Treatment                  Follow-Up 
Sequence 1: A1, B, A1
Randomize 1:1:1
n = 36 (Part 1)
n = 12 (Parts 2 and 3)
Sequence 2: B, A1, A1
Sequence 3: A1, A1, B
A1 = BCX7353 750 mg x1 (Part 1) 
A2 = BCX7353 500 mg x1 (Part 2)
A3 = BCX7353 250 mg x1 (Part 3)
B  = Placebo x1
 
7.1.1. 
Enrollment and Analyses 
Up to 36 subjects will be enrolled in Part 1. Upon full enrollment, enrollment into Part 2 of the 
study (maximum of 12 subjects) may immediately commence. Likewise, Part 3 (n = up to 12) 
may immediately commence upon enrollment of Part 2. 
Following the 12th subject completing Part 1, the treatment effect may be estimated. The 
predefined endpoint, determined by the Haybittle-Peto method, is the proportion of subjects with 
a stable or improved composite VAS at 4 hours postdose of an HAE attack. A Haybittle-Peto 
boundary of p < 0.001 is considered clinically significant. 
If the Haybittle-Peto analysis is run and the boundary is not crossed with 12 subjects, the 
treatment effect may be re-estimated with cumulative data after each treated attack in accordance 
with the fully sequential analysis method. At each evaluation, the treatment effect may be 
assessed using the Haybittle-Peto boundary (p < 0.001).  
Alternatively, if the boundary is not crossed with 24 subjects enrolled or the Heybittle-Peto 
analyses are not performed, treatment differences may be assessed using available data in Parts 
1, 2 and 3 in order to plan subsequent studies. 
7.1.2. 
Study Conduct Overview 
At the Screening visit, potential subjects will be given a diary and receive instruction on the 
correct completion of the diary in real-time to record attack symptoms and severity and any 
medication usage during an attack. During the 35-day screening period, subjects will be required 
to: 1) phone the on-call Investigator (or designee) at the onset of pain or swelling associated with 
an HAE attack; 2) complete details in real time of this HAE attack; and 3) phone the on-call 
Investigator (or designee) again in at least 4 hours time.  Completion of these procedures will 
confirm that the subject is able and competent to perform on-study requirements in early 
identification of an attack and treating and documenting an HAE attack.  
Eligible subjects will return to the clinic to attend a Baseline visit. At the conclusion of the 
Baseline visit, subjects will receive their first (single) randomized dose of study drug for 
treatment of attacks by self-administration. The IMP is supplied as a powder form of drug in a 
bottle that will require reconstitution to a liquid formulation with vehicle, by the subject, prior to 
self-administration. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
43 
At the Baseline visit, all subjects will be instructed on how to prepare and use study drug to treat 
a protocol-qualified HAE attack and will receive further instruction on the correct completion of 
a diary in real-time immediately prior to and after study drug administration.  
Specifically, subjects will be instructed with respect to treatment of attacks with study drug by 
self-administration as follows: 
1. At the first symptom of swelling or pain known to be associated with a potentially 
protocol-qualified attack, the subject will phone their on-call study Investigator (or 
designee) who will review the subject’s symptoms by phone. The Investigator will 
confirm that their symptoms constitute an acute attack that qualifies for treatment with 
study drug.  
Protocol-qualified attacks approved for study drug treatment must meet all of the 
following: 
• have pain and/or swelling associated with an HAE attack reported as a symptom 
• subject has contacted Investigator within approximately 1 hour of onset time of 
HAE pain and/or swelling  
• not involve pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant) without delay. 
• not be an abdominal attack that has already resulted in vomiting. Such attacks 
should be treated using the subject’s standard of care acute attack treatment (e.g., 
C1 INH, icatibant). 
• have an identifiable onset time, with the exception that abdominal attacks with an 
onset during sleep may be permitted for study drug treatment. Onset time for 
abdominal attacks will be time the subject woke up with symptoms. Peripheral 
attacks starting with an onset during sleep will not be approvable for study drug 
treatment. 
• occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor 
antagonist (i.e. Firazyr) OR treated with human recombinant C1 INH (i.e. 
Ruconest) OR any non-targeted therapy (i.e. pain medication, anti-spasmodic, 
anti-emetic, tranexamic acid) OR was not treated with any medication: new 
attack can be treated with IMP if has been 48 hours since the complete 
resolution of all symptoms of the previous HAE attack AND the Investigator 
believes it is a new (de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH 
(i.e. Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent 
detergent plasma): new attack can be treated with IMP if it has been 96 hours 
since the complete resolution of all symptoms of the previous HAE attack 
• occur at least 96 hours after complete recovery from a procedure or injury  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
44 
• occur at least 14 days from a previous dose of study drug 
2. Only after receiving confirmation by the on-call Investigator (or designee) should a 
subject reconstitute study drug with vehicle and take it to treat the HAE attack.  
Reconstitution and ingestion of the study drug should occur almost immediately (within 
5 minutes) following the phone call, with the goal for subjects to take study drug within 
approximately one hour of the onset of symptoms. 
3. At 4 hours post study drug intake, subjects who are not experiencing improvement or 
who are experiencing progression of the HAE attack can use their standard of care acute 
attack treatment, if warranted. However, if the subject feels that an attack is progressing 
rapidly after administration of study drug or intraoral symptoms develop, the subject 
may treat the attack with their standard of care attack medication prior to 4 hours.  
4. The subject will call the on-call study Investigator (or designee) at least 4 hours after 
taking study medication (or earlier if they have any concerns over the course of their 
symptoms) to review their response to study drug and diary completion. The on-call 
study Investigator (or designee) will call the subject if they have not heard from the 
subject within 5 hours of their initial phone call. Subjects who did not require standard 
of care at 4 hours will be reminded at the telephone call, by the Investigator, that they 
may use standard of care at any time point at their own discretion if not experiencing 
improvement or if they are experiencing progression of the HAE attack. An exception to 
the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours 
post-study medication. In this case, the subject will be required to call the on-call 
Investigator (or designee) upon waking.  
Subjects will complete a diary questionnaire and a 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling immediately prior to study drug 
administration and at 1, 2, 3, 4, approximately 8 and at 24 hours after study drug administration. 
Subjects sleeping during these timepoints (see #4 exception above) will be required to complete 
the diary questionnaire upon waking. Subjects will also be asked to track the start and stop times 
of any attacks not treated with study drug that occur after the baseline visit through the last study 
visit (Post-Attack 3 visit). 
At each clinic visit following treatment of an attack with study drug, the diary will be reviewed. 
Any re-education required to ensure correct diary completion will be performed and safety 
assessments will be completed. At Post-Attack 1 and Post-Attack 2 clinic visits, the subject will 
be dispensed their next randomized dose of study drug and a new attack diary. Completed diaries 
will be collected at each visit to avoid subjects referencing back to previous attack entries.   
Each subject will continue on study to treat 3 protocol-qualifying attacks with study drug. Clinic 
visits will be scheduled 10 to 14 days after each attack that is treated with study drug. Any 
additional attacks that occur in the intervening periods between study visits may be treated 
according to standard of care for the subject. 
Sites must attempt to contact subjects every 7 days from the last clinic visit to inquire about the 
occurrence of an attack if the subject has not contacted the site during this timeframe.  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
45 
Subjects will be asked to participate in an optional observational substudy to obtain diary data on 
all HAE attacks, commencing from the Post-Attack 3 visit.  Consenting subjects will receive a 
diary and instruction for completion at the Post-Attack 3 visit. For the next 12 weeks, subjects 
will complete diaries provided on an as-needed basis with periodic subject contact to ensure 
adherence with diary completion. 
7.2. 
Endpoints 
7.2.1. 
Efficacy Endpoints 
The efficacy endpoints of this study are as follows: 
• Proportion of subject attacks with an improved or stable 3-symptom composite VAS 
score at 4 hours post-dose. The 3-symptom composite will be calculated as the 
average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject 
is considered improved or stable if the change from baseline (time of drug 
administration) in VAS is less than or equal to 0 
• Proportion of subject attacks with a patient global assessment of improved or stable 
symptoms at 4 hours post-dose   
• Proportion of subject attacks with no symptoms or mild symptoms of an HAE attack 
at 4 hours post-dose 
• Proportion of subject attacks requiring standard of care attack treatment through 
24 hours post-dose 
• Time to use of standard of care acute attack treatment through 24 hours post-dose 
• Time to stable or improved symptoms by composite VAS score through 24 hours 
post-dose 
• Time to symptom relief (first documented time point when a subject experiences a 
50% reduction in the 3-symptom composite VAS from the pretreatment composite 
score) 
• Time to almost complete symptom relief (first documented time point when a subject 
records a VAS score < 10 mm in the 3-symptom composite VAS score) 
• Time to initial symptom relief (time from ingestion of study medication to report that 
the worst symptoms of the attack are over) 
• Time to complete symptom relief (time from ingestion of study medication to no 
HAE attack symptoms) 
7.2.2. 
Safety Endpoints 
Safety endpoints will include the number and proportion of subjects who: discontinue due to a 
treatment-emergent AE; experience a treatment-emergent SAE; experience a Grade 3 or 4 
treatment-emergent AE; and experience a treatment emergent Grade 3 or 4 laboratory 
abnormality. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
46 
7.2.3. 
Other Secondary Endpoints 
Other secondary endpoints will include treatment satisfaction, as assessed by the TSQM. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
47 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Up to 36 evaluable subjects with Type 1 or 2 HAE are planned to be enrolled in Part 1, up to 
12 evaluable subjects in Part 2, and up to 12 evaluable subjects in Part 3. An evaluable subject is 
one who treats 3 attacks with study drug and for which there is diary information recorded for 
each treated attack.  
Subjects who complete Part 1 will not be eligible to participate in Parts 2 or 3. Likewise, subjects 
who complete Part 2 will not be permitted to participate in Part 3. 
Subjects who prematurely withdraw from the study may be replaced at the Sponsor’s discretion. 
Any subject who 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, defined having a C1 
INH functional level below 50% of normal and a C4 level below the lower limit of the 
normal reference range, as assessed at the Screening visit. 
Should the C4 level be within the normal range, as is the case in a small percentage of 
subjects with HAE, C4 may be drawn during an attack for re-testing or the SERPING-1 
gene may be analyzed for a known mutation associated with HAE Types 1 or 2. Either 
will be considered confirmation of eligibility. 
4. Access to and ability to use standard of care acute attack treatment. Standard of care 
acute attack treatment is defined as a medication approved by the relevant competent 
authority for the treatment of attacks of HAE (e.g., icatibant, ecallantide, plasma-derived 
C1INH, recombinant C1INH). 
5. 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 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:  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
48 
 surgical sterilization (i.e., bilateral tubal ligation 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 an 
acceptable effective contraceptive method (as defined 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 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."  
6. Male participants must comply with the following requirements through the end of the 
study: 
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 an acceptable effective contraceptive method. At least 1 or more of the 
following methods are acceptable:  
 surgical sterilization (ie, vasectomy or bilateral tubal ligation of a 
female partner) 
 partner’s placement of an IUD or IUS 
 partner’s use of any form of hormonal contraception that is associated 
with inhibition of ovulation (oral, injectable, intravaginal, implantable 
or transdermal) 
 use of a condom with or without spermicidal 
foam/gel/film/cream/suppository 
 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 or exclusively having 
male sexual partners are acceptable for the purposes of this study. Abstinence in 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
49 
this study is defined as “true abstinence: when this is in line with the preferred 
and usual lifestyle of the subject.”  
7. Any regularly administered concomitant medication recorded at the Screening visit and 
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 (screening through 
follow-up). 
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. To be dispensed study drug at 
baseline, the subject must demonstrate adequate compliance with all study procedures 
required from the Screening visit through randomization, including phoning the 
investigator and diary recording of at least one HAE attack during the screening period. 
9. Must have an HAE attack rate of at least 1 unique attack per month for 3 months (up to 
93 days) within the 4 months prior to the Screening visit. A unique attack is defined as 
an attack that is not recorded on contiguous days to another attack. For the purposes of 
this protocol, two attacks that are recorded on contiguous days are one attack with an 
onset day/time of the first attack. 
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.  
8.2.2. 
Exclusion Criteria 
Subjects must meet none of the following exclusion criteria to be eligible for participation in this 
study: 
1. No HAE attack reported to the on-call Investigator (or designee) during the 35-day 
screening period. 
2. 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 increase the risk of participation for that subject.   
3. 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. 
4. Clinically significant abnormal ECG at the Screening visit. This includes, but is not 
limited to, a QTcF > 470 msec for women, a QTcF > 450 msec for men, a PR > 220 
msec (both sexes), or ventricular and/or atrial premature contractions that are more 
frequent than occasional, and/or as couplets or higher in grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any 
other clinically significant cardiovascular abnormality such as poorly controlled 
hypertension. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
50 
6. Known family history of sudden cardiac death from causes other than HAE. Family 
history of sudden death from HAE is not exclusionary. 
7. History of or current implanted defibrillator or pacemaker. 
8. Any laboratory 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 C1 INH 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, which was associated with 
swelling, a severe rash requiring treatment/hospitalization, or anaphylaxis. 
15. Hypersensitivity reaction to BCX7353.  
16. Use of tranexamic acid, androgens or C1 INH for prophylaxis of HAE attacks within the 
7 days prior to the Screening visit or initiation during the study. Use of a C1 INH 
therapy for treatment of attacks is not excluded at any time, nor is C1 INH for pre-
procedure prophylaxis. 
17. Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, 
and CYP3A4 and have a narrow therapeutic range, within 7 days of the baseline visit or 
planned initiation during the study. For the purpose of this protocol, these include, but 
are not limited to the following: warfarin, phenytoin, s-mephenytoin, thioridazine, 
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfenadine and desogestrel. 
18. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study.  
19. Use of a medication that is clinically known to prolong the QT interval and is 
metabolized by CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to baseline 
or initiation during the study. 
20. Current participation in any other investigational drug study or received another 
investigational drug within 30 days of the Screening visit. 
21. An immediate family relationship to either Sponsor employees, the Investigator or 
employees of the study site named on the delegation log. 
Medications prohibited for use during the study are addressed in Section 9.7.1. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
51 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Subject Discontinuation from Study  
Participation in the study is strictly voluntary; a subject may withdraw consent to contribute 
additional study information at any point. A subject who withdraws consent 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 from the study must be recorded in the 
subject’s medical records (source documents) and also in the electronic case report form (eCRF). 
If at any point in the study the clinic is unable to contact the subject after appropriate attempts 
have been made according to local clinic standards, the subject will be considered to have 
withdrawn consent. 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 will 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 an Early Termination visit and all procedures as outlined in 
Section 10.3.5. 
• Intercurrent illness or emergence of a new illness/medical condition that would, in the 
judgment of the Investigator, affect assessments of clinical status to a significant 
degree 
• Subsequent determination that inclusion/exclusion criteria were not met 
• Emergence of any laboratory abnormality or AE that in the judgment of the 
Investigator compromises the ability to continue study-specific procedures or is 
considered not to be in the subject’s best interest due to an altered risk/benefit profile 
• 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)  
• Criteria outlined in Sections 8.3.2.1 and 8.3.2.2. 
8.3.2.1. 
Discontinuation Due to QT Prolongation 
Any subject will be discontinued from further dosing if the following QTcF criteria are met: 
• The subject has a QTcF > 500 msec (confirmed on repeat testing) 
or  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
52 
• The subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
from the value obtained predose at baseline 
8.3.2.2. 
Discontinuation Due to Rash 
All subjects with a suspected drug rash should undergo specific rash evaluation as described in 
Section 11.1.11. Subjects with a study drug related Grade 3 or 4 rash as described by the DMID 
criteria “Skin-mucocutaneous” will be discontinued from study drug and treated according to 
best medical practice. A Grade 3 rash is defined as vesiculation or moist desquamation or 
ulceration and a Grade 4 rash is defined as exfoliative dermatitis, mucous membrane 
involvement or erythema multiforme or suspected Stevens-Johnson or necrosis requiring surgery 
Subjects with a Grade 1 or 2 study-drug related rash may be continued on BCX7353 if both 
investigator and subject deem it appropriate.  
8.3.2.3. 
   End of Trial Definition 
The end of the trial will be defined as when the last subject completes the Post-Attack 3 visit. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
53 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
The study drug or IMP in this study consists of BCX7353 powder and matching placebo powder 
for reconstitution as oral solutions. Subjects will be randomized to 1 of 3 treatment sequences 
and will receive 2 single doses of BCX7353 and 1 single dose of matching placebo: 
• Two single oral doses of BCX7353 750 mg and one oral dose of matching placebo 
(Part 1) 
• Two single oral doses of BCX7353 500 mg and one oral dose of matching placebo 
(Part 2) 
• Two single oral doses of BCX7353 250 mg and one oral dose of matching placebo 
(Part 3) 
The active ingredient for this study is BCX7353. All clinical doses of BCX7353 provided in this 
protocol are in reference to the hydrochloride (HCl) salt. BCX7353 is a white to tan powder. The 
IMP is formulated as a single unit dose drug in a bottle formulation that will be reconstituted 
with an oral vehicle prior to dosing.  The oral vehicle to be used for reconstitution is a 
SyrPalta:Sterile Water for Irrigation solution and is supplied with the IMP. 
The taste-masked placebo for this study is lactose monohydrate which is an off-white powder. 
The IMP is formulated as a single unit dose drug in a bottle formulation that will be reconstituted 
with an oral vehicle prior to dosing. The oral vehicle to be used for reconstitution is a SyrPalta, 
Sterile Water for Irrigation and Bitrex® 0.256%w/v (50ppm) solution and is supplied with the 
IMP. 
Quotient Clinical (Nottingham, UK) will manufacture the IMP.   
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 
Oral vehicle and study drug will each be packaged in appropriately sized high density 
polyethylene (HDPE) bottles with tamper evident polypropylene lids.  Each kit dispensed to a 
subject will contain one of each bottle.   
Each kit will be labelled with the information required by 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/or kit treatment number.   
The IMP will be stored according to the Investigational Medicinal Product Dossier (IMPD).   
Study drug will be stored between 15°C−25°C (room temperature). 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
54 
9.3. 
Blinding and Randomization 
9.3.1. 
Blinding 
This is a double-blind study. As such, study drug treatment sequence will be blinded to the 
Investigator, study staff, study subjects, and clinical research organization (CRO) staff. Sponsor 
employee(s) not regularly interacting with the clinical sites will also be blinded to the treatment 
sequence of individual subjects, with the exception of Sponsor staff responsible for managing 
clinical supplies.  
The project statistician performing the analyses with a Haybittle-Peto boundary for significance 
may become unblinded after the 12th subject completes Part 1. Sponsor employees may be 
unblinded at the same time or at any point thereafter. 
9.3.2. 
Randomization 
Up to 36 subjects will be sequentially enrolled into Part 1 of the study and randomized to receive 
a treatment sequence containing one of the following: 
• Treatment A1: Single oral dose of BCX7353 750 mg (Part 1)  
• Treatment B: Single oral dose of placebo 
Initially in Part 1, 12 subjects will be randomized 1:1:1 to the following treatment sequences 
(n = 4 subjects per treatment sequence): 
• Sequence 1:  ABA 
• Sequence 2:  BAA 
• Sequence 3:  AAB 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single 
oral doses of BCX7353 500 mg in Part 2; and Treatment A3 = single oral doses of BCX7353 
250 mg in Part 3. 
A subject will be randomized to a treatment sequence at or prior to the Baseline visit.  
Subject randomization will occur only after the following steps have been completed and 
reviewed by the Sponsor: 
a) The following data is provided to the Sponsor: qualifying historical HAE attack data, 
concomitant and past medications, C1INH function and C4 level (or SERPING-1 
mutation), and the data collected on the HAE medical and medication history form.  
AND 
b) A site-documented screening HAE attack has occurred (i.e., subject phones Investigator 
prior to the attack and approximately 4 hours later) 
For the documented attack, the completed diary does not have to be collected to randomize a 
subject; however, the on-call Investigator (or designee) should ensure the subject has 
competently completed the attack diary. 
Specific details of the randomization and kit shipment processes will be communicated to the 
sites. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
55 
Study drug will be dispensed to subjects in a quantity sufficient for the treatment of one acute 
attack. Each subject will be assigned study drug a total of 3 times, which will be dispensed at 
Baseline and at the clinic visits following the first and second attack.  
Information on unblinding in the event of a SAE is provided in Section 12.1.8. 
9.4. 
Study Drug (Investigational Medicinal Product) Reconstitution and 
Administration  
Subjects will take all study drug doses by self-administration after approval from the on-call 
Investigator or designee. After authorization to treat the attack, subjects should reconstitute and 
ingest study drug and the rinse (see below). Reconstitution and ingestion of the study drug 
should occur almost immediately (within 5 minutes) following the phone call, with the goal for 
subjects to take study drug within or approximately one hour of the onset of symptoms. 
To prepare drug to ingest, subjects should reconstitute their study drug by pouring the entire 
contents of the vehicle (liquid) into the bottle containing the powder. The bottle containing the 
liquid and powder should be recapped and shaken vigorously for at least 15 seconds. After 
drinking the entire volume of the reconstituted study drug, subjects will rinse the bottle with 
water (not provided in the study drug kit) by shaking for 5 seconds and ingest the rinse. To the 
extent possible, the entire dose of study drug plus the rinse should be taken within 5 minutes 
from the time of reconstitution. 
Where practical, study drug is recommended to be taken without food and to delay food at least 
one hour (to allow for gastric emptying).  If the subject desires to further cleanse their pallet after 
ingesting the water rinse, hard candy, mouthwash, tongue or teeth brushing or chewing gum is 
recommended. Further instructions on subject preparation of study drug will be provided. 
9.5. 
Study Drug Dose Modification 
Subjects will be instructed to take the entire study drug dose as indicated by the protocol.   
If tolerability issues prevent enrollment of Part 1 at the 750 mg dose, the Sponsor may reduce the 
dose of study drug for new subjects in Part 1 to a dose of 500 mg. Written instructions will be 
communicated to all sites on documentation of the dose to be given to new subjects in Part 1 if 
this occurs. If the Part 1 dose is reduced and at least 12 subjects are treated with an active study 
drug dose of 500 mg, a 250 mg active dose may be assessed in Part 2. Any further dose level 
changes warranted for Part 2 and Part 3 will be instituted via protocol amendment.   
9.6. 
Study Drug (Investigational Medicinal Product) Accountability 
Accountability of returned study drug bottles will be performed by site personnel at the study 
visits following each attack. Returned drug bottles must be retained and reviewed during 
monitoring visits by the clinical research associate (CRA) (Section 14.2). 
The Investigator/pharmacist must maintain accurate records (including date) of the disposition of 
all IMPs received from the Sponsor. The Sponsor will supply a specific drug accountability form 
to each site. At the end of the study, information describing study drug supplies 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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
56 
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, all medication not dispensed or administered will be collected under 
supervision of the CRA and returned to the Sponsor or destroyed on site as dictated by the 
appropriate Standard Operating Procedure at the participating institution.  
9.7. 
Concomitant Medications and Other Restrictions 
All subjects in the study must refrain from taking prohibited concomitant medications as outlined 
in Section 9.7.1.  
Any regularly administered concomitant medication at screening 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 30 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/Restrictions 
 
The following medications are excluded during the study (Section 8.2.2): 
• Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, 
and CYP3A4 and have a narrow therapeutic range, within 7 days of the baseline visit or 
planned initiation during the study. For the purposes of this protocol, these include: 
warfarin, phenytoin, s-mephenytoin, thioridazine, alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine, androgens and desogestrel. 
Additional medications may be added to this list of excluded CYP substrate medications 
as the Sponsor becomes aware of evolving data. The Sponsor may add to the 
exclusionary list based upon review of regulatory labelling for individual medications, 
regulatory guidances, peer-reviewed publications, and regularly-updated drug interaction 
reference databases (e.g., University of Washington School of Pharmacy Drug Interaction 
Database Program).  Any updates to the excluded list will be shared with clinical sites. 
• Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study (potential for exacerbation of HAE).  
• Use of C1 INH, tranexamic acid or androgens for prophylaxis of HAE attacks within the 
7 days prior to the screening visit or initiation during the study. Use of a C1 INH therapy 
for treatment of attacks is not excluded at any time. 
• Use of a medication that is clinically known to prolong the QT interval and is 
metabolized by CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to baseline 
or initiation during the study.  
A list of these medications will be shared with the clinical sites. In order to construct this 
list, drugs with a known risk of torsades de pointes from the Arizona Center for 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
57 
Education and Research on Therapeutics (https://www.crediblemeds.org) will be 
examined against labelling for CYP substrate specificity.  
 
• Current participation in any other investigational drug study or having received another 
investigational drug within 30 days of the Screening visit  
The following classes of medications are restricted during the study based upon in vitro 
transporter data: 
• Daily use (more than 5 consecutive days) of a medication that is known to induce or 
inhibit drug transporters P-gp or BCRP to a clinically significant degree 7 days prior to 
baseline or subsequent initiation during the study. This includes foods or beverages 
containing grapefruit or Seville oranges 
• Use of a medication (more than 5 consecutive days) that primarily relies upon BCRP or 
P-gp transport proteins for systemic disposition 7 days prior to baseline or subsequent 
initiation during the study that is known or suspected to have clinically significant safety 
concerns with increased exposure. 
The Sponsor will compile and provide a spreadsheet outlining these restricted medications 
based upon regulatory labelling for individual medications, regulatory guidances, peer-
reviewed publications and regularly-updated drug interaction reference databases (e.g., 
University of Washington School of Pharmacy Drug Interaction Database Program). 
A drug interaction study designed to elucidate the clinical relevance of the inhibition 
potential of BCX7353 on BCRP and P-gp transport and whether the pharmacokinetics of 
BCX7353 is affected by P-gp or BCRP inhibitors is planned. If the results of this study 
indicate that there is no clinically significant transport inhibition on or by BCX7353, these 
restricted medications will be permissible for use on study. A memo outlining the findings 
and impact will be sent to each study Investigator. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
58 
10. 
STUDY CONDUCT 
10.1. 
Overview 
This is a randomized, double-blind, placebo-controlled study. The duration of a subject’s 
participation in this study is dependent on the timing and frequency of on-study acute attacks 
eligible for treatment with study drug. Assuming that subjects will have 1 eligible attack every 
4 weeks, it is anticipated that minimally a subject’s participation would be approximately 
19 weeks (inclusive of the screening period, wash-out periods of 10 to 14 days in duration in 
between treated attacks, and a final follow-up visit [at least 16 days after the third attack]). Each 
eligible subject who consents to participate in the study will receive a total of 2 single doses of 
BCX7353 and 1 dose of matching placebo. All subjects will undergo a screening period of up to 
35 days, and 4 clinic visits; visits will occur at Baseline, within 10 to 14 days after the first and 
second study drug treated attacks, and at least 16 days following the last study drug treated 
attack. Subjects who consent to the optional observational substudy after the last study visit 
(Post-Attack 3 visit) will participate in study activities for approximately 12 additional weeks. 
After the Baseline visit, at the first symptom of swelling or pain associated with an attack, the 
subject will be asked to phone the on-call study Investigator (or designee) who will review the 
subject’s symptoms by phone and confirm that they constitute an appropriate acute attack that 
qualifies for treatment with study drug, including ensuring that the subject is in an environment 
that he/she deems suitable for completion of the timed diary. Following confirmation by the 
Investigator, subjects should use study drug to treat the HAE attack, within approximately 1 hour 
from the onset of the first symptoms.  
Subjects will fill out a diary questionnaire and a 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling prior to and at 1, 2, 3, 4, approximately 
8, and at 24 hours after record of study drug administration.  
If the subject prematurely discontinues from the study, they will be requested to attend an early 
termination visit. 
10.2. 
  Schedule of Assessments 
The schedule of assessments for this study is summarized in Table 4; the optional substudy 
assessment schedule can be found in Table 5. 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                                                      BCX7353 
59 
Table 4. 
Schedule of Assessments for Study BCX7353-202 
 
Screening 
Day  
−35 to −1 
Baseline 
Attack 1 
Telephone 
Contacts  
Post-
Attack 1 
Visit (10-
14 days) 
Attack 2 
Telephone 
Contacts  
Post- 
Attack 2 
Visit (10-
14 days) 
Attack 3 
Telephone 
Contacts  
Post-
Attack 3 
Visit/ 
Follow-up 
(16 days + 
3 days) 
 
 
Early 
Termination  
Visit 
Informed consenta 
X 
 
 
 
 
 
 
X 
 
Telephone contactb 
X 
 
X 
  
X 
  
X 
 
 
Clinic visitsc 
X 
X 
  
X 
 
X 
 
X 
X 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
HAE attack frequency 
confirmation 
X 
 
 
 
 
 
 
 
 
HAE medical and 
medication history 
X 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
Xd 
 
 
 
 
 
 
Xd 
Drugs of abuse screene 
X 
 
 
 
 
 
 
 
 
HIV/HCV/HBV serology 
X 
 
 
 
 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
C1 INH function and C4 
X 
 
 
 
 
 
 
 
 
Pregnancy testg 
X 
X 
 
X 
 
X 
 
X 
X 
Safety laboratory evaluations 
and urinalysis testingh 
X 
X 
 
X 
 
X 
 
X 
X 
Troponin I & Troponin T 
 
X 
 
X 
 
X 
 
X 
X 
CK-MB 
 
X 
 
X 
 
X 
 
X 
X 
C3 
 
X 
 
 
 
 
 
 
 
C1 INH antigen level 
 
X 
 
 
 
 
 
 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                                                      BCX7353 
60 
 
Screening 
Day  
−35 to −1 
Baseline 
Attack 1 
Telephone 
Contacts  
Post-
Attack 1 
Visit (10-
14 days) 
Attack 2 
Telephone 
Contacts  
Post- 
Attack 2 
Visit (10-
14 days) 
Attack 3 
Telephone 
Contacts  
Post-
Attack 3 
Visit/ 
Follow-up 
(16 days + 
3 days) 
 
 
Early 
Termination  
Visit 
Randomizationi 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
Xj 
 
Xj 
 
Xj 
Xj 
ECGk 
X 
X 
 
X  
 
X 
 
X 
X 
Vital signsl 
X 
X 
 
X 
 
X 
 
X 
X 
Diary dispensing/ 
instruction/review/ 
collectionm 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary completion 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing/accountability 
and reconstitution 
instructionn 
 
X 
 
X 
 
X 
 
X 
X 
TSQMo 
 
X 
 
X 
 
X 
 
X 
 
a 
Signing of informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures are 
performed. Informed consent for the observational substudy may be obtained at the follow-up visit or earlier. 
b 
Screening telephone contact: Subjects are instructed to contact the site as soon as they become aware of the onset of symptoms of pain or swelling 
associated with an HAE attack during the screening period. The on-call Investigator (or designee) will review the subject’s symptoms by phone and 
confirm the date of the call. The Investigator may fill out a form to document the conversation. Approximately 4 hours after the initial call, the subject will 
again contact the on-call Investigator as is expected during the study. 
         Attack 1, 2, 3 contact: Subjects are instructed to contact the on-call Investigator (or designee) as soon as they become aware of the onset of symptoms of 
pain or swelling associated with a potentially protocol-qualified HAE attack. The on-call Investigator (or designee) will review the subject’s symptoms by 
phone and confirm that they constitute an acute attack that qualifies for treatment with study drug, including ensuring that the subject is in an environment 
that he/she deems suitable for completion of the timed diary. The Investigator will fill out a form to document the conversation. Following treatment of the 
attack, the subject will again contact the on-call Investigator (or the Investigator will contact the subject) at least 4 hours after treatment with study drug to 
review the subject’s response to treatment and to confirm adequate documentation of the attack in the Diary. The on-call Investigator (or designee) will call 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                                                      BCX7353 
61 
the subject if the subject has not contacted the on-call Investigator (or designee) within 4-5 hours of the initial phone call. A follow-up visit to the clinic will 
be scheduled. Sites must attempt to contact subjects every 7 days from the last clinic visit to inquire about the occurrence of an attack. 
c 
Clinic visits are scheduled for Screening, Baseline and 10 to 14 days following the first and second attack treated with study drug. The Post-Attack 3 visit 
suffices as the end of study visit and will be held approximately 16 days after the third attack. Study drug cannot be authorized for administration for at 
least 14 days from a previously treated attack. 
d 
 Weight only. 
e 
Analytes to be measured can be found in Table 6. 
f 
Follicle-stimulating hormone will be measured in women declaring themselves postmenopausal ≤ 2 years. 
g 
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). 
h 
Safety laboratory parameters and urinalysis testing as described in Table 6. 
i 
 Randomization to a treatment sequence should occur prior to or during the Baseline visit, following confirmation of eligibility and Sponsor approval.  
j 
Post-baseline, physical examinations will be targeted to reported signs and symptoms.  
k 
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. 
l 
Vital signs include measurement of heart rate, blood pressure and temperature.  
m 
Diaries will be dispensed at Screening, Baseline, and Post-Attack Visits 1 and 2. The Investigator (or designee) will provide diary instruction at Screening 
and will review diary entries on an ongoing basis. During each visit, any issues warranting diary re-education must occur on an as-needed basis. The 
completed diary will be collected at Baseline and Post-attack Visits 1 to 3. For subjects participating in the observational substudy, a diary will be dispensed 
at the Post-Attack 3 visit. 
n 
Subject will be dispensed study drug for self-administration at Baseline, Post-Attack 1 visit and the Post-Attack 2 visit. Reconstitution and dosing 
instructions will be reviewed with the subject. Accountability will be conducted at the Post-Attack visits. 
o     At baseline, the TSQM will be completed in reference to the subject’s currently used acute attack medication prescribed/authorized by their HAE treater; at 
each subsequent study visit, the TSQM will be completed in reference to the attack previously treated with study drug.

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
62 
Table 5. 
Schedule of Assessments for Optional Observational Substudy 
 
Post-Attack 
3 Visit 
Week 4 of 
Observational 
Perioda 
Week 8 of 
Observational 
Perioda 
Week 12 of 
Observational 
Perioda 
Informed consentb 
X 
 
 
 
Telephone contactc 
 
X 
X 
X  
Clinic visits 
X 
 
 
 
Diary 
dispensing/instruction/review/collectiond 
X 
X 
X 
X 
Diary completion 
 
 
AE assessment 
X 
Xe 
Xe 
Xe 
a 
The 12-week observational period begins from dispensation of HAE diary for recording of all attacks after 
completion of the Post-Attack 3 visit. 
b 
Signing of informed consent for the optional observational study may occur at the Post-Attack 3 visit or any 
time prior to this visit. Subjects will be asked to participate in the substudy following completion of Post-
Attack 3 visit if approved by the Sponsor. 
c 
During the substudy, subjects will be primarily contacted via telephone; however, a clinic visit is allowed to 
replace the telephone contact if warranted.    
d 
Diaries to record details of all HAE attacks occurring after the Post-Attack 3 visit will be dispensed at the Post-
Attack 3 visit and as needed thereafter. Completed diaries will be collected from the subject (in-person or via 
post) approximately every 4 weeks. The Investigator (or designee) will provide diary instruction at the Post-
Attack 3 visit and will review diary entries upon collection for correct completion and follow-up with the 
subject as needed. 
e       Only AEs assessed as possibly, probably or definitely related to the previously taken study drug administered 
will be recorded. 
10.3. 
Study Visits 
10.3.1. 
Screening 
Prospective subjects should be screened within 35 days prior to baseline.  
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  
• Review of HAE attack frequency documentation 
• HAE, medical, and medication history  
• Complete physical exam 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
63 
• 12-lead ECG  
• Height/weight/body mass index (BMI) estimation  
• Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Serum pregnancy test for female subjects of child-bearing potential 
• Blood collection for clinical chemistry, hematology, coagulation, HBV/HIV/HCV 
serology, C4 and C1 INH functional level, FSH (for women who declare that they 
have been postmenopausal ≤ 2 years) 
• Urine collection for urinalysis and drugs of abuse screen 
• Recording of AEs and concomitant medications  
• Dispensing of HAE attack diary and any applicable subject instruction sheets 
• Instructions on procedures to take during at least one HAE attack during the 
screening period: phoning the on-call Investigator (or designee) at the outset of HAE-
associated pain or swelling, completing the diary, and placing a second call to the on-
call Investigator (or designee) approximately four hours after the initial call.  
All screening procedures are outlined in Table 4 and are described in Section 11.  
A subject will be randomized to a treatment sequence at or prior to the Baseline visit. Subject 
randomization will occur after the subject has been fully determined to be eligible during 
screening (see Section 9.3.2).  
If the Investigator has not received a call for an HAE attack through Day 35 of the screening 
period, the subject is considered a screening failure. If agreed by the Sponsor or designee, 
subjects having an attack late in the course of the screening period may prolong the screening 
period beyond 35 days to allow for randomization and shipment time of study drug to the clinical 
site, if applicable.  
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 who do not 
enter the study. 
10.3.2. 
Baseline  
Subjects who meet all study eligibility criteria, who agree to participate, have demonstrated 
competence in phoning an investigator for an HAE attack and completing an attack diary during 
the screening period and who are authorized for randomization by the Sponsor will be asked to 
return for a Baseline visit. Inclusion/ exclusion criteria will be reviewed to ensure continued 
subject eligibility. Subjects are asked to fast overnight for at least 8 hours prior to the blood draw 
for laboratory testing. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
64 
The following assessments will be completed: 
• Review of inclusion and exclusion criteria 
• Review of medical history 
• Review of concomitant medications  
• Administration of the TSQM (the TSQM will be completed in reference to the 
subject’s currently used acute attack medication prescribed/authorized by their HAE 
treater) 
• Weight  
• Vital signs (heart rate, blood pressure and temperature) 
• 12-lead ECG 
• Complete physical exam  
• Assessment of any AEs that 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 
• Blood collection for C1 INH antigen level, C3, CK-MB, Troponin I, and Troponin T 
• Study drug dispensing for treatment of an acute HAE attack by self-administration 
• Instruction on reconstitution of study drug and administration 
• Screening HAE diary collection and review 
• HAE diary dispensing for recording Attack 1, daily HAE diary and any applicable 
subject instruction sheets 
• Instructions on treatment of attacks by self-administration with study drug. Subjects 
should also be taught to record start and stop time and treatment of any additional 
HAE attacks that occur following the Baseline visit. 
10.3.3. 
Telephone Contacts  
Subjects will be instructed to contact site personnel at the first symptom of swelling or pain 
associated with a potentially protocol-qualified HAE attack, and if treated with study drug, at 
approximately 4 hours following treatment. If the subject has not contacted the on-call study 
Investigator (or designee) within 5 hours, the on-call Investigator will call the subject. The on-
call Investigator (or designee) will review the treatment and progression of the HAE attack with 
the subject and document the conversation.  Subjects who did not require standard of care at 4 
hours will be reminded at the telephone call by the Investigator that they may use standard of 
care at any time point at their own discretion if not experiencing improvement or who are 
experiencing progression of the HAE attack. Subjects will also be reinstructed on diary 
completion. AEs and concomitant medications will also be collected by phone. Exceptions to the 
return phone call at 4 hours are discussed in Section 11.2.2. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
65 
The site staff will schedule a clinic visit within 10 to 14 days after the administration of study 
drug and remind the subject to bring their HAE attack diary and study drug containers to their 
next visit.  
Sites must attempt to contact subjects approximately every 7 days from the last clinic visit (i.e., 
after the Baseline visit, Post-Attack 1 clinic visit, and Post-Attack 2 clinic visit) to inquire about 
the occurrence of an attack if the subject has not contacted the site during this time frame.  
10.3.4. 
Clinic Visits Following Study Drug Administration  
Subjects will return to the clinic following the administration of study drug to treat an acute 
attack. Subjects will attend a total of 3 on-study clinic visits: Post-Attack 1 clinic visit, Post-
Attack 2 clinic visit, and Post-Attack 3 clinic visit. After Attack 1 and Attack 2, subjects will 
return to the clinic 10-14 days after administration of study drug. Subjects will not be authorized 
to treat a subsequent attack until at least 14 days have elapsed since the last study drug 
administration. After Attack 3, subjects will return to the clinic for a follow-up visit 16 days after 
their last use of study drug (visit window permissible up to 19 days). 
The following assessments will be performed at each visit: 
• Targeted physical examination   
• Vital signs (blood pressure, heart rate and temperature) 
• 12-lead ECG (including comparison of QTcF to Baseline value) 
• Review of concomitant medications and AEs 
• Administration of TSQM questionnaire (TSQM will be completed in reference to the 
attack previously treated with study drug) 
• Blood collection for clinical chemistry, hematology and coagulation 
• Blood collection for CK-MB, Troponin I and Troponin T  
• Urine collection for urinalysis and urine pregnancy test for female subjects of 
child-bearing potential 
• Study drug accountability  
• Post-Attack 1 and 2 clinic visits only: dispense study drug  
• Collection of subject-completed HAE attack diary and review 
• Post-Attack 1 and 2 clinic visits only: HAE diary dispensing for recording Attacks 2 
and 3, daily HAE diaries and any applicable subject instruction sheets 
• Review/re-education, as applicable, of completion of HAE attack diary, dosing 
instructions, phone call(s) to investigators (Post-Attack 1 and 2 clinic visits only). 
Subjects should record start and stop time and treatment of any additional HAE 
attacks that occur prior to the Post-Attack 3 visit. 
• Post Attack 3 visit, for those participating in the optional observational study:  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
66 
o Signing of informed consent for participation in the optional observational 
study (consent may be signed prior to this visit) 
o Instruct and dispense diary to record details of any HAE attacks that occur 
10.3.5. 
Early Termination Visits 
Subjects who discontinue treatment early (i.e., prior to the treatment of 3 acute attacks) must 
complete an early termination visit as outlined in Section 10.3.5. 
Assessments to be performed at this visit are described in Section 11. In the event that there are 
clinically significant findings from safety assessments that are ongoing at the time of the visit, 
the subject will be followed at additional unscheduled study visits until the findings are resolved 
or stabilized at a new baseline. 
The following assessments will be performed at the early termination visit: 
• Subject weight  
• Targeted physical examination   
• Vital signs (blood pressure, heart rate and temperature) 
• 12-lead ECG (including comparison of QTcF to Baseline value) 
• 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 CK-MB, Troponin I and Troponin T 
• Study drug accountability  
• Review and collection of the diary  
10.3.6. 
Optional Observational Substudy 
Subjects who complete the study will be offered an opportunity to participate in an observational 
substudy at the Post Attack 3 visit. The subjects will provide consent and will record details of 
all HAE attacks into an HAE diary, dispensed at the Post-Attack 3 visit that occur for 
approximately 12 weeks.  
The following assessments will be performed after the Post-Attack 3 visit: 
• Week 4, 8, 12 of the observational period: phone call to discuss completion of the 
HAE attack diary, collection of completed diaries (in person or via mail) and whether 
additional diaries are needed. In addition, AEs assessed as possibly, probably or 
definitely related to study drug will also be collected 
• Week 4, 8, 12: review of completed HAE diaries for correctness/completeness  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
67 
11. 
ASSESSMENTS 
The schedule of procedures/assessments to be conducted is outlined by study day in Table 4 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 history will 
be captured for each subject participating in the study at the Screening visit. Medical history and 
review of inclusion and exclusion criteria will also be rechecked at the Baseline visit.  
Contraceptive methods enabling eligibility will be captured in source documentation at the 
screening visit. 
11.1.1. 
HAE Medical and Medication History 
An 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 Sponsor confirmation of the subject 
and randomization (see Section 9.3.2). 
11.1.2. 
Physical Examination 
A full physical examination should be conducted at Screening and Baseline. All subsequent 
physical examinations may be targeted (i.e., symptom-driven). Genitourinary and breast 
examinations may be omitted when not required by normal site practice. 
11.1.3. 
Weight/Body Mass Index 
For determination of height and weight, subjects should be 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 
directly on a hard copy of the ECGs. Copies of the ECGs may be requested by the Sponsor. 
All ECGs will be captured as single assessments.  
An ECG should be repeated during the clinic visit if possible for a change from baseline in QTcF 
> 60 msec or a QTcF interval > 500 msec for confirmation of the change. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
68 
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 also be obtained at all visits.  
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 6. Laboratory samples should be obtained in the fasted 
state. 
Laboratory samples will be routinely analysed 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 laboratory kit contents reordering instructions, sample 
collection, handling, storage and shipment. Results from the laboratory values should be 
reviewed as received by the Investigator. Evidence of this review should be provided in the 
source records and may include printing of the laboratory reports with a signature attesting to a 
review. For out-of-range lab findings, the interpretation of clinically significant or not clinically 
significant should be denoted in the source records. Clinically significant laboratory findings in 
the opinion of the Investigator should be recorded as an AE and handled as described in 
Section 12.1.  
Table 6. 
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, phosphorus)  
• Creatine kinase 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• MCH 
• MCHC 
• MCV 
• White blood cell count, with differential 
(lymphocytes, monocytes, neutrophils, 
eosinophils, and basophils) 
• Platelets 
• Creatinine and calculated creatinine 
clearance 
• Gamma-glutamyltransferase (GGT) 
• Lactate dehydrogenase (LDH) 
• Total serum protein 
• Uric acid 
• Amylase  
*reflex to lipase for amylase > 2x ULN 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
69 
 
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 
• Microscopy if dipstick is abnormal  
Additional Tests 
• Follicle-stimulating hormone (FSH; screening) 
for women postmenopausal ≤ 2 years 
• Hepatitis B surface antigen, Hepatitis C 
antibody, HIV antibody (screening) 
• Troponin I 
• Troponin T 
• CK-MB 
• C1 INH function 
• C4  
• C1 INH antigen 
• C3 
Coagulation 
• Prothrombin time (PT) and international 
normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
 
Creatinine clearance (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 hepatitis C infection. Subjects with a positive Hepatitis C antibody but have no 
evidence for HCV RNA upon reflex testing are eligible for study participation. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
70 
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 
C1 INH functional level and C4 will be measured at screening to establish the laboratory 
diagnosis of HAE Type 1 or 2. These tests should be drawn at least 3 days after a previous dose 
of C1 INH. 
Should C4 be normal, as is the case in a small percentage of subjects with HAE, C4 may be 
drawn during an attack or the SERPING-1 gene may be analyzed and the subject confirmed 
eligible if a known mutation associated with HAE Types 1 or 2 is identified. 
C1 INH antigen level will be drawn for demography on enrolled subjects at the Baseline visit.  
11.1.10. 
Other Laboratory Assessments 
Troponin I, Troponin T and CK-MB will be measured in this study at all time points beginning at 
Baseline (i.e., Post-Attack 1, 2, and 3 clinic visits and early termination visit [if applicable]). C3 
levels will be taken at Baseline on all subjects and will only be drawn on-study if required for 
AE assessment (see Section 11.1.11). 
11.1.11. 
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 the rash is diagnosed via the Event of Special Interest Form 
(Section 12.1.5.1). In the event the site is notified of a rash on the weekend or holiday, 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, regardless of 
causality, as soon as logistically possible:   
• Full dermatological exam to include the anatomical location(s) of the rash, 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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
71 
• 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. 
• 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.  
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: 
• Blood taken for clinical chemistry, hematology including differential, and C3 level. 
Table 6 outlines the clinical chemistry and hematology analytes to be assessed. 
• Urine sent to local laboratory for urine eosinophils (if evaluation is available locally) 
• 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.  
 
11.2. 
Subject-Completed Assessments 
11.2.1. 
Treatment Satisfaction Questionnaire 
To assess treatment satisfaction of the medication a TSQM will be administered once at Baseline 
and at each clinic visit following treatment of an acute attack with study drug. At Baseline, the 
TSQM will be completed in reference to the subject’s currently used acute attack medication 
prescribed/authorized by their HAE treater; at each subsequent study visit, the TSQM will be 
completed in reference to the attack previously treated with study drug 
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 Diaries and Phone Calls 
11.2.2.1. 
Screening through Post-Attack 3 Visit 
The Sponsor will supply an attack diary for subject documentation of one HAE attack occurring 
during the screening period and for each of 3 study-drug treated attacks. To ensure compliance 
with on-study requirements in treating an appropriate attack with study drug after the Baseline 
visit, subjects will be required to complete timed attack details of at least 1 HAE attack during 
the screening period after approval of the on-call Investigator (or designee). Subjects will also be 
required to complete the details of three HAE attacks that are treated with study drug, each after 
approval from the on-call Investigator (or designee). 
All attacks for which acute attack diaries are completed by the subject will be included in the 
eCRF. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
72 
Apart from the principal Investigator at each clinical site, the Sponsor will approve on-call study 
Investigators (or designees). Approval will be based upon demonstration that the proposed on-
call Investigator (or designee) ordinarily has oversight of the care of HAE patients.  
The diaries will be composed of a questionnaire and 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling. The questionnaire includes queries 
about symptom location, severity/limitation of activities and a global assessment that 
qualitatively compares HAE symptomatology against that experienced prior to study drug intake. 
The diaries will include questions/VAS to be completed prior to study drug administration and 1, 
2, 3, 4, approximately 8 and at 24 hours post study drug intake (or post call for a screening 
attack). All medications used from the time of symptom onset through 24 hours postdose will 
also be captured in the diary, including standard of care treatment for acute attacks and any 
symptomatic treatments such as analgesics. 
At the Screening, Baseline, and Post-Attack 1 and Post-Attack 2 visits, attack diaries will be 
dispensed and the subject will be instructed on completing the diary (written instructions may 
also be provided). In addition, subjects will be informed of what is expected regarding attacks 
likely to be approved for study drug treatment by the Investigator and also administration of 
standard of care rescue medication on a continuing basis. 
At the Baseline and Post-Attack 1, 2, and 3 visits, sites must collect and review the diary for 
completeness and plausibility; any re-education required to ensure correct diary completion will 
be performed. Study staff are not permitted to make any entries into the diary regarding HAE 
attack information.  
Diary instruction will include demonstration on how to properly complete the VAS, review of all 
questions for understanding, and those questions that allow more than one response. Subjects 
must be instructed to complete all questions unless medically prevented from doing so or the 
subject is sleeping after a treated attack, and the importance of completing the diary at the 
scheduled time points must be stressed.   
Following the Baseline visit and prior to the Post-Attack 3 visit, subjects will be asked to record 
the start and stop time of all HAE attacks that occur and any standard of care administration. 
11.2.2.1.1. Documented Screening Attack 
The documented screening attack is intended as a practice for on-study requirements in the 
identification, approval, and documentation of an HAE attack treated with study drug. As such, 
the steps required in identifying, approving and documenting the attack should be as close to as 
would be expected or required after the Baseline visit. All steps must take place (initial call for 
HAE symptom review, HAE attack diary documentation, return call) to assess a subject’s 
understanding and compliance with the study requirements. The Investigator (or designee) may 
request that the subject complete more than one documented screening attack if he or she is not 
satisfied that the subject has demonstrated compliance with the procedures required for treating 
and documenting attacks. 
At the first symptom of swelling or pain associated with at least one HAE attack occurring 
during the Screening period, the subject will phone their on-call study Investigator (or designee) 
who will review the subject’s symptoms by phone. It is preferable that the subject call the 
Investigator within one hour of symptoms and that the attack is one that is protocol-qualified 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
73 
on-study (see Section 11.2.2.1.2). Subjects will not be asked to avoid standard of care attack 
treatment for four hours from the phone call.  
During the documented Screening HAE attack, subjects will record the occurrence and details of 
the HAE attack in the diary immediately after the call to the Investigator as well as any 
medications used since the onset of symptoms. Subjects will fill out the diary questionnaire and a 
3-component VAS at 1, 2, 3, 4, approximately 8 and at 24 hours after the phone call. Any 
questions regarding study drug administration may be left blank.  
The subject will be asked to phone the on-call study Investigator (or designee) at least 4 hours 
after the phone call to review diary completion. The on-call study Investigator will call the 
subject if they have not heard from the subject within 5 hours of their initial phone call.  
An exception to the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours post-study 
medication. In this case, the subject will be required to call the on-call Investigator (or designee) 
upon waking. The on-call Investigator (or designee) and subject may agree at the initial attack 
approval phone call that the subject will try to rest to avoid an Investigator call 5 hours later. For 
subjects who were sleeping during diary-required timepoints after the phone call, only the 4 hour 
timepoint in the diary questionnaire is required to be completed at the time they awake and any 
medications taken. 
The on-call Investigator (or designee) will document the details of both calls. 
11.2.2.1.2. On-Study Attacks 
After the Baseline and Attack 1 and 2 visits, the subject will phone their on-call study 
Investigator (or designee) at the first symptom of swelling or pain associated with a potentially 
protocol-qualified HAE attack. The Investigator (or designee) will review the subject’s 
symptoms and confirm that they constitute an acute attack that qualifies for treatment with study 
drug, including ensuring that the subject is in an environment that he/she deems suitable for 
completion of the timed diary.  
Protocol-qualified attacks approved for treatment must meet all of the following: 
• have pain and/or swelling associated with an HAE attack reported as a symptom 
• subject has contacted Investigator within approximately 1 hour of onset time of HAE 
pain and/or swelling 
• not involve HAE pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant). 
• not be an abdominal attack that has already resulted in vomiting. Such attacks should 
be treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant). 
• have an identifiable onset time, with the exception that abdominal attacks with an 
onset during sleep may be permitted for study drug treatment. Onset time for 
approved abdominal attacks will be time the subject woke up with symptoms. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
74 
Peripheral attacks starting with an onset during sleep are not to be authorized for 
study drug treatment. 
• 
occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor antagonist 
(i.e. Firazyr) OR treated with human recombinant C1 INH (i.e. Ruconest) OR 
any non-targeted therapy (i.e. pain medication, anti-spasmodic, anti-emetic, 
tranexamic acid) OR was not treated with any medication: new attack can be 
treated with IMP if has been 48 hours since the complete resolution of all 
symptoms of the previous HAE attack AND the Investigator believes it is a new 
(de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH (i.e. 
Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent detergent 
plasma): new attack can be treated with IMP if it has been 96 hours since the 
complete resolution of all symptoms of the previous HAE attack 
• 
occur at least 96 hours after complete recovery from a procedure or injury 
• 
occur at least 14 days from a previous dose of study drug 
Following confirmation by the Investigator that an attack may be treated with study drug, 
subjects should reconstitute and take study drug almost immediately (within 5 minutes) 
following the approval phone call, with the goal for subjects to take study drug within or 
approximately one hour of the onset of symptoms. Subjects will be asked to avoid food for at 
least one hour after taking study drug and will be asked to withhold standard of care attack 
treatment for four hours from administration of study drug (see Section 9.2). If symptoms are 
progressing rapidly or if intraoral symptoms occur, subjects may treat the attack with their 
standard of care attack medication prior to 4 hours. 
The subject will be asked to phone the on-call study Investigator (or designee) at least 4 hours 
after taking study medication (or earlier if they have any concerns over the course of their 
symptoms) to review their response to study drug and diary completion, unless they are sleeping. 
The on-call study Investigator will call the subject if they have not heard from the subject within 
5 hours of their initial phone call. Subjects who did not require standard of care at 4 hours will be 
reminded at the telephone call by the Investigator that they may use standard of care at any time 
point at their own discretion if not experiencing improvement or who are experiencing 
progression of the HAE attack.  
An exception to the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours post-study 
medication. In this case, the subject will be required to call the on-call Investigator (or designee) 
upon waking. The on-call Investigator (or designee) and subject may agree at the initial attack 
approval phone call that the subject will try to rest to avoid an Investigator call 5 hours later. 
Subjects will record the occurrence and details of the HAE attack immediately prior to treating 
the approved HAE attack with study drug. Subjects will also fill out the diary questionnaire and a 
3-component VAS at 1, 2, 3, 4, approximately 8 and at 24 hours after record of study drug 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
75 
administration. All medications taken after study drug administration through 24 hours will also 
be captured. For subjects who were sleeping during these timepoints after administration of study 
drug, subjects are only required to fill out the 4 hour timepoint in the diary questionnaire and any 
medications taken at the time they awake.   
The on-call Investigator will document the details of both calls involving approval of and 
follow-up after study drug treatment. If duplicate data is collected on this form and in the HAE 
diary, the HAE diary will always be source documentation. In the event that a diary field is 
empty when reviewed subsequently at the Post-Attack 1, 2, or 3 visit, the details of the 
Investigator form may serve as source documentation. 
11.2.2.2. 
Optional Observational Substudy 
Subjects who complete randomized dosing and who provide consent will be offered an 
opportunity to participate in an observational substudy. Consenting subjects will be provided an 
HAE attack diary at the Post-Attack 3 visit and will record details of all HAE attacks that occur 
for approximately 12 weeks. Resupply of diaries will be provided as needed. Completed diaries 
should be returned to the site, in person or via mail, approximately every 4 weeks. 
Subjects will be provided further instruction on completing the diaries at home for any attacks 
that occur for subsequent 12 weeks. Subjects will record the occurrence and details of each HAE 
attack in the diary, beginning from the time of onset of pain or swelling associated with an HAE 
attack. Subjects will fill out the diary questionnaire and a 3-component VAS at 1, 2, 3, 4, 
approximately 8 and at 24 hours after the attack started, as well as any medications used since 
the onset of symptoms.   
During Weeks 4, 8, 12 of the observational period, the Investigator (or designee) will phone the 
subject to discuss completion of the HAE attack diary, collection of completed diaries and 
whether additional diaries are needed. In addition, AEs assessed as possibly, probably or 
definitely related to study drug will also be collected. After receipt of the Week 4, 8, 12 diaries, 
the Investigator (or designee) will review completed HAE diaries for correctness/completeness. 
   

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
76 
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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
77 
surgical measures permitted by the clinical study protocol and the conditions(s) leading to these 
measures are not AEs, if the condition(s) was (were) known before the start of study treatment. 
In the latter case the condition should be reported as medical history. 
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. For this study, examples of such events may include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in subject hospitalization.  
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. 
BioCryst also considers abortions, whether elective or spontaneous, fetal demise, and still births 
as SAEs. 
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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
78 
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 until the post –attack 3 visit of the study drug phase. All 
AEs and SAEs are to be reported on the AE CRF. For subjects who continue in the optional 
observational substudy, only those AEs deemed possibly, probably or definitely related to the 
previously taken study drug need to be recorded on the AE CRF. These AEs will be recorded in 
the same manner and include the same information as AEs during the study phase. 
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 in the main 
study, 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 identify subjects by unique code numbers assigned to the latter 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 15.1). Any AEs not 
covered by the DMID criteria will be assessed and classified into 1 of 4 clearly defined 
categories as follows: 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
79 
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. 
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). 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
80 
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. 
Investigators or designees at each site are responsible for retaining copies of all suspected 
unexpected severe adverse reaction (SUSAR) reports (initial and follow-up) and other safety 
information (eg, revised IB) in their files. 
BioCryst or its designee will submit all SUSAR reports (initial and follow-up) or other safety 
information (eg, 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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
81 
12.1.5.1. Reporting Events of Special Interest 
Although not an SAE, all events of treatment-emergent rash regardless of severity or 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 
eCRF in real time. All additional follow-up evaluations of the event must be reported to BioCryst 
or its designee on the form 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. In addition, the report form will allow a full clinical 
description and information regarding the evaluation that cannot be reported in the EDC.  
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 
Confirmation and Outcome” form that will be provided by the Sponsor or its designee so that the 
pregnancy may be followed and an outcome determined. Any AEs or SAEs experienced by a 
pregnant subject are to be reported as directed above in Section 12.1.2 and Section 12.1.5. Any 
complications reported in a subject’s pregnant partner should be reported on the Pregnancy 
Confirmation and Outcome form. All pregnancies must be followed to outcome which occurs 
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 competent 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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
82 
competent authority within 7 days. The reporting to the Sponsor will be performed by the party 
who suspects the serious breach.  
12.1.8. 
Emergency Procedures 
Access to study drug/IMP assignment will be available immediately if the Investigator deems it 
necessary to break the study blind in the interest of a subject’s medical safety. In addition, the 
blind may be broken 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 unblinding of the subject; however, the final 
decision to break the treatment code in emergency situations resides solely with the Investigator. 
Detailed instructions for immediate unblinding in the interactive web response system used by 
the site to randomize a subject will be provided. 
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 
good medical practice. 
In the event that 2 subjects experience similar Grade 3 or 4 treatment-emergent laboratory 
abnormality or AE that is suspected to be IMP 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 3 or4 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 12.1.1.3 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. Only one dose of study drug is 
provided to each subject at a time, so overdose is not of concern in the study. The maximum dose 
to be administered in the current study is 750 mg. Single doses of up to 1000 mg, 7 days of 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
83 
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.   
12.3. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will review safety data on an as needed 
basis. The DMC will be convened 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 DMC members. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
84 
13. 
STATISTICS 
13.1. 
Sample Size Considerations 
Given the exploratory nature of this study, the sample size was not chosen based on statistical 
considerations, but rather to provide preliminary safety and efficacy data on BCX7353 in 
subjects with HAE when treated in accordance with this study.  
13.2. 
Hypothesis Testing 
An analysis may be conducted during Part 1, using the Heybittle-Peto boundary for significance, 
to determine whether there is a clinically important treatment effect with BCX7353. The 
endpoint for this analysis is the proportion of subject attacks with a stable or improved VAS at 4 
hours postdose in the full analysis set.  The null hypothesis evaluated (H0) is that the proportion 
of subject attacks treated with BCX7353 with stable or improved VAS at 4 hours postdose is the 
same as proportion of subject attacks treated with placebo with stable or improved VAS at 4 
hours postdose (i.e., no treatment difference). The alternative hypothesis (H1) is that the 
proportion of subject attacks treated with BCX7353 with stable or improved VAS at 4 hours 
postdose is greater than the proportion of subject attacks treated with placebo with stable or 
improved VAS at 4 hours postdose (i.e., treatment difference). 
13.3. 
Statistical Methods 
A detailed statistical analysis plan (SAP) will be developed and finalized prior to database lock. 
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. 
13.3.1. 
Analysis Populations 
The analysis populations are defined below.   
13.3.1.1. Full Analysis Set  
The Full Analysis Set (FAS) population will include all subjects/subject attacks treated. 
Subjects/subject attacks will be analyzed according to the treatment randomized. The FAS 
population will be the primary population for efficacy analyses. 
13.3.1.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment received. This population will be used for 
all analyses of accountability, demographics, and safety. 
13.3.2. 
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 sequence 
using descriptive statistics. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
85 
Disease and treatment characteristics including years since initial diagnosis of HAE, number of 
days since last HAE attack, documented attack frequency, and pattern of on-demand therapy will 
be summarized by treatment sequence 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 will be 
presented. 
13.3.3. 
Analysis of Efficacy Variables 
As this is the first study of BCX7353 in the treatment of acute attacks, the analysis of attack 
resolution will be described in a number of ways which will be fully detailed in the SAP. The 
endpoint that may be utilized to first examine efficacy is the proportion of subject attacks with a 
stable or improved VAS at 4 hours postdose in the full analysis set. The number and proportion 
of subject attacks with a stable or improved VAS at 4 hours postdose will be summarized by 
treatment group. Attacks that require standard of care medication prior to the 4 hour time point 
will be considered as failure (i.e., not having a stable or improved VAS at 4 hours postdose). To 
assess treatment differences, a logistic mixed effect model including treatment, period and 
sequence as fixed effects, and subject within sequence as a random effect will be utilized. Other 
binary endpoints will be analyzed in a similar manner.  
The 3-symptom composite VAS and its associated changes from baseline will be summarized for 
each attack by time point and treatment group. Treatment differences in the change from baseline 
values at each time point will be assessed with a mixed effect linear model with factors for 
treatment, period, sequence, and baseline value as fixed effects, and subject within sequence as a 
random effect. Analyses of other continuous variables will be analyzed in a similar manner. 
The time to use of standard of care medication will be estimated using the method of 
Kaplan-Meier. For each attack, subjects who do not use standard of care medication will be 
censored at the end of the attack observation period (i.e., 24 hours). Treatment differences will 
be assessed using an appropriate proportional hazards model. Analyses of other type to event 
variables will be analyzed in a similar manner. 
Location of attacks, duration of attacks, and number of acute HAE medications administered will 
be summarized for each treatment group. 
13.3.4. 
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 the 
day of subject dosing to treat an attack without an associated onset time may have occurred after 
the initiation of study drug. Hence, AEs occurring on the day of subject dosing to treat an attack 
with no associated onset time will be assumed to be treatment emergent. AEs will be attributed 
to the corresponding treatment assignment of the corresponding treatment period.  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-

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
86 
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 treatment group. Laboratory abnormalities will be graded 
according to the DMID Adult Toxicity Table (Publish Date: Draft, November 2007, see 
Appendix 15.1). Any graded abnormality that occurs following the initiation of study drug and 
represents at least 1-grade increase from the baseline assessment for a given treatment period 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 treatment group.  
Clinically significant abnormal morphological ECG findings will be summarized by treatment 
group. 
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. 
13.3.5. 
Subject Satisfaction Analyses 
The change from baseline in the TSQM global satisfaction score as well as effectiveness, side 
effects, and convenience subscales will be summarized. Data will be listed, summarized, and 
appropriately tested for differences between active treatment and placebo and between active and 
current acute therapy utilized at baseline. 
13.3.6. 
Interim Monitoring and Statistical Stopping Rules 
The study’s design is intended to identify the dose or doses of BCX7353 shows an efficacy 
benefit over placebo.  Dosing in the study will commence at the 750 mg dose level and lower 
doses (500 mg and 250 mg) will be evaluated in successive parts of the study.   
After 12 subjects have completed Part 1 of the study, the proportion of subject attacks with a 
stable or improved VAS at 4 hours postdose may be estimated for BCX7353 750 mg and placebo 
by the study statistician using the analysis method described in Section 13.3.3. A test of no 
treatment difference is considered statistically significant with p < 0.001 (i.e., Haybittle-Peto 
boundary is crossed). Treatment differences may also be assessed using available data in Parts 1, 
2 and 3 in order to plan for future studies.  
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
87 
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 substantial 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.  

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
88 
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 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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
89 
14.4. 
Study Termination and Site Closure 
Formal stopping rules for individual subjectsare listed below and also defined in Section 8.3.2.  
• Intercurrent illness or emergence of a new illness/medical condition that would, in the 
judgment of the Investigator, affect assessments of clinical status to a significant 
degree 
• Subsequent determination that inclusion/exclusion criteria were not met 
• Emergence of any laboratory abnormality or AE that in the judgment of the 
Investigator compromises the ability to continue study-specific procedures or is 
considered not to be in the subject’s best interest due to an altered risk/benefit profile 
• 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)  
• A subject has a QTcF > 500 msec (confirmed on repeat testing) 
• A subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
from the value obtained predose at the baseline visit 
• A subject has a study drug related Grade 3 or 4 rash as described by the DMID 
criteria “Skin-mucocutaneous”  
 Overall, the Sponsor may suspend enrollment into the study, suspend treatment of ongoing 
subjects, or terminate the study to ensure that subjects’ safety and welfare are protected. 
The entire study, or individual sites, will be terminated for any of the following reasons: 
• Request of a Competent Authority 
• Recommendation of the independent DMC 
• Inaccurate or incomplete data recording 
• Non-compliance with study protocol 
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 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
90 
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 and secure 
maintenance of the confidential nature of their personal data. Only a subject identification 
number and subject identifiers permitted by local regulation will identify subject data retrieved 
by BioCryst. However, in compliance with federal regulations, BioCryst requires the Investigator 
to permit BioCryst’s representatives and, when necessary, representatives of the FDA or other 
regulatory authorities to review and/or copy any medical records relevant to the study, 
maintaining pseudo anonymity. 
All parties will abide by all applicable laws and regulations regarding subject privacy and 
confidentiality, including the Health Insurance Portability and Accountability Act (HIPAA), 
where this rule is applicable, and the requirements of the Data Protection Act in the EU, where 
applicable. A valid authorization and consent must meet the specifications of the applicable laws 
and regulations relating to such personal data and health information. It is the responsibility of 
the Investigator and institution to obtain such waiver/authorization in writing from the 
appropriate individual. HIPAA authorizations are required for US sites only. 
14.7. 
Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict 
confidence along with all information furnished by BioCryst. Except as provided through written 
agreement between BioCryst, independent analysis and/or publication of these data by the 
Investigator or any member of his/her staff is not permitted without prior written consent of 
BioCryst. Such consent will not be withheld unreasonably. BioCryst is in agreement with the 
principle of full disclosure of clinical trial results. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
91 
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. 
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. 
Cicardi, M., R. J. Levy, D. L. McNeil, H. H. Li, A. L. Sheffer, M. Campion, P. T. Horn and W. 
E. Pullman (2010). "Ecallantide for the treatment of acute attacks in hereditary angioedema." N 
Engl J Med 363(6): 523-531. 
Craig, T. J., R. J. Levy, R. L. Wasserman, A. K. Bewtra, D. Hurewitz, K. Obtulowicz, A. Reshef, 
B. Ritchie, D. Moldovan, T. Shirov, V. Grivcheva-Panovska, P. C. Kiessling, H. O. Keinecke 
and J. A. Bernstein (2009). "Efficacy of human C1 esterase inhibitor concentrate compared with 
placebo in acute hereditary angioedema attacks." J Allergy Clin Immunol 124(4): 801-808. 
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. 
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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
92 
Levy, R. J., W. R. Lumry, D. L. McNeil, H. H. Li, M. Campion, P. T. Horn and W. E. Pullman 
(2010). "EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for 
acute attacks of hereditary angioedema." Ann Allergy Asthma Immunol 104(6): 523-529. 
Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-481. 
Longhurst, H. J. (2010). "Management of acute attacks of hereditary angioedema: potential role 
of icatibant." Vasc Health Risk Manag 6: 795-802. 
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. 
Lumry, W. R., H. H. Li, R. J. Levy, P. C. Potter, H. Farkas, D. Moldovan, M. Riedl, H. Li, T. 
Craig, B. J. Bloom and A. Reshef (2011). "Randomized placebo-controlled trial of the 
bradykinin B(2) receptor antagonist icatibant for the treatment of acute attacks of hereditary 
angioedema: the FAST-3 trial." Ann Allergy Asthma Immunol 107(6): 529-537. 
Malbran, A., M. Riedl, B. Ritchie, W. B. Smith, W. Yang, A. Banerji, J. Hebert, G. J. Gleich, D. 
Hurewitz, K. W. Jacobson, J. A. Bernstein, D. A. Khan, C. H. Kirkpatrick, D. Resnick, H. Li, D. 
S. Fernandez Romero and W. Lumry (2014). "Repeat treatment of acute hereditary angioedema 
attacks with open-label icatibant in the FAST-1 trial." Clin Exp Immunol 177(2): 544-553. 
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. 
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. 
Riedl, M., M. Campion, P. T. Horn and W. E. Pullman (2010). "Response time for ecallantide 
treatment of acute hereditary angioedema attacks." Ann Allergy Asthma Immunol 105(6): 430-
436 e432. 
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. 
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. 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
93 
Wasserman, R. L., R. J. Levy, A. K. Bewtra, D. Hurewitz, T. J. Craig, P. C. Kiessling, H. O. 
Keinecke and J. A. Bernstein (2011). "Prospective study of C1 esterase inhibitor in the treatment 
of successive acute abdominal and facial hereditary angioedema attacks." Ann Allergy Asthma 
Immunol 106(1): 62-68. 
Zuraw, B., M. Cicardi, R. J. Levy, J. H. Nuijens, A. Relan, S. Visscher, G. Haase, L. Kaufman 
and C. E. Hack (2010). "Recombinant human C1-inhibitor for the treatment of acute angioedema 
attacks in patients with hereditary angioedema." J Allergy Clin Immunol 126(4): 821-827 e814. 
Zuraw, B. L., P. J. Busse, M. White, J. Jacobs, W. Lumry, J. Baker, T. Craig, J. A. Grant, D. 
Hurewitz, L. Bielory, W. E. Cartwright, M. Koleilat, W. Ryan, O. Schaefer, M. Manning, P. 
Patel, J. A. Bernstein, R. A. Friedman, R. Wilkinson, D. Tanner, G. Kohler, G. Gunther, R. 
Levy, J. McClellan, J. Redhead, D. Guss, E. Heyman, B. A. Blumenstein, I. Kalfus and M. M. 
Frank (2010). "Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema." N 
Engl J Med 363(6): 513-522. 
Zuraw, B. L. and S. C. Christiansen (2011). "Pathophysiology of hereditary angioedema." Am J 
Rhinol Allergy 25(6): 373-378. 
 

Protocol BCX7353-202 
BioCryst Pharmaceuticals, Inc. 
Version 4.0 
CONFIDENTIAL                                               BCX7353 
 
94 
APPENDICES 
15.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) 
 
https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf 
 
Copies of the DMID Toxicity Table will be available to the medical staff throughout the project. 

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

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

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

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

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

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

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

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

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

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

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