A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in Previously Treated Hemophilia B Patients
Phase: PHASE1
Conditions: Hemophilia B
Sponsor: ISU Abxis Co., Ltd.

ISU ABXIS 
 
Protocol No.: ISU304-001 
 
 
Confidential 
 
Protocol Ver.5.3_20180911 
 
 
 
Clinical Trial Protocol 
 
Protocol No. 
ISU304-001 
Protocol Version/Date 
5.3 (2018-09-11) 
Study Drug 
ISU304 
Study Title 
A Phase 1, Open-label, Multi-center, Dose-escalation Study to 
Investigate the Safety, Pharmacokinetics and Pharmacodynamics of 
ISU304 in Previously Treated Hemophilia B Patients 
Phase 
Phase 1 
Contract Research 
Organization 
DreamCIS Inc. (CEO: Jessica Liu) 
10F, Jeokseon-Hyundai B/D 
130 Sajik-ro, Jongno-gu, Seoul, Korea 03170 
Sponsor 
ISU ABXIS (CEO: Seokju Lee) 
5F, Global R&D Center Building C 
22 Daewangpangyoro 712-beongil, Bundang-gu, Seongnam-si, 
Gyeonggi-do, Korea 13488 
Study Duration 
Approximately 24 months after the protocol approval from the 
institutional review boards (IRBs) 
Confidentiality Statement 
© ISU ABXIS 
This protocol is the property of ISU ABXIS and may not – in full or 
in part – be passed on, reproduced, published, or otherwise used 
without the express permission of ISU ABXIS. 
 

ISU ABXIS 
 
Protocol No.: ISU304-001 
 
 
Confidential 
 
Protocol Ver.5.3_20180911 
 
 
Study Protocol Approval Page 
 
 
Protocol No.: 
ISU304-001 
Protocol Version: 
5.3 
Study Title: 
A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate 
the Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in 
Previously Treated Hemophilia B Patients 
 
 
This protocol has been reviewed and approved by the sponsor. 
 
 
Sponsor 
 
 
 
Seokju Lee 
 
 
 
ISU ABXIS 
 
 
 
 
Signature 
 
Date 
 
 
By signing below, I agree to all conditions relating to the clinical study as set out in this protocol. 
 
I fully understand the protocol, and agree to adhere to the protocol, KGCP, and regulatory 
requirements in all circumstances with the only exceptions where necessary to protect the subjects. 
 
 
Coordinating investigator 
 
 
 
Churwoo You, MD 
 
 
 
Department of Pediatrics & Adolescent 
Medicine, Eulji University Hospital 
 
 
 
 
Signature 
 
Date 
 
 

ISU ABXIS 
 
Protocol No.: ISU304-001 
Page 1 
 
Confidential 
 
Protocol Ver.5.3_20180911 
 
Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 4 
SYNOPSIS ............................................................................................................................................. 6 
STUDY SCHEDULES AND PROCEDURES ............................................................................... 10 
1 
STUDY BACKGROUND AND OBJECTIVE ................................................................. 13 
1.1 
Background ............................................................................................................................ 13 
1.2 
Theoretical Rationale ............................................................................................................ 14 
1.2.1 
Results from Toxicity Studies ........................................................................................ 15 
1.2.2 
Results from Pharmacokinetic/Pharmacodynamic Studies ............................................ 17 
1.2.3 
Rationale for Dose Determination ................................................................................ 20 
1.2.4 
Benefit-Risk Assessment................................................................................................ 29 
1.3 
Objective................................................................................................................................ 30 
2 
INVESTIGATIONAL PRODUCTS AND OTHER DRUGS IN THE STUDY ......... 31 
2.1 
Investigational Products ....................................................................................................... 31 
2.1.1 
Study Drug ..................................................................................................................... 31 
2.1.2 
Active Control ................................................................................................................ 32 
2.1.3 
Expected Adverse Events Related to the Investigational Product ............................ 32 
2.2 
Investigational Product Management .................................................................................. 32 
2.2.1 
Packaging and Labeling of Investigational Product ................................................... 32 
2.2.2 
Handling and Storage of Investigational Products ..................................................... 33 
2.3 
Rescue Drug ......................................................................................................................... 33 
2.4 
Concomitant and Prohibited Medications .......................................................................... 33 
2.4.1 
Concomitant Medications .............................................................................................. 33 
2.4.2 
Prohibited Medications .................................................................................................. 34 
3 
STUDY POPULATION ........................................................................................................ 35 
3.1 
Inclusion Criteria .................................................................................................................. 35 
3.2 
Exclusion Criteria ................................................................................................................. 35 
3.3 
Planned Number of Subjects .............................................................................................. 36 
4 
STUDY METHOD ................................................................................................................ 37 
4.1 
Study Design ........................................................................................................................ 37 
4.2 
Study Duration ...................................................................................................................... 39 
4.3 
Indication ............................................................................................................................... 39 
4.4 
Administration of Investigational Products and Follow Up Periods .............................. 39 
4.5 
Measures to Minimize Bias ................................................................................................... 40 
4.5.1 
Subject Identification Codes ......................................................................................... 40 
4.5.2 
Blinding ........................................................................................................................... 40 
4.5.3 
Randomization ................................................................................................................ 40 

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5 
STUDY PROCEDURE ......................................................................................................... 41 
5.1 
Measurements ........................................................................................................................ 41 
5.1.1 
Informed Consent ........................................................................................................... 41 
5.1.2 
Inclusion/Exclusion Criteria ........................................................................................... 41 
5.1.3 
Demographics ................................................................................................................. 41 
5.1.4 
Hemophilia B Status ..................................................................................................... 41 
5.1.5 
Medical and Medication History .................................................................................. 42 
5.1.6 
Physical Examination ..................................................................................................... 42 
5.1.7 
Vital Signs ...................................................................................................................... 42 
5.1.8 
Electrocardiogram ........................................................................................................... 43 
5.1.9 
Laboratory Tests ............................................................................................................. 43 
5.1.10 
FIX Inhibitor and Anti-drug Antibody Test ............................................................... 44 
5.1.11 
Administration of Investigational Product ................................................................... 45 
5.1.12 
Blood Collection ............................................................................................................ 45 
5.1.13 
Pharmacokinetic/ Pharmacodynamic Endpoints ........................................................... 48 
5.1.14 
Concomitant Medications .............................................................................................. 49 
5.1.15 
Adverse Events (AEs) ................................................................................................... 49 
5.2 
Detailed Procedure for Each Visit ..................................................................................... 51 
5.2.1 
Cohort 1 and Cohort 2 ................................................................................................. 51 
5.2.2 
Cohort 3 .......................................................................................................................... 55 
5.2.3 
Cohort 4 .......................................................................................................................... 60 
5.2.4 
Cohort 5 ........................................................................................................................... 62 
5.2.5 
Unscheduled Visits (if needed) .................................................................................... 65 
5.2.6 
Post-Study Safety Visit ................................................................................................... 65 
6 
SUBJECT WITHDRAWAL OR TERMINATION ........................................................... 67 
6.1 
Reasons for Withdrawal or Termination ............................................................................ 67 
6.2 
Handling of Subject Withdrawals or Termination ............................................................. 67 
7 
STATISTICAL CONSIDERATIONS ................................................................................... 69 
7.1 
Endpoints ............................................................................................................................... 69 
7.1.1 
Basic Subject Information ............................................................................................. 69 
7.1.2 
Safety Endpoints ............................................................................................................ 69 
7.1.3 
Pharmacokinetic/ Pharmacodynamic Endpoints ........................................................... 69 
7.2 
Statistical Analysis ............................................................................................................... 69 
7.2.1 
Analysis Population ....................................................................................................... 69 
7.2.2 
Analysis of Basic Subject Information ........................................................................ 70 
7.2.3 
Safety Analysis ............................................................................................................... 70 
7.2.4 
Pharmacokinetic/ Pharmacodynamic Analysis ............................................................. 71 
7.2.5 
Handling of Missing Values ......................................................................................... 71 
8 
ADVERSE EVENTS (AES) ................................................................................................ 72 
8.1 
Definition of Terms ............................................................................................................. 72 
8.2 
Collection and Documentation of Adverse Events .............................................................. 72 
8.3 
Assessment of Adverse Events ............................................................................................ 73 
8.3.1 
Severity ........................................................................................................................... 73 

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8.3.2 
Causal Relationship with Investigational Product ....................................................... 73 
8.4 
Adverse Event Reporting...................................................................................................... 75 
8.4.1 
SAE Reporting ............................................................................................................... 75 
8.4.2 
SUSAR Reporting .......................................................................................................... 75 
8.5 
Pregnancy Reporting ............................................................................................................ 76 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE CONSIDERATIONS ....................... 77 
9.1 
Study Centers ........................................................................................................................ 77 
9.2 
Institutional Review Boards ................................................................................................ 77 
9.3 
Subject Information Sheet and Informed Consent Form ................................................. 77 
9.4 
Adherence to the Protocol .................................................................................................. 77 
9.5 
Post-study Treatment for Subjects ........................................................................................ 78 
9.6 
Subject Indemnification ........................................................................................................ 78 
9.7 
Monitoring ............................................................................................................................. 78 
9.8 
Storage of Clinical Study Data .......................................................................................... 78 
9.9 
Data Safety Monitoring Board and Data Monitoring Committee .................................. 79 
9.10 
Audit and Inspection ............................................................................................................ 79 
9.11 
Confidentiality ....................................................................................................................... 79 
10 
REFERENCES ....................................................................................................................... 81 
11 
APPENDIX ............................................................................................................................. 82 
 
 
 
 

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List of Abbreviations and Definition of Terms 
ADR 
: Adverse Drug Reaction 
AE 
: Adverse Event 
AESI 
: Adverse Event of Special Interest 
ALT (SGPT) 
: Alkaline Transaminase (Serum Glutamic Pyruvic Transaminase) 
aPTT 
: activated Partial Thromboplastin Time 
AST (SGOT) 
: Aspartate Transaminase (Serum Glutamic Oxaloacetic Transaminase) 
AUC 
: Area Under Curve 
AUC(0-inf) 
: Area Under the FIX activity time Curve from time zero to infinity 
AUC(0-t) 
: Area Under the FIX activity time Curve from zero to a definite time t 
BU 
: Bethesda Unit 
BUN 
: Blood Urea Nitrogen 
CL 
: Total plasma clearance; the volume of blood from which the drug is total 
removed per unit time 
Cmax 
: Observed maximum plasma concentration after administration 
CRF 
: Case Report Form 
DMC 
: Drug Monitoring Committee 
DSMB 
: Data Safety Monitoring Committee 
FIX 
: Factor IX 
rFIX 
: Recombinant Factor IX 
GMP 
: Good Manufacturing Practice 
HBV 
: Hepatitis B Virus 
HCV 
: Hepatitis C Virus 
HIV 
: Human Immunodeficiency Virus 
IRB 
: Institutional Review Board 
IU 
: International Unit 
IV 
: Intravenous 
K 
: Incremental recovery 
KGCP 
: Korean Good Clinical Practice 
MedDRA 
: Medical Dictionary for Regulatory Activities 
MRT 
: Mean Residence Time 
NAb 
: Neutralizing Antibody 

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NOAEL 
: No Observed Adverse Effect Level 
PD 
: Pharmacodynamic 
PK 
: Pharmacokinetic 
PT 
: Prothrombin Time 
RBC 
: Red Blood Cell 
SAE 
: Serious Adverse Event 
SC 
: Subcutaneous 
SUSAR 
: Suspected Unexpected Serious Adverse Reaction 
t1/2 
: Terminal phase elimination half-life 
TAT 
: Thrombin-Antithrombin Complex 
Tmax 
: Time to maximum plasma concentration 
Vss 
: Volume of distribution at steady state 
WBC 
: White Blood Cell 
γ-GT 
: Gamma-Glutamyl Transpeptidase 
 
 

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Synopsis 
Study title 
A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate the 
Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in Previously 
Treated Hemophilia B Patients 
Study centers/ 
Coordinating 
investigator 
Study Centers: 
Eulji University Hospital 
 
Severance Hospital 
 
Pusan National University Hospital 
Coordinating Investigator: Prof. Churwoo You, Eulji University Hospital 
Study duration 
Approximately 24 months after the protocol approval from the institutional 
review boards (IRBs) 
Indication 
Previously treated hemophilia B patients 
Study objective 
To investigate the safety, pharmacokinetics and pharmacodynamics of ISU304 
(recombinant factor IX with increased activity) in previously treated hemophilia 
B patients 
Phase and design 
Phase 1, open-label, multi-center, dose-escalation 
Investigational 
products 
 
Study drug: ISU304 75, 150IU/kg, intravenous or subcutaneous 
administration 
 
Active control: BeneFIX 75 IU/kg, intravenous administration 
 
Rescue drug: Treatment currently used by subject to treat hemophilia B 
Administration and 
follow-up period 
 
Cohort 1 (n=3): 7 days 
Single intravenous administration of BeneFIX (75 IU/kg) with 72 hours of 
observation, followed by single intravenous administration of ISU304 (75 
IU/kg) with 72 hours of observation 
 
Cohort 2 (n=3): 7 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 (75 
IU/kg) with 72 hours of observation 
 
Cohort 3 (n=3): 9 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 
(150 IU/kg) with 120 hours of observation 
 
 
Cohort 4 (n=5): 10 days  
One subcutaneous administration of ISU304 (150 IU/kg) per day for 6 days 
with 240 hours of observation  
 
Cohort 5 (n=minimum 3, maximum 5): 15 days 
Single intravenous administration of ISU304 (75 IU/kg) is followed by 

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subcutaneous ISU304 (150 IU/kg) administration for 9 days with 312 hours 
of observation 
Planned number of 
subjects 
At least 12 subjects 
Inclusion criteria 
1) Previously treated male patients with moderate or severe hemophilia B 
(documented FIX activity ≤ 2% and exposed to any FIX product for ≥ 150 
exposure days (estimated)) 
2) Patients must be 12 to 65 years old at the time of screening 
3) Patients who have discontinued a previously treated FIX product at least 4 
days prior to the administration of investigational product 
4) HIV negative, or if HIV positive with a CD4 count > 200/μL (documented 
< 200 particles/μL or ≤ 400,000 copies/mL) at the time of screening 
5) Voluntary consent to participate in the study 
Exclusion criteria 
1) Patients with a history or a family history of FIX inhibitors 
2) Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from 
inhibitor tests) at the time of screening 
3) Patients who have a history of thromboembolic events (myocardial 
infarction, cerebrovascular disease, venous thrombosis, etc.) 
4) Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX 
product or hamster protein 
5) Patients receiving treatment with a FIX product or a bypass agent within 4 
half-lives for the agent used (at least 96 hours) prior to the administration 
of the investigational product 
6) Patients who have been exposed to long-term administration (exceeding 14 
days) of immunomodulating agents or immunosuppressants such as α-INF 
or adrenocortical hormones over the past 3 months or who are currently 
receiving or planning to receive such treatment during the study period 
7) Patients who have been administered vaccines during the period of 6 
months prior to the administration of the investigational product or plan to 
receive vaccines during the study period  
8) Patients with any other co-existing bleeding disorder (Von Willebrand 
disease, etc.) 
9) Patients with positive D-dimer results (≥ 0.5 µg/mL) at the time of 
screening 
10) Patients with platelet counts less than 100,000/μL at the time of screening 
11) Patients with ALT, AST levels 5 times greater than upper normal limit or 
total bilirubin, serum creatinine levels 2 times greater than upper normal 
limit at the time of screening 
12) Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive 
and require medical treatment at the time of screening 

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13) Patients scheduled for surgery during the study period 
14) Patients participated in another study within 30 days before screening or 
scheduled to participate in any other study during the study period 
Study timeline/ 
Data collection 
This study is a phase 1, open-label, multi-center, dose-escalation study to 
investigate the safety, pharmacokinetics and pharmacodynamics of ISU304 in 
previously treated hemophilia B patients. 
All subjects shall give their written consent before participating in this study 
and only those who meet all of the inclusion criteria and none of the exclusion 
criteria will be administered the investigational products.  
This study is comprised of 5 cohorts. Each cohort will receive an identical 
intravenous administration of 75 IU/kg, with subcutaneous administrations 
doubling from 75 IU/kg until 150 IU/kg. 
During the study period, a subject may be hospitalized to facilitate the 
collection of blood samples for pharmacokinetic (PK)/pharmacodynamic (PD) 
analysis. Hospitalization itself will not be considered as a serious adverse event 
if no adverse event occurs. PK/PD analysis and safety assessments will be 
conducted for each cohort. The Data Safety Monitoring Board (DSMB) and 
Drug Monitoring Committee (DMC) will be operated after the end of Cohorts 1 
to 4. These committees will monitor the PK/PD and safety data from each 
cohort to determine the continuation of next cohort (Cohorts 2 to 5), target dose, 
and blood sampling period for PK/PD (including timing of collection). 
Additional subjects may be enrolled in all cohorts or cohorts may be canceled 
depending on the results of PK/PD analysis. 
Safety endpoints 
 
Adverse events after the administration of investigational products 
(local/systemic/other)1 
 
Physical examination2 
 
Vital signs 
 
Electrocardiogram 
 
Laboratory tests 
 
FIX inhibitors (or neutralizing antibodies) and anti-drug antibodies to 
investigational products 
Pharmacokinetic/ 
Pharmacodynamic 
endpoints 
 
PK endpoints: observed maximum plasma concentration (Cmax), terminal 
phase elimination half-life (t1/2), total plasma clearance (CL), volume of 
distribution at steady state (Vss), area under curve (AUC; AUC(0-t) and 
AUC(0-inf)), mean residence time (MRT), incremental recovery (K), time to 
maximum plasma concentration (Tmax) for FIX activity and FIX product  
 
PD endpoint: activated partial thromboplastin time (aPTT) 
Other endpoints 
Demographic data, hemophilia B status, medical history, medication history 
 
 
1 Including adverse events of special interest (AESI) 
2 Includes assessment of tolerability of subcutaneous injection (excluding Cohort 1), local reactions in 
administration site and systemic reactions after subcutaneous administration of investigational products. 

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Protocol No.: ISU304-001 
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Analysis method 
 
Analysis population 
- 
Safety analysis set: All subjects who receive at least one dose of 
investigational products 
- 
PK set: Subjects in the safety analysis set who complete all procedures 
planned for the cohort and for whom PK samples3 have been obtained 
at least 4 times after administration. 
 
PK Analysis: Using WinNonlin software (Pharsight, CA, USA)4 
 
Bioavailability analysis for subcutaneous administration 
 
Other statistical analysis 
- 
For each cohort, descriptive statistics will be given for each endpoint 
for each subject using SAS software (SAS Institute Inc, Cary, USA) 
 
 
 
3 The 4 PK sampling points should include at least 2 points within 3 hours after IV administration, or within 12 
hours after SC administration. However, Cohort 4 and Cohort 5 subjects can be included in the PK set with 
samples from 6 hours after the 1st administration and 6 hours after the 6th administration. 
4 NONMEM software (ICON, MD, USA) will be used for additional analysis, if necessary. 

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Study Schedules and Procedures 
 
Screening 
1st/2nd  
Hospitali
zation 
Administration of investigational product and 
timing of blood collection for PK/PD analysisa 
Interim visit 
/End of a cohort 
Post-study 
safety visit 
Visit no. 
1st administration period 
-30 ~ 0 
-1 ~ 0 
 
 
 
 
0 
 
 
 
1 
2 
3 
4 
5 
6 
2nd administration period 
4 ~ 5 
 
 
 
 
5 
 
 
 
6 
7 
8 
9 
10 
11 
3/5(or 6) 
+14 (+7) 
Hours after administration 
NA 
NA 
Before 
administration 
0 
 
 
 
 
6 
 
24 48 72 96 120 144 
NA 
NA 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemophilia B statusc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication historyd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X X† 
X 
X† 
X 
 
Vital signse 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X X† 
X 
X† 
X 
 
Electrocardiogramf, * 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Inclusion/exclusion criteria 
X 
X1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of investigational product  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests (central laboratory)g, * 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood chemistry 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood coagulation 
X2) 
X 
 
 
 
 
 
 
X 
 
X 
X 
X X† 
X 
X† 
X 
 
BeneFIX anti-drug antibody/ 
neutralizing antibody 
X 
X3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
ISU304 anti-drug antibody/ 
neutralizing antibody 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Bethesda assay 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Safety assessmenth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X4) 
X4) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
X5) 
 
 
 
 
 
 
 
X 

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Study Schedules and Procedures (Cont’d) 
 
Screening 
1st/2nd  
Hospitaliz
ation 
Administration of investigational product and 
timing of blood collection for PK/PD analysisa 
Interim visit 
/End of a  
cohort 
Post-study 
safety visit 
Visit no. 
1st administration 
period 
-30 ~ 0 
-1 ~ 0 
 
 
 
 
0 
 
 
 
1 
2 
3 
4 
5 
6 
2nd administration 
period 
4 ~ 5 
 
 
 
 
5 
 
 
 
6 
7 
8 
9 
10 
11 
+14 (+7) 
Hours after 
administration(
±min) 
Intravenous 
administration 
N/A 
N/A 
Before 
administration 
(-30) 
0 
(+1) 
0.25 
(±3) 
0.5 
(±3) 
1 
(±3) 
3 
(±5) 
6 
(±5) 
9 
(±5) 
24 
(±15) 
48 
(±120) 
72 
(±120) 
96 
(NA) 
120 
(±180) 
144 
(NA) 
NA 
NA 
Subcutaneous 
administration 
1 
(+3) 
2 
(±3) 
4 
(±5) 
6 
(±5) 
8 
(±5) 
10 
(±5) 
12 
(±5) 
PK/PD analysis (blood collection)i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
BeneFIX 75 IU/kg w/IV 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
- 
ISU304 75 IU/kg w/IV 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
- 
Cohort 2 
ISU304 75 IU/kg w/IV 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
- 
ISU304 75 IU/kg w/SC 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
- 
Cohort 3 
ISU304 75 IU/kg w/IV 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
- 
ISU304 150 IU/kg w/SC 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4j 
ISU304 150 IU/kg w/SC 
- 
- 
X‡ 
- 
- 
- 
X‡ 
- 
- 
- 
X‡ 
- 
- 
- 
- 
- 
- 
- 
Cohort 5k 
ISU304 75 IU/kg w/IV 
- 
- 
X 
X 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
ISU304 150 IU/kg w/SC 
- 
- 
X♀ 
- 
- 
- 
- 
- 
- 
- 
X♀ 
- 
X♀ 
- 
X♀ 
- 
- 
- 
Hospitalization/dischargek 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
w/ - with; IV - intravenous administration, SC - subcutaneous administration 
*For Cohort 4 and Cohort 5, there are no hospitalizations or interim visits, thus replaced by date of 1st administration of the investigational product. 
†- Only for Cohort 4 and Cohort 5 
‡- Blood collection for PK/PD analysis in Cohort 4 take place right before each administration, 6 hours after 1st administration, 6 hours after 6th administration, and 24 hours after 6th 

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administration. 
♀- Blood collection for PK/PD analysis in Cohort 5 take place before intravenous administration, after administration, 30 min and right before subcutaneous administration, and 24, 72 and 
120 hours after 9th subcutaneous administration. 
a. Additional visit beyond the designated will be conducted upon request from a subject or subject’s representative, or by the investigator’s decision. Additional subjects may be enrolled in 
all cohorts or cohorts may be canceled depending on the results of PK/PD analysis. 
b. Gender, date of birth, age, weight, and height 
c. Documentation of the lowest FIX activity, year of diagnosis, family history of hemophilia B, history and family history of FIX inhibitors, and previous FIX treatment history 
d. Subject’s past (within 3 months prior to screening) or current medical history and medication history (within 3 months prior to screening, within 6 months for vaccines)  
e. Blood pressure, pulse rate, respiration rate, and body temperature 
f. Actual recording date/time, PR, QRS, QT, corrected QT intervals, and investigator’s assessment 
g. All hematology, blood chemistry, blood coagulation, serology, urinalysis, and Bethesda assay shall be conducted at the central laboratory (SCL; Seoul Clinical Laboratories, KR). Anti-
drug antibody/neutralizing antibody tests for BeneFIX and ISU304 shall be conducted at the other central laboratory (HTI, Haematologic Technoilgies Inc., USA). However, tests requiring 
analysis within 24 hours (hematology, urine test) can be conducted at each site. As aPTT is a PD endpoint, it is collected during the PK/PD sampling period. Sample storage and disposal will 
be carried out according to central laboratory’s recommended procedure. For laboratory test conducted for confirmation of inclusion/exclusion criteria, retest is allowed during the screening 
period as judged by the Investigator.  
Hematology: RBC, WBC with differential count (Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil), Hemoglobin, Hematocrit, Platelet count, CD4 count (Screening only) 
Blood chemistry: Total protein, Albumin, Creatinine, BUN, Uric acid, Total bilirubin, AST (SGOT), ALT (SGPT), γ-GT 
Blood coagulation: aPTT, PT international normalized ratio, PT sec, TAT, D-dimer, F1+2, Fibrinogen  
Serology: anti-HBV (HBs Ag), anti-HCV (Anti-HCV Ab), anti-HIV (Anti-HIV Ab) 
Urinalysis: pH, Protein, Glucose, Urobilinogen, Microscopic exam (if abnormal dipstick test): RBC, WBC 
h. Safety endpoints are collected until the end of each cohort. 
i. PK/PD analysis are carried out at the designated central laboratory (HTI). Target dose, and blood sampling period (including timing of collection) in Cohorts 2 to 4 will be determined 
based on the PK/PD analysis of the preceding cohort. Subjects from Cohort 1 ~ 3 are expected to participate in Cohort 4.  
The following endpoints will be estimated and analyzed at the central laboratory (HTI) for each subject: observed maximum plasma concentration (Cmax), terminal phase elimination half-life 
(t1/2), total plasma clearance (CL), volume of distribution at steady state (Vss), area under curve (AUC; AUC(0-t) and AUC(0-inf)), mean residence time (MRT), incremental recovery (K), time 
to maximum plasma concentration (Tmax) for FIX activity and FIX product 
j. The investigational product is administered daily for 6 days. 
k. ISU304 75 IU/kg is intravenously administered at the first day and this is followed by subcutaneous administration of ISU304 150 IU/kg within 30 min. Afterwards, ISU304 150 IU/kg is 
subcutaneously administered once a day for 8 days, with a 24 hour interval.   
l. Subjects who have completed blood collection during hospitalization may make outpatient visits for the remaining blood sample collections. Cohort 4 does not need hospitalization. 
1) The final decision on eligibility is made based on data collected during screening. 
2) Only D-dimer is assessed at screening. 
3) Subjects in Cohort 1 who have been administered BeneFIX will be tested for BeneFIX anti-drug antibodies and neutralizing antibodies. 
4) Information on previous concomitant medication may be collected before the 2nd administration of the investigational product within the same cohort. 
5) AEs including injection site reactions must be observed for at least 30 minutes to 1 hour after the administration of the investigational product. 

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1 
Study Background and Objective 
1.1 
Background 
Hemophilia B is an X chromosome related congenital bleeding disorder caused by a deficiency of the 
clotting factor IX (FIX). This disorder is caused by a mutation of the clotting factor, and it typically 
affects males while females are usually carriers(1). The worldwide prevalence of hemophilia B ranges 
from 0.9 to 3.2 cases per 100,000 males(2). 
FIX activity is usually expressed in international units (IU/mL), wherein 1 IU/mL (100 IU/dL) 
represents 100% FIX activity in 1 mL of normal blood plasma. The FIX activity range of normal 
individuals is about 0.5 ~ 1.5 IU/mL (50 ~ 150% or 50 ~ 150 IU/dL), and varying symptoms of 
hemophilia occur at lower activity levels(3). Patients whose FIX activity is below 0.01 IU/mL (< 1%) 
are classified as severe cases, who experience spontaneous bleeding in the joints and muscles. In some 
cases, bleeding can be life-threatening and require immediate treatment. While the symptoms of 
bleeding are usually life-long, some children with severe hemophilia may not have bleeding 
symptoms until later when they begin walking or running. Patients with mild hemophilia may not 
bleed excessively until they experience trauma or surgery(1). 
Bleeding can be prevented and hemostasis can be induced when bleeding occurs in severe hemophilia 
patients by supplementing the deficient clotting factor. In other words, FIX products can be 
administered as prophylaxis therapy (administration of clotting factor to prevent spontaneous or 
trauma induced bleeding) or as on-demand therapy to induce hemostasis when bleeding occurs 
(administered in the presence of clinically clear bleeding). Prophylaxis is a form of therapy that 
prevents bleeding and joint damage, with the goal of preserving normal musculo-skeletal functions(1). 
Plasma-derived FIX products have made prophylaxis therapy possible since 1970s. Due to safety 
issues, however, recombinant FIX (rFIX) products have been used more frequently in the treatment of 
hemophilia B in recent decades(4). The first-generation rFIX products have relatively short half-lives, 
which necessitate frequent infusion. To address this issue, the second-generation products combined 
with substances that can increase the half-life of FIX are being developed. The second-generation 
rFIX products have been used for prophylaxis therapies by intravenous administration once a week to 
once every two weeks. Although the second-generation products have reduced the inconvenience of 
frequent infusions associated with the first-generation products, there is still room for improvement as 
these products still have to be administered intravenously. rFIX products currently approved for the 
Korean market include BeneFIX (Pfizer Ltd.) and Rixubis (Baxalta Inc.) but the second-generation 
rFIX products are still yet to be approved.  

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1.2 
Theoretical Rationale 
All FIX products currently available are administered intravenously. While intravenous administration 
is useful for hemostasis during acute bleeding, it is inconvenient for patients who require long-term 
prophylaxis therapy due to frequent administration schedules. 
Subcutaneous administration is generally preferred over intravenous administration because it enables 
at-home injection, improves the quality of life, and reduces health care costs(6). Although biological 
agents such as insulin, growth hormones and antibodies have been developed as subcutaneously 
administered products, a subcutaneous FIX product has yet to be developed. Due to the characteristics 
of the administration route, subcutaneous products are limited in terms of administration volume 
(typically 1 ~ 2 mL). Currently developed FIX products have low activity levels per unit volume 
(maximum of 600 IU/mL for BeneFIX), making them unsuitable for subcutaneous administration 
with volume limitations. For example, a 50 IU/kg dose to a patient who weighs 60 kg, would require a 
total dose of 3,000 IU, which translates to 5 mL in administration volume. The low bioavailability of 
subcutaneous FIX injections also makes subcutaneous injections more challenging. In nonclinical 
studies on animal subjects, subcutaneous bioavailability of FIX ranged from 25 to 86% according to 
species(7, 8, 9). Liles et al (1997) proposed a subcutaneous bioavailability of 33% from one hemophilia 
B patient(9). The low bioavailability means that subcutaneous administration requires higher doses 
compared to intravenous and thus the volume also increases. With the increase in administration 
volume, treatment costs are also expected to escalate. 
In order to make a FIX product that can be injected subcutaneously, a FIX product with a high level of 
specific activity had to be developed. With high specific activity, the FIX activity per unit volume also 
increases, reducing the administration volume required. As the amount of FIX required also decreases 
with high specific activity, there is the added advantage of being able to produce highly concentrated 
FIX products without a corresponding increase in production cost.  
In order to produce an rFIX product with high coagulation activity, a structure-based rationale design 
was employed. Through this method, we produced a wide range of FIX variants, to develop a 
modified FIX (named ISU304) with high coagulation activity through biological screening (Patent 
No.: WO2012061654 A1). ISU304 was created by introducing 3 point mutations in 2 loops within the 
FIX protein. With these point mutations, arginine-318 is transformed into tyrosine (Arg318Tyr), 
arginine-338 into glutamic acid (Arg338Glu), and threonine-343 into arginine (Thr343Arg). One of 
the mutations (Arg318Tyr) is located in ‘loop-150’, which is also known as the autolysis loop, while 
the other two (Arg338Glu and Thr343Arg) are located in ‘loop-170’. The mutation in ‘loop-170’ can 
significantly enhance affinity to the cofactor VIII and stabilize activated FIX (FIXa). The mutation in 

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‘loop-150’ is also expected to stabilize the activation structure of FIXa, as well as directly interact 
with factor X, a substrate of FIX and Anti-thrombin III (ATIII), a key inhibitor. In conclusion, these 
minimal mutations in the 3D molecular structure (3 amino acid mutations) allow ISU304 to 
demonstrate 3 times the catalytic efficiency to factor X (substrate), 10 times higher affinity to cofactor 
FVIIIa and 15 times the resistivity to inhibitor ATIII compared to wild-type FIX. These characteristics 
resulted in ISU304 demonstrating 20 times the in vitro coagulation activity as well as 20 times 
increased titer in hemostatic potency study with hemophilic mice models compared to BeneFIX.  
The pharmacokinetic characteristics of ISU304 in subcutaneous and intravenous administrations have 
been observed in animal tests. ISU304 and BeneFIX displayed similar pharmacokinetic profiles when 
identical doses of each (75 IU/kg and 250 IU/kg) were intravenously administered to hemophilic 
mice. Subcutaneously administered ISU304 and BeneFIX demonstrated respective bioavailabilities of 
16 ~ 22% and 30 ~ 35% in normal mice and minipig with half-lives increasing two-fold or more in 
subcutaneous administration compared to intravenous administration. When ISU304 was 
subcutaneously administered daily in 230 IU/kg doses to hemophilic mice with severe hemophilia 
FIX activity levels (< 1.1 IU/dL), they were able to maintain FIX activity as mild hemophilia levels (> 
5 IU/dL). When 300 IU/kg was subcutaneously administered daily to hemophilic dogs for 6 days, FIX 
activity in plasma increased up to 50 IU/dL, which falls within the FIX activity range of normal 
individuals (50 ~ 150 IU/dL). With the increase in plasma FIX activity, a decrease in whole blood 
coagulation time was also observed. 
In conclusion, ISU304 is a FIX product that shows markedly improved specific activity compared to 
existing products. Currently developed ISU304 product offers per unit volume activity levels (> 7,500 
IU/mL) over 10 times higher than the maximum activity of BeneFIX (600 IU/mL), making it possible 
to administer 75 ~ 300 IU/kg doses to patients that weigh 70 kg, with dose volumes of just 0.7 ~ 3 
mL. It was also demonstrated that coagulation activity levels akin to mild hemophilia patients or 
normal individuals could be maintained through repeated subcutaneous administrations. Therefore, 
ISU304 is deemed to be an appropriate product for subcutaneous injection as originally aimed and the 
objective of this clinical study is to verify this estimation. 
1.2.1 
Results from Toxicity Studies 
Toxicity studies on ISU304 consistently showed that ISU304 was well tolerated in mice, rats, 
monkeys, and rabbits. All of them showed there was no death or clinically significant findings caused 
by the study treatment. The maximum tolerated doses in rats and monkeys were above 3.0 mg/kg 
(12,900 ~ 15,200 IU/kg) when intravenously administered 2 times a week for 4 weeks, and above 1.0 

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mg/kg (4,600 IU/kg) for daily subcutaneous administrations over 2 weeks in rats. The table below 
summarizes the preclinical toxicity studies. 
Type of study 
Animal 
species/strain 
Administrat
ion method 
Administrat
ion period 
Dose (mg/kga) 
Study No. 
Preliminary toxicity 
Mouse/ICR 
IV 
1 day 
0, 0.3, 1, 3, 10 
15-KE-056 
Acute toxicity 
Rat/CD 
IV 
2 weeks 
0, 0.3, 3 
2470-007 
Monkey/ 
Cynomolgus 
IV 
2 weeks 
0, 0.3, 1, 3 
2470-008 
Repeated 
administration 
toxicity, local 
tolerance, 
antigenicity 
Rat/CD 
IV 
4 weeks 
0, 0.3, 1, 3 
2470-002 
Monkey/ 
Cynomolgus 
IV 
4 weeks 
0, 0.3, 1, 3 
2470-003 
Rat/CD 
SC 
2 weeks 
0, 0.1, 0.3, 1 
2470-012 
Other toxicity 
 
 
 
 
 
Plasma generation 
Rabbit/NZW 
IV 
10 min 
0, 0.3, 1, 3 
331676 
†- Underline indicates no-observed-adverse-effect level (NOAEL) 
Specifically, study15-KE-056 investigated the toxicity of a single intravenous administration of 
ISU304 in mice. There were no deaths or clinically significant findings caused by study treatment. 
The results indicated that the maximum tolerated dose was above 10 mg/kg (54,000 IU/kg) for a 
single intravenous dose of ISU304 administered to mice. 
Studies 2470-007 and 2470-008 estimated maximum tolerated doses in rats and monkeys respectively, 
by administrating repeated weekly intravenous doses of ISU304 over two weeks. For both studies, 
there were no deaths or clinically significant findings caused by study treatment. The results indicated 
that the maximum tolerated doses were above 3.0 mg/kg (15,100 IU/kg) for repeated intravenous 
administrations of ISU304 to rats and monkeys. 
Additionally, studies 2470-002 and 2470-003 were repeated dose toxicity studies with intravenous 
doses of ISU304 administered twice a week over 4 weeks to rats and monkeys respectively. For both 
studies, there were no deaths or clinically significant findings caused by study treatment. The results 
indicated that the maximum tolerated doses were above 3.0 mg/kg (12,900 ~ 15,200 IU/kg) for 
repeated intravenous administrations of ISU304 to rats and monkeys. 
Study 2470-012 administered ISU304 daily to rats for over 2 weeks to test the toxicity of 
subcutaneous administration. There were no deaths or clinically significant findings caused by study 

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treatment. The results indicated that the maximum tolerated dose was above 1.0 mg/kg (4,600 IU/kg) 
for repeated intravenous administration of ISU304 to rats and monkeys. 
Study 31676 examined the thrombogenic risk in rabbits after intravenous administration of ISU304 or 
BeneFIX. Wessler’s stasis model showed that there was no thrombosis across dose levels until 3.0 
mg/kg. ISU304 had shorter activated partial thromboplastin time (aPTT) and longer prothrombin time 
(PT) compared to BeneFIX. The no-observed-adverse-effect-level (NOAEL) was defined as 3.0 
mg/kg (15,100 IU/kg). 
The above results clearly demonstrate the safety of ISU304. The maximum intravenous dose for 
ISU304 in this study has been defined as 75 IU/kg (0.0335 mg/kg), 260 times lower than the 
maximum tolerated dose of 12,900 ~ 15,200 IU/kg (3 mg/kg) verified in the pre-clinical studies. The 
maximum subcutaneous dose for ISU304 is 300 IU/kg, about 12 times lower than the maximum 
tolerated dose of 4,600 IU/kg (1 mg/kg) verified in the pre-clinical studies. Therefore, the ISU304 
administration doses to be used in this clinical study are deemed to be well within the range of safety 
based on the results of preclinical toxicity studies.  
1.2.2 
Results from Pharmacokinetic/Pharmacodynamic Studies 
The pharmacokinetic/pharmacodynamic characteristics of ISU304 were examined in previous studies. 
The table below summarizes the outcomes of these preclinical pharmacokinetic/pharmacodynamic 
studies. 
Type of 
study 
Animal 
species 
Administ
ration 
method 
Dose (mg/kg) 
Results 
Study No. 
Blood 
concentra
tion after 
single 
dose 
Hemophili
c mice 
IV 
 
ISU304: 
0.05, 0.19, 0.75, 
3.0 (250, 1,000, 
4,000, 16,000 
IU/kg) 
 
BeneFIX: 
0.92 (250 IU/kg) 
- Proportionate increases in Cmax and AUC to 
increases in ISU304 dose. 
- Similar pharmacokinetic parameters to 
antigens (t1/2, Cmax, C0, AUC0-t, AUC0-inf, 
MRT) when ISU304 and BeneFIX with 
similar amounts of protein are 
administered. 
15-KE-190 
Hemophil
ic mice 
IV 
 
ISU304: 
0.01 (75 IU/kg) 
 
BeneFIX: 
0.28 (75 IU/kg) 
- Similar pharmacokinetic profiles (Cmax, 
MRT, t1/2) and systemic exposure (< 2 fold 
difference) to ISU304 and BeneFIX 
activity when identical activated doses (75 
IU/dL) are administered. 
- The high specific activity of ISU304 causes 
significantly lower exposure in terms of 
antigens compared to BeneFIX. 
17-KE-036 

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Type of 
study 
Animal 
species 
Administ
ration 
method 
Dose (mg/kg) 
Results 
Study No. 
Normal 
mice 
SC  
IV 
 
ISU304, SC: 
0.02, 0.05, 0.15 
(90, 
230, 
690 
IU/kg) 
 
ISU304, IV: 
0.05 (230 IU/kg) 
 
BeneFIX, SC: 
0.15 (42 IU/kg) 
- Increased half-life of ISU304, decreased 
Cmax in subcutaneous administration 
compared to intravenous. 
- BA of ISU304 (17 ~ 22%) and BeneFIX 
(16%) are similar. 
16-KE-091 
Monkeys 
IV 
 
ISU304, IV: 
0, 0.3, 1.0, 3.0 
(0, 1,510, 5,032, 
15,096 IU/kg) 
- Cmax and AUC increased along with an 
increase in intravenous ISU304 dose to 
monkeys. 
- Pharmacokinetic parameter comparison 
between groups difficult, due to 
quantitative restrictions. 
2470-009 
Rats 
IV 
 
ISU304, IV: 
0, 0.3, 1.0, 3.0 
(1,510, 5,032, 
15,096 IU/kg) 
- Cmax and AUC0-t increased in proportion to 
the intravenously administered ISU304 
dose. 
- Half-life of ISU304 in rats is 22 ~ 26 h. 
2470-010 
Hemophili
c mice 
SC 
 
ISU304, SC: 
0.02, 0.05, 0.15 
(90, 
230, 
690 
IU/kg) 
- When ISU304 is subcutaneously injected in 
escalating doses, the plasma concentration 
and activity of ISU304 increased in 
proportion. 
- The in-plasma levels of ISU304 antigen 
and activity measured after subcutaneous 
administration are linearly proportional to 
each other. 
16-KE-091 
Minipigs 
SC  
IV 
 
ISU304 SC: 
0.05, 0.15 (230, 
690 IU/kg) 
 
ISU304 IV (230 
IU/kg) 
 
BeneFIX SC: 
0.15 (42 IU/kg) 
- Similar pharmacokinetic profiles between 
subcutaneously administered ISU304 and 
BeneFIX. 
- Bioavailability of subcutaneously 
administered ISU304 and BeneFIX is 30 ~ 
35%. 
- Cmax is 6.6 ~ 10.8% lower in subcutaneous 
administration compared to intravenous 
administration.  
- Half-life of ISU304 (27 ~ 30 h) is longer 
than dose interval (24 h) in subcutaneous 
administration, leading to accumulation in 
plasma when administered repeatedly.  
16-KE-135 
Hemophili
c dogs 
SC  
IV 
 
ISU304, IV: 
50 IU/kg  
 
ISU304, SC: 
42, 72, 125, 143 
IU/kg 
- Bioavailability of subcutaneously 
administered ISU304 is approximately 
14%. 
- Bioavailability of subcutaneously 
administered ISU304 and BeneFIX is 30 ~ 
35%. 
- Cmax is 6.6 ~ 10.8% lower in subcutaneous 
administration compared to intravenous 
administration. 
Internally 
managed 

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Type of 
study 
Animal 
species 
Administ
ration 
method 
Dose (mg/kg) 
Results 
Study No. 
Blood  
concentra
tion 
 after  
repeated 
doses 
Hemophili
c  
mice 
IV 
 
ISU304: 
0.94 (5,000 
IU/kg) 
 
1 dose/week for 3 
weeks 
- When ISU304 was administered once a 
week for 3 weeks in 5,000 IU/kg (0.92 
mg/kg) doses, accumulation was not 
observed. 
- Plasma antigen and activity levels of 
ISU304 are linearly proportional to each 
other. 
15-KE-194 
Hemophili
c mice 
SC 
 
ISU, SC: 
0.05 (230 IU/kg) 
 
Once daily for 4 
days 
- Insignificant tendency towards 
accumulation when ISU304 is 
subcutaneously administered every day. 
16-KE-091 
Minipigs 
SC 
 
ISU304, SC 
0.1 (460 IU/kg) 
 
Once daily for 6 
days 
- Half-life of ISU304 (27 ~ 30 h) is longer 
than dose interval (24 h) in subcutaneous 
administration, leading to accumulation in 
plasma when administered repeatedly. 
16-KE-135 
Hemophili
c dogs 
SC 
 
ISU304, SC 
300 IU/kg 
 
Once daily for 6 
days 
- Half-life of ISU304 (> 50 h) is longer than 
dose interval (24 h) in subcutaneous 
administration, leading to accumulation in 
plasma when administered in repeated 
daily doses. 
Internally 
managed 
* AUC: area under curve, IV: intravenous, SC: subcutaneous 
In study 15-KE-190, mice with FIX deficiency (hemophilic mice) were administered with single 
doses of ISU304, BeneFIX, or Alprolix. The results indicated that Cmax and area under curve (AUC) 
proportionally increased as administered dose increased, but half-life was relatively consistent across 
dose levels, with a range of 19.3 to 23.4 hours. ISU304 and BeneFIX had similar half-lives while the 
half-life of Alprolix was about double the length of ISU304 and BeneFIX. Identical intravenous active 
doses (250 IU/kg) of ISU304 and BeneFIX showed similar pharmacokinetic profiles (AUC, t1/2, MRT, 
Cl, AUMC, Vz). 
Study 16-KE-036 administered single intravenous ISU304 and BeneFIX doses to hemophilic mice 
according to the dose to be administered in the clinical study (75 IU/kg) and analyzed their 
pharmacokinetic characteristics. The two drugs showed similar pharmacokinetic profiles in terms of 
FIX activity (Cmax, AUC, MRT, t1/2). The Cmax and AUC of FIX antigen differed between the two 
substances due to the difference in administered antigen volume, but the half-lives and MRT were 
similar. Study 15-KE-194 administered ISU304 in 3 repeated intravenous weekly doses to FIX 
deficient mice. The results showed that Cmax, AUC, and half-life were consistent across periods, which 
meant ISU304 was not accumulated in mice.  

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Studies 2470-009 and 2470-010 investigated pharmacokinetics of FIX following a single intravenous 
administration of ISU304 in monkeys and rats, respectively. The results showed pharmacokinetic 
characteristics across species. 
The recent studies of 16-KE-091 and 16-KE-135 analyzed pharmacokinetic characteristics of 
subcutaneously administered ISU304 in mice. While the subcutaneous administration of BeneFIX 
showed 16% bioavailability in mice and 30% bioavailability in minipigs, the subcutaneous 
administration of ISU304 showed 19 ~ 22% bioavailability in mice and 30 ~ 35% bioavailability in 
minipigs. When identical doses of ISU304 were administered to minipigs subcutaneously and 
intravenously, Cmax was approximately 7 ~ 11% lower in subcutaneous administration compared to 
intravenous administration but half-life was about 2.6 times longer. When 690 IU/kg (0.15 mg/kg) of 
ISU304 was subcutaneously administered to minipigs, Cmax was 141 ng/mL, which translates to 49% 
(49 IU/dL) in terms of activity. Supposing that subcutaneously injected ISU304 has similar Cmax in 
humans and minipigs, a single dose up to 690 IU/kg is expected to produce a FIX activity level below 
the range of normal individuals (50 ~ 150%). 
1.2.3 
Rationale for Dose Determination 
This phase 1 clinical study has been planned to investigate the safety, pharmacokinetics and 
pharmacodynamics of intravenously and subcutaneously administered ISU304 in previously treated 
hemophilia B patients. The initial dose and dose escalation plan has been determined according to the 
results of the toxicity studies after intravenous administration in rats and monkeys, the toxicity studies 
after subcutaneous administration in rats, the pharmacokinetic tests after subcutaneous and 
intravenous administration of ISU304 and BeneFIX in hemophilic mice and minipigs, as well as the 
results of pharmacokinetic studies after intravenous and subcutaneous administrations of FIX as 
reported in the existing literature.  
1) Single intravenous administration 
The initial intravenous dose of ISU304 has been set as 75 IU/kg(approximately 0.015 mg/kg) while 
the post-administration blood collection period has been set as 3 days (72 hours). The initial dose of 
75 IU/kg for ISU304 is identical to the clinical study dose of BeneFIX, a currently marketed 
hemophilia B treatment product. The blood sample collection period for PK measurements is also 
identical to that in the same study (Lambert et al., 2007). The dose is also approximately 200 times 
lower than the NOAEL identified in the preclinical toxicity study for intravenous administration (3 
mg/kg/dose (approximately 13,000 ~ 15,000 IU/kg)).  

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In the result of a pharmacokinetic study, that was carried out after intravenous administration of the 
same dose (75 IU/kg and 250 IU/kg) of ISU304 and BeneFIX in hemophilic mice, similar 
pharmacokinetic profiles between the two substances were confirmed (Fig. 1.1 (A)). 
In the EMA approval assessment report for Rixubis (EMEA/H/C/003771/0000), a biosimilar product 
of BeneFIX, the result of comparative PK in hemophilic mice and monkeys in the non-clinical study 
showed a similarity in their PK profiles. The similar PK profiles between two products were also 
confirmed in humans through comparative PK clinical studies.  
Considering the results of the above tests and non-clinical/clinical studies of similar products, it is 
deemed that similar PK profiles in animal testing predict similar PK profiles in humans as well. 
Therefore, since ISU304 and BeneFIX show similar PK profiles in animals, it may be predicted that 
they will show similar PK profiles in humans as well. Consolidating all results, it is expected that the 
intravenous administration of ISU304 (75 IU/kg) will show a PK profile similar to BeneFIX. This 
dose concentration is deemed to be safe as it falls within the approved range for BeneFIX (50 ~ 100 
IU/kg) (Product Monograph for BeneFIX, 2012) and the normal range for humans (50 ~ 150 IU/dL). 
 
Fig 1.1 The time-concentration curves of FIX in hemophilic mice and hemophilia patients 
(A) The comparison of PK between ISU304 and BeneFIX in hemophilic mice, (B) The plasma 
concentration-time profile of 75 IU/kg rFIX (BeneFIX) intravenously administered to hemophilia patients  
(Lambert et al., 2009) 
According to the clinical study data for BeneFIX reported in the above literature (Fig. 1.1 (B)), when 
75 IU/kg of FIX is intravenously administered, Cmax is approximately 55 IU/dL while AUC0-72h is 
851±215 IU/dL*h, and blood concentration falls to 2.5 IU/dL 72 hours after administration (Fig 
1.1(B): Lambert et al., 2009).  
Blood concentration is expected to drop to 1 ~ 2%, 72 ~ 96 hours after a 75 IU/kg dose of ISU304 in 
this clinical study as well, similarly to BeneFIX. Thus, the blood collection period of 72 hours is 
deemed to be appropriate considering the subject’s safety (Product Monograph for BeneFIX, 2012). 

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2) 
Single subcutaneous administration 
As there is no commercially available rFIX protein product developed for subcutaneous 
administration, the initial subcutaneous doses in this clinical study have been set as 75, 150, and 300 
IU/kg, based on animal testing results (on normal mice, hemophilic mice, hemophilic dogs and 
minipigs, etc.) obtained in the course of the development of ISU304, as well as results reported from a 
study on subcutaneous administration of FIX on humans.  
The aspects of NOAEL, AUC and Cmax have been considered in the initial doses and adminis
tration periods planned in this study, andthe rationale for determination of the initial subcutan
eous injection dose could be obtained as shown in . 
Table 1.1. 
Table 1.1 The rationale for Determination of Initial Subcutaneous Injection Dose 
Administration 
Route 
Data  
Species 
NOAEL 
AUC 
Cmax 
Dose 
Relative 
value 
IU/dL*h 
Relative 
value 
IU/dL 
Relative 
value 
mg/kg 
IU/kg 
IV 
Injection 
Toxicokinetics 
Monkeys 
3 
14,826 
198 
1,164,928 
1,369 
56,882 
1,034 
Rats 
3 
12,915 
172 
129,581 
152 
20,061 
364 
Clinical 
Design1) 
Humans 
0.01 
75 
1 
851 
1.0 
55 
1.0 
SC 
Injection 
Toxicokinetics 
Rats 
1 
4,305 
57 
9332) 
1.5 
49 
0.9 
Clinical 
Design3) 
Humans 
0.01 
75 
1 
2633) 
0.3 
5.1 
0.1 
0.03 
150 
2 
5263) 
0.6 
10.2 
0.2 
0.05 
300 
4 
1,0523) 
1.2 
20.4 
0.4 
Note 1. Estimated value based on literature (Lambert et al., 2007) 
Note 2. AUC0-24 hr 
Note 3. Assumption of PK parameters of ISU304 75 IU/kg administered subcutaneously to humans: Cmax 5.1 
IU/dL, Tmax: 8 h, t1/2: 33.8 h, Bioavailability(BA): 31%, The plasma drug concentration decreases exponentially 
from Cmax. 
 
The initial subcutaneous administration dose of ISU304 has been set as 75 IU/kg (approximately 
0.015 mg/kg). This is about 60 times lower than the subcutaneous NOAEL (1 mg/kg/dose, 4,305 
IU/kg) and 200 times lower than the intravenous NOAEL (3 mg/kg/dose, 12,915 ~ 14,826 IU/kg) 
determined in preclinical toxicity studies.  
AUC, which indicates systemic exposure and Cmax, which indicates the toxicity of initial exposure 
were also reflected in the initial subcutaneous administration dose. The expected AUC value for a 
subcutaneous 75 IU/kg dose was 263 IU/dL*h (supposing about 30% of AUC compared to 
intravenous), which was 150 times and 5 times lower than the systemic exposure in rats from 

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intravenous and subcutaneous administrations respectively (AUC in intravenous administration: 
129,581 IU/dL; AUC in subcutaneous administration: 933 IU/dL*h), as determined in a preclinical 
toxicity study. The expected Cmax value for a subcutaneous 75 IU/kg dose (5.1 IU/kg: supposed to be 
9% of Cmax value for intravenous administration) was 3,900 times and 10 times lower than Cmax value 
for intravenous and subcutaneous NOAEL doses respectively (Cmax in intravenous dose: 20,061 
IU/dL; Cmax in subcutaneous dose: 49 IU/dL). 
In terms of NOAEL, AUC, and Cmax, the initial subcutaneous administration dose of 75 IU/kg is 
deemed to be within a safe range. In the actual clinical study, the dose will be doubled, after checking 
the safety of the earlier dose, to a maximum dose of 150 IU/kg as part of dose escalation study. At the 
end of the study on each dose, the Data safety Monitoring Committee will evaluate the safety before 
proceeding to the next planned dose.  
Safety in terms of NOAEL 
The rationale for the safety of a subcutaneous administration of ISU304 (75 IU/kg) was obtained 
through a preclinical toxicity study. In terms of dose, 75 IU/kg is approximately 170 ~ 200 times 
lower than the NOAEL for intravenous administration (on rats and monkeys, 3 mg/kg/dose (12,915 ~ 
14,826 IU/kg/dose)) and approximately 60 times lower than the NOAEL for subcutaneous 
administration (on rats, 1 mg/kg/dose (4,305 IU/kg/dose)) determined in preclinical toxicity studies. 
The exposure dose after subcutaneous administration in humans is expected to be 263 IU/dL*h (about 
30% of bioavailability), which is about 4,400 times (against monkeys) and 490 times (against rats) 
lower than the exposure dose confirmed in intravenous administration toxicity studies (1,164,928 
IU/dL*hr in monkeys and 129,581 IU/dL*hr in rats). Therefore, it was judged that the safety against 
the exposure was confirmed in a sufficiently wide range. 
Safety in terms of AUC 
The bioavailability of subcutaneously administered ISU304 in preclinical studies was 30% or lower 
(hemophilic dog: 9%, normal mouse: 20%, minipig: 32%) compared to bioavailability in intravenous 
administration (100%). Furthermore, the bioavailability reported in a PK test for subcutaneous FIX 
administration on 1 hemophilia patient was also 33% (Lilies et al., 1997). The results of these 
preclinical and clinical studies were reflected in the initial subcutaneous administration dose. 
As the exposure to the drug is lower for subcutaneous administration compared to intravenous, the 
initial dose of 75 IU/kg, which is used in intravenous administration, is deemed appropriate for the 
initial subcutaneous dose. When the PK parameters of ISU304 administered subcutaneously were 

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assumed (Cmax 5.1 IU/dL, Tmax: 8 h, t1/2: 33.8 h, The plasma drug concentration decreases 
exponentially from Cmax.) based on the preclinical and clinical results discussed earlier, the AUC was 
263 IU/dL*h, that is 31% bioavailability. This level of exposure is 90 times and 3.5 times lower than 
the systemic exposure from intravenous and subcutaneous NOAEL doses respectively (AUC in 
intravenous administration: 129,581 IU/dL*h; AUC in subcutaneous administration: 933 IU/dL*h) in 
a  toxicity study in rats, it was considered that the safety was sufficiently secured. 
Safety in terms of Cmax 
The blood concentration of FIX in normal individuals is within the 50 ~ 150 IU/dL range. As a 
correlation between high FIX concentration and deep vein thrombosis has been reported, this study 
aims to stay within the normal range for maximum blood concentration (Cmax) of ISU304 (Lowe et al., 
2001). As determined in preclinical animal PK studies, since Cmax(CmaxSC/CmaxIV x 100%) in a 
subcutaneous administration is about 2 ~ 9% lower than  Cmax in an intravenous administration, it is 
considered safe to administer higher doses compared to the doses in intravenous administration (Table 
1.2). The highest Cmax was observed in minipigs known to be similar to human skin. As this was 9.3% 
against the Cmax in intravenous administration, this was used to predict the Cmax in subcutaneous 
administration of ISU304. Since the Cmax in intravenous administration of ISU304 is estimated to be 
55 IU/dL, similar to the one of BeneFix, the Cmax in subcutaneous administration is expected to be 5.1 
IU/dL (55 IU/dL x 93%) (Table 1.2). This shows a similar level to the Cmax value (4.8 IU/kg) in 
administration of 7.5 IU/kg estimated from the Cmax value, measured in a hemophilia patient after 
subcutaneous administration of plasma-derived FXI according to the literature (Lilies et al., 1997). In 
addition, since it is at least about 10  to 10,000 times lower than the Cmax values in the NOAEL 
determined in preclinical toxicity studies (repeated IV dose toxicity study in monkeys: 56,882 IU/dL; 
repeated IV dose toxicity study in rats: 20,061 IU/dL; repeated SC dose toxicity study in rats: 49 
IU/dL), it was deemed that the safety was sufficiently secured in terms of Cmax. 
Determination of blood sample collection period for PK analysis 
The determination of the blood sample collection period for PK analysis after subcutaneous 
administration is not only important for PK analysis but also for subject safety. A longer blood 
collection period is advantageous for understanding PK, but a lowered blood concentration of FIX (< 
1 IU/dL) increases the risk of bleeding. On the other hand, observation over a sufficient period of time 
after administration is necessary for the PK analysis of this product. Therefore, an appropriate time 
period which is both sufficient for PK analysis and subject safety has to be determined. For this, we 
referred to preclinical pharmacokinetic data for ISU304 in subcutaneous administration.  

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In order to determine the blood collection period after subcutaneous injection, key PK parameters 
(Tmax, Cmax, t1/2) were assumed and the blood concentration of the investigational product over time 
was predicted. 
The estimated pharmacokinetic parameters after subcutaneous administration of ISU304 in humans 
are assumed based on the results of non-clinical pharmacokinetic studies on ISU304 (in a minipig, 
type B hemophilic dog, hemophilic mouse, and normal mouse), the result of the clinical study on FIX 
subcutaneously administered to a hemophilia patient (Lilies et al., 1997), the result of clinical study 
on recombinant FIX administered intravenously (Lambert et al., 2007; Product monograph for 
BeneFIX, 2012) (Table 1.2). When the same dose (75 IU/kg) of ISU304 and BeneFIX were 
administered to hemophilia mice, it showed a similar level of Cmax (ISU304: 22.4 IU/dL; BeneFIX: 
22.7 IU/kg) and half-life (ISU304: 12.9 h; BeneFIX: 11.2 h). Based on this preclinical 
pharmacokinetic study, it was expected that the administration of the similar dose of ISU304 and 
BeneFIX in hemophilia patients would show similar Cmax and half-life (t1/2). Cmax and half-life of 
BeneFIX administered to type B hemophilia patients are known to be 55 IU/dL and 18.8 hours, 
respectively (Lambert et al., 2007; Monograph for BeneFIX, 2012). Therefore, the Cmax of ISU304 
administered intravenously (75 IU/kg) was set based on the Cmax (55 IU/dL) of BeneFix administered 
intravenously. 
When a drug is administered subcutaneously, the plasma concentration of the drug is affected by the 
distribution rate from subcutaneous tissue to blood and the elimination rate from plasma. Due to the 
differences in structural and physiological characteristics of subcutaneous tissues between humans 
and animals, there are limitations in predicting pharmacokinetics of subcutaneous administration to 
humans based on the results from non-clinical studies. Despite the limitations, the subcutaneous 
tissues of a pig/mini-pig are more similar to the ones in humans than other animals, therefore, it was 
suggested that they are more suitable for subcutaneous test for the biological products (Rose et al., 
1977; Richter et al., 2012; Zheng Y et al., 2012). The drug distribution rate depends on the structure of 
the subcutaneous tissue, which affects the drug distribution patterns (Richter et al., 2012). Thus, the 
distribution patterns of biological drug administered subcutaneously in pigs and minipigs will be more 
similar to the ones in humans, when compared to the ones in rodents. The Cmax value after 
subcutaneous administration was assumed in order to model pharmacokinetics of subcutaneous 
administration and the Cmax value after subcutaneous administration in a minipig, in which the rate of 
drug distribution from veins to subcutaneous tissues is considered similar to one in humans due to the 
structural similarity in subcutaneous tissues, was used as a reference. Cmax after subcutaneous 
administration in minipig was 9.3% of Cmax after intravenous administration. Based on this, the Cmax 

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value after subcutaneous administration of ISU304 in a human was estimated to be 5.1 IU/dL (CmaxIV 
x 9.3%=55 IU/dL x 9.3%). 
Table 1.2 Estimated Cmax, t1/2, Tmax and AUC after single IV/SC administration of ISU304 75 IU/kg 
Dose 
75 IU/kg1) 
Cmax 
(IU/dL) 
t1/2 
(h) 
Tmax 
(h) 
AUC 
(IU/dL*h) 
CmaxIV CmaxSC 
IV vs 
SC 
Cmax 
(%) 
t1/2IV 
t1/2SC 
IV vs 
SC t1/2 
Ratio 
(fold) 
TmaxSC AUCIV AUCSC 
BA 
(%) 
ISU304: Human (estimated)2) 
55 
5.1 
9.3 
18.8 
33.8 
1.8 
8 
851 
263 
31 
BeneFIX: Human3) 
55 
ND 
ND 
18.8 
ND 
ND 
ND 
851 
ND 
ND 
pdFIX: Human4) 
ND 
4.3 
ND 
ND 
ND 
ND 
8 
ND 
ND 
33 
ISU304: Minipig5) 
56 
5.2 
9.3 
11.2 
28.1 
2.5 
6 - 8 
555 
180 
32 
ISU304: Type B hemophilic 
dog6) 
99 
2.8 
2.8 
51.2 135.4 
2.6 
48 ~ 72 3,818 
360 
9 
ISU304: Hemophilic mouse 7) 
22 
0.9 
4.0 
12.3 
ND 
ND 
6 - 24 
229 
ND 
ND 
ISU304: Normal mouse 8) 
20 
1.1 
5.6 
9.6 
17.5 
1.8 
8 
191 
38 
20 
* Non-clinical results used to predict pharmacokinetic parameters in humans are shown in gray cells. 
1) PK parameters were calculated proportionally, assuming that a FIX product was administered at a dose of 75 IU/kg. 
2) Estimated PK parameters of ISU304 in human 
3) Lambert et al., 2007, Monograph for BeneFIX, 2012; 
4) Liles et al., 1997 
5-8) Result of non-clinical PK study on ISU304 
 
When a drug is administered subcutaneously, subcutaneous tissues play a role as a drug reservoir that 
gradually releases the drug to plasma. This results in a different pharmacokinetic profile from 
intravenous administration and a big difference in a half-life. Since the drug enters blood from 
subcutaneous tissues and at the same time the drug degradation occurs in blood, it shows the same 
aspect like the half-life of the drug is increased. In a non-clinical study on subcutaneous injection, the 
half-life in groups of subcutaneous administration was increased by 1.8 ~ 2.6 times (normal mouse: 
1.8 times; mini-pig: 2.5 times; type B hemophilic dog: 2.6 times) depending on the animal species, 
compared to the groups of intravenous administration. Since the increase in half-life varies by animal 
species, to apply the value directly to the estimation of increase in half-life in humans. However, 
considering the safety of clinical study, the half-life (t1/2) was calculated with an assumption of the 
minimum increase in the half-life (1.8 times) (t1/2SC = t1/2IV x 1.8). It was also assumed that the drug 
administered subcutaneously decreased exponentially from the Cmax. Bioavailability calculated after 
subcutaneous administration based on this assumption was 31%, similar to the bioavailability (33%) 
of pdFIX administered subcutaneously in humans. . 

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The drug concentration-time graph obtained with these assumptions is presented in Fig 1.2. Cmax was 
approximately 5 IU/kg for Cohort 2, which is planned to receive a subcutaneous administration of 75 
IU/kg of ISU304, and the plasma activity was predicted to drop to 1 IU/dL after about 3 days (88 
hours). Therefore, the blood collection period for Cohort 2 was set as 3 days. Although changes in 
drug concentration should be tracked for duration about 3 times the half-life (120 hours or 5 days) in 
PK analysis, the blood collection period was set as 3 days to ensure safety. At initial stage of study 
protocol development, single administration of ISU304 300 IU/kg was considered for Cohort 4 with 
the below rationale (After conducting Cohort 1 to Cohort 3, Cohort 4 was deleted based on PK/PD 
results and dose of Cohort 5 was changed to ISU304 150 IU/kg). Cmax for Cohort 3 and Cohort 4 
which will receive subcutaneous ISU304 doses of 150 IU/kg and 300 IU/kg each, was 10 IU/kg and 
20IU/dL respectively. Time taken before plasma activity fell to 1 IU/dL was 124 hours (5 days) and 
156 hours (6 days) respectively. The blood collection periods for these two cohorts are identical at 5 
days, in order to allow comparison between the groups. As the blood collection period (120 hours) is 
longer than 3 times the expected half-life (34 hours), this length is deemed to be appropriate for PK 
analysis as well. Even at the highest dose of 300 IU/kg, Cmax is below the range of normal individuals, 
thus it was deemed to be appropriate in terms of safety as well. 
 
Fig 1.2 Time-FIX concentration graphs by subcutaneous administration dose.  
(A) Linear scale, (B) Log scale. 
When doses are 75, 150, and 300 IU/kg, time taken for plasma FIX concentration to fall to 1 IU/dL is 88, 124, 
and 126 hours respectively. 
 
3) Repeated subcutaneous administration 
In the preclinical pharmacokinetic study on repeated administration, the drug concentration in plasma 
was increased due to the drug accumulated in plasma when it was administered 6 times daily. 
Accumulation ratio calculated using the increase in trough levels (Accumulation ratio = 1st dose 

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trough level/last dose trough level) was 2.5 times and 13.6 times in minipig and type B hemophilic 
dog, respectively (Table 1.3). The longer the half-life was, the greater the accumulation ratio was. 
 
 
Table 1.3 Estimated accumulation ratios after repeated SC administration of ISU304 75 IU/kg in 
human/animal model 
75 IU/kg1) 
t1/2SC 
1st dose 
trough 
6th dose 
trough 
Accumulation 
Ratio (fold)2) 
ISU304: Human (estimated)3) 
33.8 
3.7 
9.0 
2.4 
ISU304: Minipig 4) 
28.1 
3.6 
9.2 
2.5 
ISU304: type B hemophilic dog 5) 
135.4 
0.9 
11.9 
13.6 
1) PK parameters were calculated proportionally assuming the FIX administration at a dose of 75 IU/kg. 
2) Accumulation ratio = 1st dose trough/last dose trough 
3) Estimated value of ISU304 in human 
4-5) Values calculated based on the results of non-clinical studies on repeated administration 
 
Using the results from single dose simulations for ISU304, changes in blood concentration of ISU304 
from daily subcutaneous administration doses of 75, 150, and 300 IU/kg (single subcutaneous doses 
administered to Cohorts 2 ~ 4) over 6 days have been simulated (Fig 1.3 and Table 1.4). The 
accumulation ratio was estimated to be 2.4 times greater when the drug was administered repeatedly 6 
times a day. 
 
Fig 1.3 Time-FIX concentration graph by dose in repeated subcutaneous administration over 6 days 
Cmax (300 IU/kg: 241 IU/dL; 150 IU/kg: 20 IU/dL; 75 IU/kg: 10 IU/dL) for each dose level presented. 

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Looking at the results of repeated single subcutaneous doses of 75, 150, and 300 IU/kg over 6 days, 
the activity concentration in plasma increased daily and Cmax on day 6 is predicted to be 10, 20, and 41 
IU/dL respectively, which falls below the normal range of FIX blood concentration (normal clotting 
FIX concentration in humans: 50 ~ 150 IU/dL). Based on this, the maximum repeated dose was set as 
300 IU/kg. Exposure to the substance over 6 repeated daily subcutaneous administrations in terms of 
expected AUC and Cmax is several hundred times (182 ~ 727 times) or several thousand times (3,161 ~ 
12,958 times) lower than for a single intravenous infusion to monkeys, thus ensuring a sufficient 
margin of safety in systemic exposure. 
Table 1.4 Safety margin simulation for repeated subcutaneous doses 
Simulation 
ISU304 (6 repeated daily SC injections) 
75 IU/kg 
150 IU/kg 
300 IU/kg 
AUC0-312h 
(IU/dL*h) 
1,604 
3,208 
6,416 
Tmax 
128 
128 
128 
Cmax 
10 
20 
41 
Margin of safety1 
(Ratio, AUC) 
726 
363 
182 
Margin of safety2 
(Ratio, Cmax) 
12,958 
6,479 
3,161 
Time for drug 
concentration to 
decrease ≤ 1 IU/dL 
88 hr 
(3 day) 
124 hr 
(5 day) 
156 hr 
(6 day) 
Note 1. Margin of safety ratio calculations based on value from single IV dose toxicity study on monkeys (1,164,928 
IU/dL*hr) 
Note 2. Margin of safety ratio calculations based on value from single IV dose toxicity study on monkeys 
(129,581 IU/dL*hr) 
 
1.2.4 
Benefit-Risk Assessment 
Based on clinical studies and post-marketing experience of the active control (i.e., BeneFIX), the most 
serious adverse events are systemic hypersensitivity reactions, including bronchospastic reactions 
and/or hypotension, anaphylaxis, and the development of high-titer inhibitors necessitating alternative 
treatments to FIX replacement therapy. Among these, patients with known hypersensitivity, allergy, or 
anaphylaxis to any FIX product, or patients with inhibitor or family history of inhibitor will be 
excluded from this clinical study by evaluating exclusion criteria. Additional tests will be conducted 
in a post-study safety visit 2 weeks (+1 week) after cohort termination to check for inhibitor 
development in subjects.  

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Looking at preclinical toxicity animal studies, No AE to the administered product was observed in 
single intravenous (maximum 10 mg/kg (54,000 IU/kg)), repeated intravenous (maximum 3 mg/kg 
(12,915 ~ 14,826 IU/kg)), and repeated subcutaneous administrations (maximum 1 mg/kg (4,305 
IU/kg)). Therefore, the intravenous injection (75 IU/kg) and subcutaneous injection doses (75, 150, 
300 IU/kg) planned in this study is deemed to be relatively safe, considering preclinical data.  
Although prophylaxis therapy has been reported to improve patient prognosis in hemophilia B, the 
ratio of hemophilia B patients who receive continued prophylaxis therapy is not high. As 
subcutaneous injections offer patients increased convenience and ease in self-administration compared 
to intravenous, it is expected to allow many patients to use FIX products in continuous prophylaxis 
therapy. In particular, it is expected to contribute greatly to pediatric treatment.  
All things considered, the benefit of treatment in this clinical study is expected to exceed the risk. 
1.3 
Objective 
To investigate the safety, pharmacokinetics and pharmacodynamics of ISU304 (recombinant FIX with 
increased activity) in previously treated hemophilia B patients. 

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2 
Investigational Products and Other Drugs in the Study 
2.1 
Investigational Products 
2.1.1 
Study Drug 
 
Name: ISU304 
 
Active ingredient: recombinant factor IX (rFIX) with increased activity 
 
Volume: 2.0 mg/vial 
 
Formulation: 208 mM Glycine, 25 mM Sucrose, 40 mM NaCl, 8 mM L-Histidine, 0.004% Tween 
80, pH 6.8, lyophilized injection in a glass vial 
 
Storage condition/shelf life: 2 ~ 8℃/approximately 24 months 
 
Expected indications: Control and prevention of bleeding episodes, and peri-operative 
management in patients with hemophilia B 
 
Dosage and administration:  
ISU304 is administered intravenously or subcutaneously by dissolving a lyophilized powder in an 
injectable formulation. The investigational product dose will be determined according to 
individual needs, and calculated using the formula below.  
Required FIX quantity (IU) 
= 
Weight (kg) 
× 
desired FIX increase (IU/kg) in cohort 
Intravenous bolus injection 
Intravenous administration should be conducted by bolus injection. The investigator should observe to 
see whether any suspected adverse events (including hypersensitivity) with possible relation to the 
administration occurs. 
 
Subcutaneous bolus injection 
 
<Administration site> 
When administering a 1 ~ 2 mL volume, it is best 
to use a syringe and needle. The thinner the 
needle, the better: 28 gauge and 6 mm is 
recommended. When the volume exceeds 2 mL, a 
smaller gauge (thicker needle) and slightly longer 
needle (8 mm) can be used to minimize injection 
time. 

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2.1.2 
Active Control 
 
Name: BeneFIX 
 
Active ingredient: recombinant factor IX (rFIX)  
 
Volume: 1,000 IU/mL 
 
Formulation: 0.234% NaCl, 8 mM L-histidine, 0.8% Sucrose, 208 mM Glycine, 0.004% 
Polysorbate 80, lyophilized injection in a glass vial 
 
Storage condition/shelf life: below 30℃ (do not freeze)/2 years 
 
Therapeutic indications: Control and prevention of bleeding episodes, and peri-operative 
management in patients with hemophilia B 
 
Dosage and administration: refer to intravenous administration of study drug 
2.1.3 
Expected Adverse Events Related to the Investigational Product 
Based on clinical studies and post-marketing experience of the active control (i.e., BeneFIX), the most 
serious adverse events are systemic hypersensitivity reactions, including bronchospastic reactions 
and/or hypotension and anaphylaxis, and the development of high-titer inhibitors necessitating 
alternative treatments to FIX replacement therapy. 
In detail, the most common adverse events observed in clinical studies (> 5%) were headaches, 
dizziness, nausea, injection site reaction, injection site pain, and skin-related hypersensitivity reactions 
(e.g., rash, hives). Also, the following post-marketing adverse events have been reported: inadequate 
FIX recovery, inadequate therapeutic response, inhibitor development, anaphylaxis, angioedema, 
dyspnea, hypotension, and thrombosis.  
Considering the findings from previous studies and the mechanism of study drug, it is expected that 
the study drug will be associated with similar adverse events to the active control. 
2.2 
Investigational Product Management 
2.2.1 
Packaging and Labeling of Investigational Product 
Investigational products shall be manufactured in accordance with good manufacturing practice 
(GMP), and provided to principal investigators and/or sub-investigators who have been delegated 
study related activities by principal investigators. Each of the following items should be presented on 
the packaging of investigational products according to Article 69, paragraph 6 of “Regulation on 
Safety of Medicinal Products, etc. (Ordinance of the Prime Minister No. 1353, 2017.01.04). 

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1. Mark of “For clinical studies” 
2. Code name of product or common name of active ingredient 
3. Serial No. and use-by (expiry) date or retest date 
4. Method of storage 
5. Name and address of a person who receives approval of clinical study protocol 
6. Mark of “Not for any purpose other than clinical study” 
2.2.2 
Handling and Storage of Investigational Products 
 
Investigational products should be stored at required temperature conditions, and used only on 
subjects with prescriptions from the principal investigator and/or sub-investigator. 
 
The sponsor should deliver the investigational products directly to the clinical study pharmacist 
and get a receipt at the study center after discussion with the principal investigator. The 
investigational products should be labeled with “For clinical studies”. 
 
The clinical study pharmacist should ensure that the investigational products are only used in 
clinical studies. 
 
During the clinical study, the sponsor should monitor the supply and storage of investigational 
products, and take appropriate actions when necessary. 
 
When the clinical study is prematurely terminated or completed, or the investigator has failed to 
follow the protocol, unused investigational products should be collected and disposed from the 
study center. The clinical study pharmacist will return the unused investigational products to the 
sponsor and keep receipt. 
2.3 
Rescue Drug 
The rescue drug used in the study will be the treatment currently being administered to the subject for 
hemophilia B. The rescue drug must be recorded in the Case Report Form (CRF). 
2.4 
Concomitant and Prohibited Medications 
2.4.1 
Concomitant Medications 
The following drugs are allowed during the study period. 
1) Drugs deemed necessary by the investigator for the management of underlying diseases or 
adverse events (excluding prohibited medications) 

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All concomitant medications (including any treatment for the subject’s current disease or adverse 
event) taken during the study will be recorded in the CRF in detail: product name (or active 
ingredients), purpose of administration, dose, start/stop date, etc. 
2.4.2 
Prohibited Medications 
The following drugs are prohibited during the study period. 
 
1) Anticoagulant or antiplatelet drugs 
2) Non-steroidal anti-inflammatory drugs (NSAIDs) that could cause platelet dysfunction (with the 
exception of Acetaminophen, within domestic legal limits) 
3) Immunomodulating agents or immunosuppressants such as α-INF or adrenocortical hormones, 
and vaccines  
If a prohibited medication is required for the treatment of the subject during the study, investigator 
should immediately terminate the study of the subject. 

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3 
Study Population 
3.1 
Inclusion Criteria 
In order to participate in this study, an individual must meet all of the following criteria. 
1) Previously treated male patients with moderate or severe hemophilia B (documented FIX activity 
≤ 2% and exposed to any FIX product for ≥ 150 exposure days (estimated) at the time of 
screening) 
2) Patients must be 12 to 65 years old at the time of screening 
3) Patients who have discontinued a previously treated FIX product at least 4 days prior to the 
administration of investigational product 
4) HIV negative, or if HIV positive with a CD4 count > 200 μL (documented < 200 particles/μL or 
≤ 400,000 copies/mL) at the time of screening 
5) Voluntary consent to participate in the study 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria shall be excluded from the study. 
1) Patients with a history or a family history of FIX inhibitors 
2) Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from inhibitor tests) at the 
time of screening 
3) Patients who have a history of thromboembolic events (myocardial infarction, cerebrovascular 
disease, venous thrombosis, etc.) 
4) Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX product or hamster 
protein 
5) Patients receiving treatment with a FIX product or a bypass agent within 4 half-lives for the agent 
used (at least 96 hours) prior to the administration of the investigational product 
6) Patients who have been exposed to long-term (exceeding 14 days) administration of 
immunomodulating agents or immunosuppressants such as α-INF or adrenocortical hormones 
over the past 3 months or who are currently receiving or planning to receive such treatment 
during the study period 
7) Patients who have been administered vaccines during the period of 6 months prior to the 
administration of the investigational product or plan to receive vaccines during the study period 
8) Patients with any other co-existing bleeding disorder (Von Willebrand disease, etc.) 
9) Patients with positive D-dimer results (≥ 0.5 µg/mL) at the time of screening 
10) Patients with platelet counts less than 100,000/μL at the time of screening 

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11) Patients with ALT, AST levels 5 times greater than upper normal limit or total bilirubin, serum 
creatinine levels 2 times greater than upper normal limit at the time of screening 
12) Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive and require medical 
treatment at the time of screening 
13) Patients scheduled for surgery during the study period 
14) Patients participated in another study within 30 days before screening or scheduled to participate 
in any other study during the study period 
3.3 
Planned Number of Subjects 
At least 12 subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled, including subjects participating the study redundantly.  

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4 
Study Method 
4.1 
Study Design 
This study is a phase 1, open-label, multi-center, dose-escalation study to investigate the safety, 
pharmacokinetics and pharmacodynamics of ISU304 in previously treated hemophilia B patients. All 
subjects shall give their written consent before participating in this study and only those who meet all 
of the inclusion criteria and none of the exclusion criteria will be administered the investigational 
products.  
This study is comprised of 5 cohorts. Each cohort will receive an identical intravenous administration 
of 75 IU/kg, with subcutaneous administrations doubling from 75 IU/kg until 150 IU/kg. 
During the study period, a subject may be hospitalized to facilitate the collection of blood samples for 
pharmacokinetic (PK)/pharmacodynamic (PD) analysis. Hospitalization itself will not be considered 
as a serious adverse event if no adverse event occurs. PK/PD analysis and safety assessments will be 
conducted for each cohort. The Data Safety Monitoring Board (DSMB) and Drug Monitoring 
Committee (DMC) will be operated after the end of Cohorts 1 to 4. These committees will monitor 
the PK/PD and safety data from each cohort to determine the continuation of next cohort (Cohorts 2 to 
5), target dose, and blood sampling period for PK/PD (including timing of collection). It was planned 
that additional subjects may be enrolled in all cohorts at the early stage of the clinical study, and 
cohorts may be canceled depending on the results of PK/PD analysis. Since it was confirmed to delete 
Cohort 4 based on the results of Cohort 3 and to determine 150 IU/kg as the dose of ISU304 in 
repeated administration. In addition, based on the results of Cohort 4, Cohort 5 was included which 
administers IV Bolus of ISU304 75 IU/kg followed by daily subcutaneous administration of ISU304 
150 IU/kg for 9 days. The clinical study design is as follows.   

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4.2 
Study Duration 
Approximately 24 months after the protocol approval from the institutional review boards (IRBs) 
4.3 
Indication 
Previously treated hemophilia B patients 
4.4 
Administration of Investigational Products and Follow Up Periods 
 
 
Cohort 1 (n=3) 
: 7 days 
Single intravenous administration of BeneFIX (75 IU/kg) with 72 hours of 
observation, followed by single intravenous administration of ISU304 (75 
IU/kg) with 72 hours of observation 
 
Cohort 2 (n=3) 
: 7 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 (75 
IU/kg) with 72 hours of observation 
 
Cohort 3 (n=3) 
: 9 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 (150 
IU/kg) with 120 hours of observation 
 
 
 
 
Cohort 4 (n=5) 
: 6 days 
Single subcutaneous administration of ISU304 (150 IU/kg) per day for 6 days 
with 144 hours of observation 
* At least 5 Subjects including the subjects from Cohorts 1 ~ 3 are expected to 
participate in Cohort 4. 
 
Cohort 5 
(n=3~5) 
: 15 days 
Single intravenous administration of ISU304 (75 IU/kg) is followed by 
subcutaneous ISU304 (150 IU/kg) administration for 9 days with 312 hours of 
observation 
The baseline for all cohorts will be at the time before the intravenous or subcutaneous administration 
of the investigational products. Additional subjects may be enrolled in all cohorts or cohorts may be 
canceled depending on the results of PK/PD analysis. 14 days are allowed from the first 

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administration of the study drug to the second administration in cohorts 1 to 4 depending on the 
condition of subjects. If bleeding occurs 72 hours after first administration in cohorts 1 to 4 and FIX 
product is administered as a rescue medication, there must be at least of 4 days of wash-out period 
from the last administration of FIX. 
4.5 
Measures to Minimize Bias 
4.5.1 
Subject Identification Codes 
A unique identification code will be assigned to each subject according to the time of signature and 
used in lieu of the subject’s name to protect the subject’s identity. The subject identification code will 
be assigned as follows. 
Screening No.: CX-YY-SZZ (X: Cohort No. (1, 2~), YY:Center No. (01, 02 ~), S: first letter of 
‘Screening’, ZZ: Subject serial No. (01, 02 ~)) 
At the time of screening, a screening No. will be assigned to a subject according to the order of 
signature. 
Registration No.: CX-YY-RZZ (X: Cohort No. (1, 2 ~), Center No. (01, 02 ~), R: first letter of 
‘Registration’, ZZ: Subject serial No. (01, 02 ~)) 
After the final eligibility decision is made based on the inclusion/exclusion criteria, a registration No. 
is assigned to a subject prior to the 1st administration of the investigational product. 
4.5.2 
Blinding 
Not applicable 
4.5.3 
Randomization 
Not applicable 

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5 
Study Procedure 
5.1 
Measurements 
5.1.1 
Informed Consent 
Before participation in this study, a subject will provide written informed consent after receiving a full 
explanation of the study objective and procedure by the investigator. The investigator will then assign 
a unique screening number to the subject. The date of the signing of the informed consent form must 
be recorded in the CRF. 
5.1.2 
Inclusion/Exclusion Criteria 
After written informed consent is obtained, the subject will undergo the screening test. For laboratory 
test conducted for confirmation of inclusion/exclusion criteria, retest is allowed during the screening 
period as judged by the Investigator. If not eligible even after the retest, the subject is not allowed to 
enroll this study. Only subjects who are eligible according to inclusion/exclusion criteria will be 
treated with the investigational products.  
5.1.3 
Demographics 
A subject’s demographic data (i.e., gender, date of birth, age, weight (kg), and height (cm)) will be 
recorded at the time of screening.  
5.1.4 
Hemophilia B Status 
The subject’s detailed information about documentation of the lowest FIX activity, year of diagnosis, 
family history of hemophilia B, history and family history of FIX inhibitors, and previous FIX 
treatment history (drugs administered and administration period) at the time of screening are recorded. 

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5.1.5 
Medical and Medication History 
Subject’s past (within 3 months prior to screening) or current medical history and medication history 
(within 3 months prior to screening, within 6 months for vaccines) will be obtained by interview 
and/or medical records at the time of screening.  
5.1.6 
Physical Examination 
The following system organs are assessed at the time of screening, right before investigational product 
administration, 6 hours after investigational product administration, all planned visits after 
administration, interim visits, and end of a cohort (as there is no interim visit for Cohort 4 and Cohort 
5, this is replaced by the date of the 1st investigational product administration, and all planned visits 
after administration is set to 24 hours after each investigational product administration): 
Skin/extremities, HEENT (head, eye, ear, nose, and throat), chest & lung, abdomen, musculoskeletal 
system, nervous system, and genitourinary system. Also, tolerability of subcutaneous injection 
(excluding Cohort 1), local reactions in administration site, and systemic reactions are assessed after 
administration of investigational products. 
If a clinically significant abnormal finding is observed in the physical examination, it should be 
recorded as current medical history (at the time of screening) or an adverse event (after the 
administration of investigational products) on the CRF. 
5.1.7 
Vital Signs 
The subject’s vital signs (systolic and diastolic blood pressure (mmHg), pulse rate (bpm), respiration 
rate (bpm), and body temperature (℃)) should be measured and recorded at the time of screening, 
right before investigational product administration, 6 hours after investigational product 
administration, all planned visits after administration, interim visits, and end of a cohort (as there is no 
interim visit for Cohort 4 and Cohort 5, this is replaced by the date of the 1st investigational product 
administration, and all planned visits after administration is set to 24 hours after each investigational 
product administration). Blood pressure is measured in a sitting position after resting sufficiently for 
at least 5 minutes. 
If a clinically significant abnormal finding is observed during the examination of vital signs, it should 
be recorded as current medical history (at the time of screening) or an adverse event (after the 
administration of investigational products) on the CRF. 

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5.1.8 
Electrocardiogram 
Electrocardiogram is obtained at the time of screening, 1st day of hospitalization, interim visits, 2nd 
hospitalization, and end of a cohort (as there is no interim visit for Cohort 4 and Cohort 5, this is 
replaced by the date of the 1st investigational product administration). The actual recording date/time, 
PR, QRS, QT, corrected QT intervals, and investigator’s assessment will be recorded in the CRF. 
Results are classified into followings: 1) Normal, 2) Abnormal, not clinically significant, or 3) 
Abnormal, clinically significant. 
If a clinically significant abnormal finding in electrocardiogram (e.g., abnormal change in QT 
interval) is observed, it should be recorded as current medical history (at the time of screening) or an 
adverse event (after the administration of investigational products) on the CRF. 
5.1.9 
Laboratory Tests 
Laboratory tests are carried out at the central laboratory (SCL; Seoul Clinical Laboratories, KR). 
However, the tests requiring analysis within 24 hours (Hematology, Urine tests) can be conducted at 
each study site. In special circumstances (blood sampling on Saturday and on the day before holidays, 
for the purpose of checking adverse events), the laboratory tests may be carried out separately at each 
study sites, and the test results shall be recorded in the CRF. 
For laboratory test conducted for confirmation of inclusion/exclusion criteria, retest is allowed during 
the screening period as judged by the Investigator. If not eligible even after the retest, the subject is 
not allowed to enroll this study. 
Hematology, blood chemistry, serology, and urinalysis are conducted at the time of screening, 1st day 
of hospitalization, interim visits, 2nd hospitalization, and end of a cohort (as there are no interim visits 
or hospitalizations for Cohort 4 and Cohort 5, they are replaced by the date of the 1st investigational 
product administration). 
 
Hematology 
: RBC, WBC with differential count (Neutrophil, Lymphocyte, Monocyte, 
Eosinophil, Basophil), Hemoglobin, Hematocrit, Platelet count, CD4 count 
(Screening only) 
 
Blood chemistry  
: Total protein, Albumin, Creatinine, BUN, Uric acid, Total bilirubin, AST 
(SGOT), ALT (SGPT), γ-GT 
 
Serology 
(Screening only) 
: anti-HBV (HBs Ag), anti-HCV (Anti-HCV Ab), anti-HIV (Anti-HIV Ab) 

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 
Urinalysis 
: pH, Protein, Glucose, Urobilinogen, Microscopic exam (if abnormal 
dipstick test): RBC, WBC 
Blood coagulation test is only conducted at the time of screening (only D-dimer test is conducted), 1st 
and 2nd hospitalization days, 6 hours after investigational product administration, all planned visits 
after administration, interim visits, and end of a cohort (as there are no interim visits or 
hospitalizations for Cohort 4 and Cohort 5, they are replaced by the date of the 1st investigational 
product administration, and all planned visits after administration is set to 24 hours after each 
investigational product administration). Blood coagulation test will include below. 
 
Blood coagulation 
: aPTT*, PT international normalized ratio (INR), PT sec, Thrombin-
antithrombin complex (TAT), D-dimer, Prothrombin fragment 1+2 
(F1+2), Fibrinogen 
*aPTT is a pharmacodynamic endpoint which shall be analyzed 
additionally in a different central laboratory (HTI; Haematologic 
Technologies Inc., USA), and the timing of blood sample collection is in 
5.1.12. 
A clinically significant abnormal laboratory test result after investigational product administration 
shall be considered an adverse event.  
Sample storage and disposal will be carried out according to central laboratory’s recommended 
procedure. 
Refer to 5.1.12 for the timing of blood collection and the amount of blood required per visit. 
5.1.10 
FIX Inhibitor and Anti-drug Antibody Test 
FIX inhibitor (or neutralizing antibody (NAb)) and anti-drug antibody test as well as a separate 
Bethesda assay shall be conducted in the central laboratories (inhibitor test, anti-drug antibody test: 
HTI, Bethesda assay: SCL) at the time of screening, 1st hospitalization, interim visit, 2nd 
hospitalization, and end of a cohort (with the exception of Bethesda assay at the time of screening). 
Tests for inhibitors and anti-drug antibodies to ISU304 and BeneFIX shall be conducted using a 
method developed by the sponsor. 
Inhibitors to ISU304 and BeneFIX are detected through the Nijmegen method. When there is a 
positive result(>0.6 BU)(14), a confirmatory test will be carried out. The inhibitor titer shall be 
recorded in Bethesda units (BUs). Anti-drug antibodies to ISU304 and BeneFIX are detected through 
a direct binding enzyme-linked immunosorbent assay (ELISA). 

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5.1.11 
Administration of Investigational Product  
Subjects will be treated with the investigational products according to the planned dosing schedule for 
each cohort. The date/time, dose, and route of administration are to be recorded in the CRF. 
5.1.12 
Blood Collection  
For PK/PD analysis, the subject’s blood samples will be collected according to defined time points 
below: The blood collection volumes for each visit by cohort are listed below, and the actual time of 
blood collection shall be recorded and used in the analysis. However, for the subject cannot visit, the 
Investigator can visit to collect the sample (select one among blood or saliva, oral epithelial cells) for 
Factor 9 gene mutation test.  
 

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Blood collection volume for laboratory tests and pharmacokinetic/pharmacodynamic analysis (estimated) 
 
Screeni
ng 
1st/2nd 
Hospitaliz
ation 
Administration of investigational product and  
timing of blood collection for PK/PD analysis 
Interim 
visit/ 
End of a 
cohort 
Post-study 
safety visit 
Blood 
collection 
volume 
per cohort 
(mL) 
Hours after 
administration 
Intravenous 
administration 
N/A 
N/A 
Before 
administratio
n 
0, 0.25, 0.5, 1, 3 
6 
9 
24 
48 
72 
96 
120 
144 
NA 
NA 
Subcutaneous 
administration 
1, 2, 4 
6 
8, 10, 12 
Blood collection volume per visit 
(mL)† 
20.7 
37.9 
32.4 
11.4 
11.4 
11.4 
8.4 
11.4 
11.4 
37.9 
21.5 
- 
Laboratory tests (mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count 
8 
8 
- 
- 
 
- 
- 
- 
- 
- 
- 
- 
8 
- 
- 
Blood coagulation 
2.7a 
8.4 
- 
- 
8.4 
- 
8.4 
8.4 
8.4  
8.4b 
8.4 
8.4b 
8.4 
- 
Bethesda assay 
 
1.5 
- 
- 
 
- 
 
 
 
 
 
 
1.5 
1.5 
Anti-drug antibodies/neutralizing antibodies to 
investigational product 
10 
20 
- 
- 
 
- 
 
 
 
 
 
 
20 
20 
IgG, IgE, Factor 9 gene mutation test d, HLA 
typing and other IR (immune response) genes 
(If required) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
3 
 
PK/PD analysis (mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
BeneFIX 75 IU/kg w/IV 
3 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
- 
- 
- 
- 
310.2 
ISU304 75 IU/kg w/IV 
- 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
- 
- 
- 
- 
Cohort 2 
ISU304 75 IU/kg w/IV 
3 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
- 
- 
- 
- 
310.2 
ISU304 75 IU/kg w/SC 
- 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
- 
- 
- 
- 
Cohort 3 
ISU304 75 IU/kg w/IV 
3 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
- 
- 
- 
- 
321.6 
ISU304 150 IU/kg w/SC 
- 
- 
3 
3 (per time) 
3 
3 (per time) 
3 
3 
3 
- 
3 
- 
- 
- 
Cohort 4e 
ISU304 150 IU/kg w/SC 
- 
- 
3 (per time) 
- 
 
- 
3 
 
3 
 
3 
 
- 
- 
145.0 
Cohort 5c 
ISU304 75 IU/kg w/IV 
- 
- 
3 
3(per time)‡ 
 
 
 
 
 
 
 
 
 
 
166.0 
ISU304 150 IU/kg w/SC 
- 
- 
3(per time)♀ 
- 
- 
- 
3 
- 
3 
 
3 
 
 
 
 
† – Volume of collected blood from a Cohort 5 subject is 11.4 mL at 96 hours after 1st administration (visit 5) and 14.4 mL at 120 hours after 1st administration (visit 6). 
‡ - At the first administration day of Cohort 5, total 3 PK/PD sample collections, right before IV administration, 0 min. and 0.5 min. will be done. 

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♀ - The first subcutaneous administration is performed within 30 min. of IV administration and PK/PD sampling is done right before subcutaneous administration for 9 days.    
a – Only D-dimer is assessed. 
b – Only for Cohort 4 and Cohort 5 
c- Only perform the neutralizing antibody test 
d- Sample collection can be performed through oral epithelial cells, saliva or blood.   
e – Blood collection for PK/PD analysis in Cohort 4 take place right before each administration, 6 hours after 1st administration, 6 hours after 6th administration, and 24 hours after 6th 
administration. 

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5.1.13 
Pharmacokinetic/ Pharmacodynamic Endpoints 
The following PK endpoints will be estimated and analyzed at the central laboratory (HTI) for each 
subject: observed maximum plasma concentration (Cmax), terminal phase elimination half-life (t1/2), 
total plasma clearance (CL), volume of distribution at steady state (Vss), area under curve (AUC; 
AUC(0-t) and AUC(0-inf)), mean residence time (MRT), incremental recovery (K), time to maximum 
plasma concentration (Tmax) for FIX activity and FIX antigen. 
For the PD endpoint, activated partial thromboplastin time (aPTT) will be estimated and analyzed at 
the central laboratory (HTI, USA). 
The subject’s blood samples will be collected according to the defined time points below for PK/PD 
analysis. 
 
Cohort 1 
Right before intravenous administration of BeneFIX , 0(immediately after 
administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min, 24hr±15min, 48hr±120min, 72hr±120min after 
administration; 
Right before intravenous administration of ISU304, 0(immediately after 
administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min, 24hr±15min, 48hr±120min, 72hr±120min after 
administration 
 
Cohort 2 
Right before intravenous administration of ISU304, 0(immediately after 
administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min, 24hr±15min, 48hr±120min, 72hr±120min after 
administration; 
Right before subcutaneous administration of ISU304, 1hr±3min, 
2hr±3min, 4hr±5min, 6hr±5min, 8hr±5min, 10hr±5min, 12hr±5min, 
24hr±15min, 48hr±120min, 72hr±120min after administration 
 
Cohort 3 
Right before intravenous administration of ISU304, 0(immediately after 
administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min, 24hr±15min, 48hr±120min, 72hr±120min after 
administration; 
Right before subcutaneous administration of ISU304, 1hr±3min, 
2hr±3min, 4hr±5min, 6hr±5min, 8hr±5min, 10hr±5min, 12hr±5min, 
24hr±15min, 
48hr±120min, 
72hr±120min, 
120hr±180min 
after 
administration 
 
 

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 
Cohort 4 
Right 
before 
1st 
subcutaneous 
administration 
of 
ISU304, 
1st 
administration+6hr, right before 2nd subcutaneous administration, right 
before 3rd subcutaneous administration, right before 4th subcutaneous 
administration, right before 5th subcutaneous administration, right before 
6th 
subcutaneous 
administration, 
6th 
administration+6hr, 
6th 
administration+24hr 
 
Cohort 5 
Right before and after intravenous administration of ISU304 75 IU/kg, 30 
min. after administration (after 1st subcutaneous administration of ISU304 
150 IU/kg), and right before 2nd subcutaneous administration of ISU304 
150 IU/kg, right before 3rd subcutaneous administration, right before 4th 
subcutaneous administration, right before 5th subcutaneous administration, 
right before 6th subcutaneous administration, right before 7th subcutaneous 
administration, right before 8th subcutaneous administration, right before 
9th subcutaneous administration, 9th subcutaneous administration+24 hr, 
9th 
subcutaneous 
administration+72 
hr, 
9th 
subcutaneous 
administration+120 hr 
5.1.14 
Concomitant Medications 
A subject’s concomitant medications at the time of screening and any changes in medications 
compared to screening should be recorded in the CRF. Rescue drugs should be recorded separately. 
5.1.15 
Adverse Events (AEs) 
The investigator should collect and review AEs of a subject after administration of the investigational 
products through interview and/or tests. AEs occurring after the administration of investigational 
products shall be classified into local, systemic, and other AEs(10, 13). The adverse events are evaluated 
using the ruler provided and thermometers at institution for accurate assessment of adverse events. 
1) Local AE 
All local AEs occurring within 1 hour after the administration of investigational products including 
pain, tenderness, erythema/redness, urticaria/pruritus, and induration/swelling should be recorded. The 
severity of the symptoms should also be recorded according to separate AE assessment criteria and the 
causal relationship with the investigational products should also be evaluated. (Appendix 4. Table – 
Assessment of Local Adverse Events) 
2) Systemic AE 

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All systemic AEs occurring within 1 hour after the administration of investigational products 
including fever, fatigue/malaise, chill/pyrexia, , headache, myalgia, arthritis(arthralgia), decreased 
appetite/loss of appetite, diarrhea, vomiting, constipation, abdominal pain, mucosal skin reaction/rash, 
vasovagal syncope, dizziness, cough, acute bronchospasm, dyspnea, and hypersensitivity should be 
recorded according to the AE assessment criteria and the causal relationship with the investigational 
products should also be evaluated. The severity of the symptoms should also be recorded according to 
separate AE assessment criteria and the causal relationship with the investigational products should 
also be evaluated. (Appendix 5. Table – Assessment of Systemic Adverse Events) 
3) Other AE 
All AEs other than local or systemic AEs occurring after the administration of investigational products 
should be recorded. The severity of the symptoms should also be recorded according to AE 
assessment criteria and the causal relationship with the investigational products should also be 
evaluated. 
Adverse events of special interest (AESIs) should be collected and analyzed separately. Following 
AESIs will be monitored. 
 
Thrombosis/embolism 
 
Spontaneous bleeding 
 
Inhibitor generation/seroconversion 
 
Anaphylaxis 
The source document on an AE should include the following: onset/end date, time (only for AESI), 
severity, outcome, action taken to investigational products, causal relationship with investigational 
products, causal relationship with other drugs, treatment given for AE, and seriousness. 
In the occurrence of AEs related to blood coagulation, a blood coagulation test shall be carried out and 
the results will be recorded in the CRF. 

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5.2 
Detailed Procedure for Each Visit 
Subjects of Cohorts 1 to 3 will be hospitalized on the day of investigational product administration to 
facilitate collection of blood samples for pharmacokinetic/pharmacodynamic (PK/PD) analysis. 
Cohort 4 and Cohort 5 subjects will be administered the investigational product on outpatient visits to 
the hospital, without the need for hospitalization. However, hospitalization or the prolongation of 
hospitalization can be conducted to facilitate the collection of samples for PK/PD analysis. 
Hospitalization itself shall not be considered as an SAE if no AE occurs during the hospitalization.  
5.2.1 
Cohort 1 and Cohort 2 
Cohort 1 will be intravenously administered 75 IU/kg of BeneFIX and blood samples will be collected 
over 3 days (72 hours) thereafter for PK/PD analysis in the 1st administration period. Then, 75 IU/kg 
of ISU304 will be intravenously administered for the 2nd administration period and blood samples will 
be collected over 3 days (72 hours) thereafter for PK/PD analysis as in the 1st administration period. 
Cohort 2 shall follow the identical procedures as Cohort 1 but will be administered different 
investigational products. Then, 75 IU/kg of ISU304 will be intravenously administered in the 1st 
administration period, followed by a subcutaneous administration of 75 IU/kg of ISU304 in the 2nd 
administration period. The detailed procedures for the respective visits are as follows.  
5.2.1.1 
Screening Visit (Day -30 to 0) 
The screening visit should be conducted within -30 days to the administration date. It should be 
scheduled in consideration of the fact that some tests for the inclusion/exclusion criteria will be 
conducted in an overseas central laboratory. The following is the procedure for the Screening Visit.  
① Obtaining written informed consent from the subject 
② Assigning screening no. 
③ Collecting demographic data, hemophilia B status, medical and medication history 
(determining eligibility based on inclusion/exclusion criteria) 
④ Physical examination, assessment of vital signs and electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests (only D-dimer test is conducted for blood 
coagulation, retest is allowed during screening period as judged by the Investigator) and FIX 
inhibitor test 

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5.2.1.2 
Visit 1 (Day -1 to 1) - 1st Hospitalization and Registration 
Visit 1 is for the 1st administration of the investigational product, and the subject is hospitalized for a 
day to conduct this visit. The subject is recommended to visit the hospital to be hospitalized on the 
day before the administration. As the timing of the 1st administration is identical to the time that the 
subject will have to visit the hospital on subsequent visits, it is important to set the time of the 1st 
administration with consideration for the subject’s schedule for the next 4 days. The investigator must 
observe the administration site for at least 30 minutes to 1 hour after the administration of 
investigational product for AEs. The following is the procedure for Visit 1. 
1st hospitalization (Day -1 to 0) 
① Assigning registration no. after final eligibility assessment 
② Hospitalization procedure for subject 
③ Checking for additional medical and medication history 
④ Electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
1st administration and blood collection for PK/PD analysis 
① Checking for additional medical history and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 
④ Administration of investigational product 
For Cohort 1, BeneFIX 75 IU/kg, intravenous administration 
For Cohort 2, ISU304 75 IU/kg, intravenous administration 
⑤ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑥ Blood sample collection for PK/PD analysis 
0(right after administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min  
⑦ Physical examination, assessment of vital signs, sample collection for blood coagulation test 
6 hours after administration 
1st discharge (Day 1) 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
24hr±15min  

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④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
⑥ Discharge procedure for subject 
5.2.1.3 
Visit 2 (Day 2) - Outpatient Visit 
The subject shall be instructed and reminded to visit the hospital within 48hr±120min from the time 
of the 1st investigational product administration for Visit 2. The following is the procedure for Visit 2. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
48hr±120min 
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.1.4 
Visit 3 (Day 3) - Interim Visit (termination of 1st administration) 
The subject shall be instructed and reminded to visit the hospital within 72hr±120min from the time 
of the 1st investigational product administration for Visit 3. Visit 3 is an interim visit marking the 
termination of the 1st administration period. The following is the procedure for Visit 3.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram 
③ Blood sample collection for PK/PD analysis 
72hr±120min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.1.5 
Visit 4 (Day 3 to 5) - 2nd Hospitalization 
Visit 4 is for the 2nd administration of the study drug, and the subject is hospitalized for a day as in 
Visit 1. The subject is recommended to visit the hospital to be hospitalized on the day before the 
administration. The timing of the 2nd administration is also identical to the time that the subject will 
have to visit the hospital on subsequent visits. Thus the time of the 2nd administration should be 
determined with consideration for the subject’s schedule.  

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An interval of at least 4 days is required between the administration of the 1st and 2nd doses. The 
investigator shall schedule the visit in consideration of this interval. Depending on the schedule, the 
procedure for Visits 3 and 4 could be conducted on the same day. Should this be the case, all 
procedures for the respective visits must be carried out without fail. The investigator must observe the 
administration site for at least 30 minutes to 1 hour after the administration of investigational product 
for AEs. The following is the procedure for Visit 4.  
2nd hospitalization (Day 3 to 4) 
① Hospitalization procedure for subject 
② Checking for AEs and concomitant medications 
③ Electrocardiogram 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
2nd administration and blood collection for PK/PD analysis (Day 4) 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 
④ Administration of investigational product 
For Cohort 1, ISU304 75 IU/kg, intravenous administration 
For Cohort 2, ISU304 75 IU/kg, subcutaneous administration 
⑤ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑥ Blood sample collection for PK/PD analysis 
For Cohort 1, 
: 0(right after administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min 
For Cohort 2, 
: 1hr±3min, 2hr±3min, 4hr±5min, 6hr±5min, 8hr±5min, 10hr±5min, 12hr±5min 
⑦ Physical examination, assessment of vital signs, sample collection for blood coagulation test 
6 hours after administration 
2nd discharge (Day 5) 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
24hr±15min  

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④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
⑥ Discharge procedure for subject 
5.2.1.6 
Visit 5 (Day 2) - Outpatient Visit 
The subject shall be instructed and reminded to visit the hospital within 48hr±120min from the time 
of the 2nd investigational product administration for Visit 5. The following is the procedure for Visit 5. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
48hr±120min 
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.1.7 
Visit 6 (Day 7) - End of a Cohort 
The subject shall be instructed and reminded to visit the hospital within 72hr±120min from the time 
of the 2nd investigational product administration for Visit 6. The following is the procedure for Visit 6.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram 
③ Blood sample collection for PK/PD analysis 
72hr±120min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
⑤ Termination of cohort and notification of post-study safety visit 
5.2.2 
Cohort 3  
Cohort 3 will be intravenously administered 75 IU/kg of ISU304 and blood samples will be collected 
over 3 days (72 hours) thereafter for PK/PD analysis in the 1st administration period. Then, 150 IU/kg 
of ISU304 will be subcutaneously administered for the 2nd administration period and blood samples 
will be collected over 5 days (120 hours) thereafter for PK/PD analysis. The detailed procedures for 
the respective visits are as follows. 

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5.2.2.1 
Screening Visit (Day -30 to 0) 
The screening visit should be conducted within -30 days to the administration date. It should be 
scheduled in consideration of the fact that some tests for the inclusion/exclusion criteria will be 
conducted in an overseas central laboratory. The following is the procedure for the Screening Visit.  
① Obtaining written informed consent from the subject 
② Assigning screening no. 
③ Collecting demographic data, hemophilia B status, medical and medication history 
(determining eligibility based on inclusion/exclusion criteria) 
④ Physical examination, assessment of vital signs and electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests (only D-dimer test is conducted for blood 
coagulation, retest is allowed during screening period as judged by the Investigator), FIX 
inhibitor test and anti-drug antibody test 
5.2.2.2 
Visit 1 (Day -1 to 1) - 1st Hospitalization and Registration 
Visit 1 is for the 1st administration of the investigational product, and the subject is hospitalized for a 
day to conduct this visit. The subject is recommended to visit the hospital to be hospitalized on the 
day before the administration. As the timing of the 1st administration is identical to the time that the 
subject will have to visit the hospital on subsequent visits, it is important to set the time of the 1st 
administration with consideration for the subject’s schedule for the next 4 days. The investigator must 
observe the administration site for at least 30 minutes to 1 hour after the administration of 
investigational product for AEs. The following is the procedure for Visit 1. 
1st hospitalization (Day -1 to 0) 
① Assigning registration no. after final eligibility assessment 
② Hospitalization procedure for subject 
③ Checking for additional medical and medication history 
④ Electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
 
1st administration and blood collection for PK/PD analysis 
① Checking for additional medical history and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 

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④ Intravenous administration of 75 IU/kg of ISU304 
⑤ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑥ Blood sample collection for PK/PD analysis 
0(right after administration)hr±1min, 0.25hr±3min, 0.5hr±3min, 1hr±3min, 3hr±5min, 
6hr±5min, 9hr±5min  
⑦ Physical examination, assessment of vital signs, sample collection for blood coagulation test 
6 hours after administration 
 
1st discharge (Day 1)  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
24hr±15min  
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
⑥ Discharge procedure for subject 
5.2.2.3 
Visit 2 (Day 2) - Outpatient Visit 
The subject shall be instructed and reminded to visit the hospital within 48hr±120min from the time 
of the 1st investigational product administration for Visit 2. The following is the procedure for Visit 2. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
48hr±120min 
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.2.4 
Visit 3 (Day 3) - Interim Visit (termination of 1st administration) 
The subject shall be instructed and reminded to visit the hospital within 72hr±120min from the time 
of the 1st investigational product administration for Visit 3. Visit 3 is an interim visit marking the 
termination of the 1st administration period. The following is the procedure for Visit 3.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram 

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③ Blood sample collection for PK/PD analysis 
72hr±120min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.2.5 
Visit 4 (Day 3 to 5) - 2nd Hospitalization 
Visit 4 is for the 2nd administration of the study drug, and the subject is hospitalized for a day as in 
Visit 1. The subject is recommended to visit the hospital to be hospitalized on the day before the 
administration. The timing of the 2nd administration is also identical to the time that the subject will 
have to visit the hospital on subsequent visits. Thus the time of the 2nd administration should be 
determined with consideration for the subject’s schedule.  
An interval of at least 4 days is required between the administration of the 1st and 2nd doses. The 
investigator shall schedule the visit in consideration of this interval. Depending on the schedule, the 
procedure for Visits 3 and 4 could be conducted on the same day. Should this be the case, all 
procedures for the respective visits must be carried out without fail. The investigator must observe the 
administration site for at least 30 minutes to 1 hour after the administration of investigational product 
for AEs. The following is the procedure for Visit 4.  
2nd hospitalization (Day 3 to 4) 
① Hospitalization procedure for subject 
② Checking for AEs and concomitant medications 
③ Electrocardiogram 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
2nd administration and blood collection for PK/PD analysis (Day 4) 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 
④ Administration of investigational product 
For Cohort 3, ISU304 150 IU/kg, subcutaneous administration 
 
⑤ Checking for AEs at least 30 min to 1 hr after investigational product administration 

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⑥ Blood sample collection for PK/PD analysis 
1hr±3min, 2hr±3min, 4hr±5min, 6hr±5min, 8hr±5min, 10hr±5min, 12hr±5min 
⑦ Physical examination, assessment of vital signs, sample collection for blood coagulation test 
6 hours after administration 
2nd discharge (Day 5)  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
24hr±15min  
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
⑥ Discharge procedure for subject 
5.2.2.6 
Visit 5 (Day 6) and Visit 6 (Day 7) - Outpatient Visit 
The subject shall be instructed and reminded to visit the hospital within 48hr±120min (for Visit 5), 
and within 72hr±120min from the time of the 2nd investigational product administration. The 
following is the procedure for Visits 5 and 6. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis 
48hr±120min, 72hr±120min 
④ Sample collection for blood coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.2.7 
Visit 7 (Day 9) - End of a Cohort 
The subject shall be instructed and reminded to visit the hospital within 120hr±180min from the time 
of the 2nd investigational product administration for Visit 7. The following is the procedure for Visit 7.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram 
③ Blood sample collection for PK/PD analysis 
120hr±180min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 

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and Bethesda assay 
⑤ Termination of cohort and notification of post-study safety visit 
5.2.3 
Cohort 4 
Cohort 4 will be subcutaneously administered 150 IU/kg of ISU304 once a day for 6 days, and blood 
samples will be collected over 240 hours thereafter for PK/PD analysis. The dose for Cohort 4 may be 
modified according to PK/PD and safety data from Cohorts 1 to 3. The detailed procedures for the 
respective visits are as follows. 
5.2.3.1 
Screening Visit (Day -30 to 0) 
The screening visit should be conducted within -30 days to the administration date. It should be 
scheduled in consideration of the fact that some tests for the inclusion/exclusion criteria will be 
conducted in an overseas central laboratory. The following is the procedure for the Screening Visit.  
① Obtaining written informed consent from the subject 
② Assigning screening no. 
③ Collecting demographic data, hemophilia B status, medical and medication history 
(determining eligibility based on inclusion/exclusion criteria) 
④ Physical examination, assessment of vital signs and electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests (only D-dimer test is conducted for blood 
coagulation, retest is allowed during screening period as judged by the Investigator), FIX 
inhibitor test and anti-drug antibody test 
5.2.3.2 
Visit 1 (Day 0) - Registration and Administration of Investigational Product 
Visit 1 is for the 1st administration of investigational product and the timing of the 1st administration is 
identical to the time that the subject will have to visit the hospital on subsequent visits. So, it is 
important to set the time of the 1st administration with consideration for the subject’s schedule in the 
next 6 days. The investigator must observe the administration site for at least 30 minutes to 1 hour 
after the administration of investigational product for AEs. The following is the procedure for Visit 1. 
① Assigning registration no. after final eligibility assessment 
② Checking for additional medical history and concomitant medications 
③ Physical examination, assessment of vital signs and electrocardiogram 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test 
and Bethesda assay before administration of investigational product 

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⑤ Subcutaneous administration of 150 IU/kg of ISU304 
⑥ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑦ Notification of visit schedule and scheduling of next visit 
5.2.3.3 
Visit 2 (Day 1) - Visit 6 (Day 5) - Repeated Administration of Investigational 
Product 
The subject shall be instructed and reminded to visit the hospital in 24hr±15min intervals starting 
from the time of the 1st investigational product administration for Visits 2 to 6. The following is the 
procedure for Visits 2 to 6. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 
④ Sample collection for coagulation test 
⑤ Subcutaneous administration of 150 IU/kg of ISU304 
⑥ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑦ Blood sample collection for PK/PD analysis (only on Visit 6) 
6hr±5min 
⑧ Physical examination, assessment of vital signs, sample collection for blood coagulation test 
6 hours after administration 
⑨ Notification of visit schedule and scheduling of next visit 
5.2.3.4 
Visit 7 (Day 6)  
The subject shall be instructed and reminded to visit the hospital within 24hr±15min from the time of 
Visit 6 for Visit 7. The following is the procedure for Visit 7.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
24hr±15min 
④ Sample collection for coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 

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5.2.3.5 
Visit 8 (Day 8)  
The subject shall be instructed and reminded to visit the hospital within 72hr±120min from the time 
of Visit 6 for Visit 8. The following is the procedure for Visit 8.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
After administration at Day 6, 72hr±120min 
④ Sample collection for coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.3.6 
Visit 9 (Day 10) – End of study 
The subject shall be instructed and reminded to visit the hospital within 120hr±180min from the time 
of Visit 6 for Visit 9. The following is the procedure for Visit 9.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
After administration at Day 6, 120hr±180min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
⑤ Termination of cohort and notification of post-study safety visit 
 
5.2.4 
Cohort 5 
For Cohort 5, single IV administration of ISU304 75 IU/kg is performed and ISU304 150 IU/kg is 
subcutaneously administered within 30 min. (±5 min.) of IV administration. Afterwards, daily 
repeated subcutaneous administration (total 9 subcutaneous injection) for 8 days is performed with 24 
hours interval. Based on the 1st subcutaneous administration, blood sampling for PK/PD analysis is 
performed for 312 hours. The details for each visit are as follows.  
      

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5.2.4.1 
Screening Visit (Day -30 to 0) 
The screening visit should be conducted within -30 days to the administration date. It should be 
scheduled in consideration of the fact that some tests for the inclusion/exclusion criteria will be 
conducted in an overseas central laboratory. The following is the procedure for the Screening Visit.  
① Obtaining written informed consent from the subject 
② Assigning screening no. 
③ Collecting demographic data, hemophilia B status, medical and medication history 
(determining eligibility based on inclusion/exclusion criteria) 
④ Physical examination, assessment of vital signs and electrocardiogram 
⑤ Blood/urine sample collection for laboratory tests (only D-dimer test is conducted for blood 
coagulation, retest is allowed during screening period as judged by the Investigator), FIX 
inhibitor test  
5.2.4.2 
Visit 1 (Day 0) - Registration and Administration of Investigational Product 
Visit 1 is for the 1st administration of investigational product (ISU304 75 IU/kg IV administration + 
ISU304 150 IU/kg subcutaneous administration) and the timing of the 1st administration is identical to 
the time that the subject will have to visit the hospital on subsequent visits. So, it is important to set 
the time of the 1st administration with consideration for the subject’s schedule in the next 9 days. The 
investigator must observe the administration site for at least 30 minutes to 1 hour after the 
administration of investigational product for AEs. The following is the procedure for Visit 1. 
① Assigning registration no. after final eligibility assessment 
② Checking for additional medical history and concomitant medications 
③ Physical examination, assessment of vital signs and electrocardiogram 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
Bethesda assay and blood sampling for PK/PD analysis before administration of 
investigational product 
⑤ IV administration of ISU304 75 IU/kg is followed by subcutaneous administration of 150 
IU/kg of ISU304 within 30 min. (±5 min.) of IV administration 
⑥ Blood sampling for PK/PD analysis right after and 30 min. after IV administration of 
ISU304 75 IU/kg  
⑦ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑧ Notification of visit schedule and scheduling of next visit 

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5.2.4.3 
Visit 2 (Day 1) - Visit 9 (Day 8) - Repeated Administration of Investigational 
Product 
The subject shall be instructed and reminded to visit the hospital in 24hr±15min intervals starting 
from the time of the 1st subcutanoues investigational product administration for Visits 2 to 9. The 
following is the procedure for Visits 2 to 9. 
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs 
③ Blood sample collection for PK/PD analysis before administration of investigational product 
④ Sample collection for coagulation test 
⑤ Subcutaneous administration of 150 IU/kg of ISU304 
⑥ Checking for AEs at least 30 min to 1 hr after investigational product administration 
⑦ Notification of visit schedule and scheduling of next visit 
5.2.4.4 
Visit 10 (Day 9)  
The subject shall be instructed and reminded to visit the hospital within 24hr±15min from the time of 
Visit 9 for Visit 10. The following is the procedure for Visit 10.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
After administration at Day 8, 24hr±15min 
④ Sample collection for coagulation test 
⑤ Notification of visit schedule and scheduling of next visit 
5.2.4.5 
Visit 11 (Day 11)  
The subject shall be instructed and reminded to visit the hospital within 72hr±120min from the time 
of Visit 9 for Visit 11. The following is the procedure for Visit 11.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
After administration at Day 8, 72hr±120min 
④ Sample collection for coagulation test 

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⑤ Notification of visit schedule and scheduling of next visit 
5.2.4.6 
Visit 12 (Day 13) – End of study 
The subject shall be instructed and reminded to visit the hospital within 120hr±180min from the time 
of Visit 9 for Visit 12. The following is the procedure for Visit 9.  
① Checking for AEs and concomitant medications 
② Physical examination, assessment of vital signs and electrocardiogram  
③ Blood sample collection for PK/PD analysis 
After administration at Day 8, 120hr±180min 
④ Blood/urine sample collection for laboratory tests, FIX inhibitor test, anti-drug antibody test, 
and Bethesda assay 
⑤ Termination of cohort and notification of post-study safety visit 
 
5.2.5 
Unscheduled Visits (if needed) 
Additional visit beyond the designated will be conducted upon request from a subject or subject's 
representative, or by the investigator’s decision. The investigator shall confirm the reason for the 
unscheduled visit with the subject or the subject’s representative. 
The following items shall be collected upon additional visits according to the investigator’s judgment 
of their necessity. 
① Weight/height 
② Checking for AEs and concomitant medications 
③ Physical examination, assessment of vital signs 
④ Blood/urine sample collection for laboratory tests 
5.2.6 
Post-Study Safety Visit 
If possible, subjects will visit the hospital 2 weeks (+1 week) after end of a cohort (or premature 
termination) to collect blood, saliva or oral epithelial cell sample for FIX inhibitor test, anti-drug 
antibody test, and Bethesda assay. If the subject is difficult to visit, the consent form should be 
delivered to the subject in advance by mail/courier. The Investigator shall explain the revised (added) 
clinical study method by wire telephone or other means and obtain written consent from the subject. 

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After the written consent has been obtained from the subject, the Investigator shall visit the subject's 
home or workplace to collect the specimen as possible among the blood, saliva, or oral epithelium. 
As the post-study safety visit is not a scheduled visit, it is not a protocol violation even if the subject 
does not carry out the post-study safety visit. However, when the result of anti-drug antibody and 
neutralized antibody test conducted at the post-study safety visit is positive, an additional visit may be 
conducted for a follow-up test to ensure the subject’s safety. 
① Checking for AEs and concomitant medications 
② Blood sample collection for FIX inhibitor test, anti-drug antibody test, and Bethesda assay 
 

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6 
Subject Withdrawal or Termination 
6.1 
Reasons for Withdrawal or Termination 
Subjects may withdraw the informed consent or discontinue their participation in the clinical study at 
any time without specifying the reasons. The investigator or sponsor is also able to discontinue the 
clinical study of a subject for safety or administrative reasons. A subject may withdraw from the study 
in any of the following cases. 
 
Withdrawal of consent by the subject or the subject’s representative 
 
Major protocol violations* 
 
Dispensing/dosing error of the investigational products 
 
Occurrence of an AE that leads to treatment discontinuation 
 
Follow-up loss 
 
Investigator or sponsor’s decision that continuation of the clinical study is not appropriate 
 
Development of FIX inhibitor (confirmed by sponsor) 
* Major protocol violations are defined as below. 
 
Failure to obtain informed consent (i.e., no documentation in source data or informed 
consent form) 
 
Violation of the inclusion/exclusion criteria 
 
Use of prohibited medication 
For minor protocol violations which are not deemed to influence the analysis of study results, the 
degree of violation or delay shall be exactly mentioned, and when the clinical study result report is 
written, the investigator, sponsor, monitor, and biostatistician shall comprehensively evaluate the 
analysis. 
6.2 
Handling of Subject Withdrawals or Termination 
The principal investigator is responsible for conducting the clinical study in accordance with the 
protocol. Investigators should take necessary actions (e.g., written notice of the next visit, phone 
monitoring, etc.) to conduct the study as planned. 

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If the subject discontinues the study for any reason, the investigator must try to collect the planned 
data for the last visit (end of a cohort) from the subject. The data collected from the subject until the 
point of discontinuation can be used in the analysis. The investigator shall inform the subject of this 
when possible. 
If the study of a subject is prematurely terminated for any reason, the investigator should promptly 
inform the subject or his representative, ask the reason for termination, and conduct appropriate 
therapy and follow-up for the subject if there is an unresolved AE.

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7 
Statistical Considerations 
7.1 
Endpoints 
7.1.1 
Basic Subject Information 
 
Demographic data, hemophilia B status, medical history, medication history 
7.1.2 
Safety Endpoints 
 
AEs after the administration of investigational products (local/systemic/other) 
 
Physical examination 
 
Vital signs 
 
Electrocardiogram 
 
Laboratory tests 
 
FIX inhibitors (or neutralizing antibodies) and anti-drug antibodies to investigational products  
7.1.3 
Pharmacokinetic/ Pharmacodynamic Endpoints 
 
PK endpoints: observed maximum plasma concentration (Cmax), terminal phase elimination half-
life (t1/2), total plasma clearance (CL), volume of distribution at steady state (Vss), area under 
curve (AUC; AUC(0-t) and AUC(0-inf)), mean residence time (MRT), incremental recovery (K), 
time to maximum plasma concentration (Tmax) for FIX activity and FIX product 
 
PD endpoint: activated partial thromboplastin time (aPTT) 
7.2 
Statistical Analysis 
7.2.1 
Analysis Population 
Analysis sets are defined as below.  
 
Safety analysis set: All subjects who receive at least one dose of investigational products 
 
PK set: Subjects in the safety analysis set who complete all procedures planned for the cohort and 
for whom PK samples have been obtained from at least 4 post-dose points; the 4 post-dose points 
should include at least 2 points within 3 hours after IV administration, or within 12 hours after SC 
administration. However, Cohort 4 and Cohort 5subjects can be included in the PK set with 

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samples from 48 hours after the 1st administration 
7.2.2 
Analysis of Basic Subject Information 
For each cohort, descriptive statistics will be given for each endpoint for each subject (i.e., mean (± 
standard deviation), median, minimum, and maximum for continuous data; frequency and percentage 
for categorical data) using SAS software (SAS Institute Inc., Cary, USA). 
7.2.3 
Safety Analysis 
7.2.3.1 
Adverse Events (AEs) 
The incidence of reported AEs (local/systemic/other) after investigational product administration shall 
be calculated by cohort, with the relevant 95% confidence intervals and number of events being 
estimated. 
The AEs shall be categorized according to severity, causal relationship with the investigational 
products, and the number of occurrences and percentage shall be calculated. The numbers of AEs, 
ADRs, and SAEs as well as the numbers of subjects experiencing them shall be calculated to estimate 
incidence. 
Additional analysis shall be conducted for AESIs using identical methods applied to AEs. 
All AEs shall be analyzed according to system organ class (SOC) and preferred term (PT) using the 
latest version of the MedDRA. 
7.2.3.2 
Physical Examination 
Normal/abnormal changes in physical examination results before and after administration of the 
investigational products shall be summarized in terms of frequency and percentage by cohort. 
7.2.3.3 
Vital Signs 
Descriptive statistics for vital signs measured before and after administration of the investigational 
products shall be presented in mean (± standard deviation), median, minimum, and maximum by 
cohort. 

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7.2.3.4 
Electrocardiogram 
Descriptive statistics from electrocardiograms conducted before and after administration of the 
investigational products shall be presented in mean (± standard deviation), median, minimum, and 
maximum by cohort. Normal/abnormal changes shall be summarized in terms of frequency and 
percentage. 
7.2.3.5 
Laboratory Tests 
Descriptive statistics from laboratory tests before and after administration of the investigational 
products shall be presented in mean (± standard deviation), median, minimum, and maximum by 
cohort. Normal/abnormal changes shall be summarized in terms of frequency and percentage. 
7.2.3.6 
FIX Inhibitors and Anti-drug Antibodies to the Investigational Products 
The analysis of FIX inhibitors (neutralizing antibodies) and anti-drug antibodies shall be conducted 
for each subject by cohort at the designated central laboratory (HTI). A separate Bethesda assay shall 
be carried out at a different central laboratory (SCL). Changes in neutralizing antibodies and anti-drug 
antibodies before and after administration of the investigational products shall be summarized in 
terms of frequency, percentage, and titer. 
7.2.4 
Pharmacokinetic/ Pharmacodynamic Analysis 
PK/PD analysis by cohort shall be conducted for PK set at the designated central laboratory (HTI). 
The descriptive statistics of PK/PD endpoints shall be presented in mean (± standard deviation), 
median, minimum, and maximum. 
PK/PD analysis will be conducted via standard non-compartmental methods using WinNonlin 
software (Pharsight, CA, USA). NONMEM software (ICON, MD, USA) will be used for additional 
analysis using the compartmental method, if applicable. In this case, data from subjects with missing 
values will be included. The bioavailability of ISU304 in subcutaneous administration will also be 
calculated. 
7.2.5 
Handling of Missing Values 
Missing values will not be replaced. 

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8 
Adverse Events (AEs) 
8.1 
Definition of Terms 
 
Adverse event (AE) 
An AE is any untoward or unfavorable medical occurrence in a human study subject, including any 
abnormal sign (e.g., an abnormal laboratory finding), symptom, or disease, temporally associated with 
the use of an investigational product, whether or not considered related to the investigational product. 
 
Adverse drug reaction (ADR) 
In the pre-approval clinical experience with a new investigational product or its new usages, 
particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to 
an investigational product related to any dose (i.e. the relationship cannot be ruled out) should be 
considered ADRs. 
 
Unexpected ADR 
An ADR, the nature or severity of which is not consistent with the applicable product information 
(e.g., investigator's brochure for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product). 
 
Serious AE and ADR (SAE and SADR) 
AEs or ADRs occurring at any dose of an investigational product that fall into any one of the 
following cases. 
– 
Occurrence of death or life threatening risk 
– 
Requires or prolongs hospitalization 
– 
Causing severe or permanent disabilities/impairment of functions 
– 
Occurrence of congenital defects or anomalies in fetus 
– 
Occurrence of other medically significant events such as drug dependency or abuse, blood 
disease, etc. 
8.2 
Collection and Documentation of Adverse Events 
AEs shall be collected during the clinical study period, from the time of investigational product 
administration to end of a cohort. Any medical incidences before the administration of the 
investigational product shall be recorded as current medical history. 

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AEs shall be reported with details on onset/end date, severity, outcome, action taken to investigational 
products, causal relationship with investigational products, causal relationship with other drugs, 
treatment given for AE, and seriousness. When documenting AEs, the investigators should record the 
overall diagnosis or symptoms using standard medical terms (according to the latest version of the 
MedDRA). 
AEs occurring during the study period shall be followed up until recovery (or stabilization), or until 
the case is lost to follow up. AEs occurring after the study completion should be reported only when 
they are serious and causally related to investigational products. 
8.3 
Assessment of Adverse Events 
8.3.1 
Severity 
The severity of an AE will be determined according to following criteria. 
 
Mild: 
Tolerable AEs 
(Although signs and symptoms are recognizable, they are easily tolerated, with mild 
discomfort not causing a loss of time in daily activities; the symptoms do not require 
treatment or medical assessment, the signs and symptoms are temporary.) 
 
Moderate: AEs presenting considerable inconvenience to activities of daily living* 
(AEs cause a low level of inconvenience or concern to the subject and may interfere 
with daily activities, but are usually improved by simple therapeutic measures; may 
cause some interference to functions.) 
 
Severe: 
AEs that make activities of daily living* impossible to conduct 
(AEs interrupt the subject’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating.) 
* Activities of daily living: all activities that occur in day-to-day life to maintain one’s own physical 
well-being (e.g., Bathing, dressing, eating, taking medications, hygiene maintenance, personal care) 
8.3.2 
Causal Relationship with Investigational Product 
The investigator evaluates all collected AEs based on temporal relationship and his/her clinical 
judgment. Causal relationships are assessed using the following categories.  
 
 
Definitely related 

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There is clear evidence to suggest a causal relationship, and other possible contributing factors can be 
ruled out. The temporal order of the investigational product administration and AE incidence is 
reasonable and the AE cannot be explained by concomitant diseases, other medications, or chemical 
substances. The AE disappears when the drug is discontinued. Symptoms upon rechallenge (when 
possible) must be pharmacologically or phenomenologically definitive. 
 
Probably related 
There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. The 
temporal order of the investigational product administration and AE incidence is reasonable and the 
possibility of the AE being caused by concomitant diseases, other medications, or chemical substances 
is low. The AE disappears when the drug is discontinued. Information of rechallenge is not necessary. 
 
Possibly related 
There is some evidence to suggest a causal relationship (e.g., the temporal order of the investigational 
product administration and AE incidence is reasonable). However, other factors may have contributed 
to the AE (e.g., the subject’s clinical condition, other concomitant events). Although an AE may only 
be evaluated as “possibly related” soon after occurrence, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”. 
 
Probably not related 
AE is deemed to be not causally related to the administration of the investigational product due to 
their temporal relationship (e.g., temporal order between administration and AE occurrence does not 
support causality), the AE is reasonably explained by concomitant diseases, other medications, or 
chemical substances (e.g., the subject’s clinical condition, other concomitant treatments). 
 
Definitely not related 
AE is clearly unrelated to the administration of the investigational product and there is clear evidence 
of a different causal factor. There must be an alternative, and definitive etiology documented by the 
clinician. 
 
Unknown 
Information is insufficient or contradictory to such an extent that a judgment cannot be made and it is 
not possible to supplement or verify such information. 

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8.4 
Adverse Event Reporting 
8.4.1 
SAE Reporting 
The principal investigator shall report all SAEs to the sponsor during the clinical study within 24 
hours from the time known to the investigator by phone/fax, regardless of causal relationship with the 
investigational products. SAEs occurring within 14 days after the completion of the study shall be 
reported by the same process. The investigator must use the subject identification code when reporting 
SAEs.  
Contact information for safety reporting to ISU ABXIS: 
PV staff  
 
 
 
E-mail 
: 
safety.isuabxis@isu.co.k
r 
Phone/Fax 
070-4665-4308 / 031-696-4771:  
Address 
: 5F, Global R&D Center Building C, 712-gil 22, Daewangpangyo-ro, 
Bundang-gu, Seongnam-si, Gyeonggi-do  
Minimum requirements for initial SAE report are as follows. 
 
Subject information 
 
Suspected drug and causal relationship with investigational products 
 
Reporting person information 
 
Name of SAE 
Investigators must conduct follow up reporting when additional information is obtained regarding 
reported SAEs. The investigator shall report periodically until the SAE is resolved (e.g., recovery or 
follow-up becomes impossible). 
8.4.2 
SUSAR Reporting 
When a Suspected Unexpected Serious Adverse Reaction (SUSAR) occurs, the principal investigator 
must report it to the IRB to determine whether the study should be continued or not, and help the 
sponsor to report the SUSAR immediately to the Ministry of Food and Drug Safety (MFDS). 
 
Fatal or life threatening SUSARs must be reported immediately. Sponsor has to report them to the 
MFDS by phone, fax, or documentation, as soon as possible, within 7 days of initial knowledge, 

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and submit a full report within 15 days of initial knowledge if possible. 
 
All other SUSARs have to be reported as soon as possible, within 15 days following initial 
reporting to or knowledge by sponsor. 
During the study period, the investigator shall ensure subject safety, and take prompt and proper 
measures to minimize AEs. The duties of the respective persons-in-charge upon the incidence of 
SUSARs are as follows. 
 
Principal investigators: immediately report the SUSAR to the IRB of each center and sponsor, 
and discontinue the clinical study in part or entirety until further instruction. 
 
Sub-investigators: immediately report the SUSAR to the principal investigator and sponsor. 
 
IRB: take measures necessary to the principal investigator (e.g., discontinuation of clinical study 
in part or entirety) 
 
Sponsor: upon receiving a SUSAR report from the principal investigators or sub-investigators, 
immediately submit a copy of the report from the principal investigator or sub-investigator to the 
MFDS and swiftly inform the study centers 
Other AEs not defined above will be tracked until 14 days after the last investigational product 
administration. 
8.5 
Pregnancy Reporting 
Pregnancy itself during the clinical study will not be regarded as an AE. Selective abortion without 
complications (not including therapeutic abortion) and hospitalization for the normal delivery of a 
healthy child are also not considered as AEs. 
However, if the subject’s spouse or female partner becomes pregnant during the study period (within 
30 days from the administration of investigational product), the subject must be immediately dropped 
out of the study. The investigator shall submit the pregnancy report to the sponsor within 24 hours 
after the investigator is made aware of pregnancy. Even if the subject withdraws or terminates the 
study, the investigator shall follow-up the progress of the pregnant woman and her fetus until delivery. 
If the pregnant woman experiences a serious complication, natural abortion, extra uterine pregnancy, 
stillbirth, neonatal death, congenital malformation, etc., these shall be deemed as SAEs, and the 
investigator shall report them. 

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9 
Ethical, Legal, and Administrative Considerations 
9.1 
Study Centers 
The directors of the study centers shall provide the locations, facilities, and professionals to enable the 
appropriate execution of the study. 
9.2 
Institutional Review Boards 
When obtaining approval for the protocol or when modifying an approved protocol, the protocol or 
modified protocol has to be approved by the IRB and the MFDS (if necessary). No subject is allowed 
to participate in the study prior to approval. 
9.3 
Subject Information Sheet and Informed Consent Form 
Prior to the execution of all study related procedures, the investigator shall fully explain the study to 
each subject (or the subject’s representative), and obtain written consent from the subject.  
The investigator shall take enough time to thoroughly assess the eligibility of each subject through 
interviews and/or tests. 
The investigator shall keep the signed original of the informed consent form in the investigator’s file, 
and provide copies of the signed informed consent form and subject information sheet to the subject 
(or representative). If the subject information sheet and informed consent form are modified, they 
shall be re-approved by the IRB, as well as the ongoing subject (or representative). 
Refer to [Attachment 2. Subject Information Sheet and Informed Consent Form] 
9.4 
Adherence to the Protocol 
The investigator will ensure that the clinical study is conducted in compliance with the Declaration of 
Helsinki to protect the subject’s rights and welfare. The investigator shall be familiar with the Korea 
Good Clinical Practice (KGCP) and the protocol, and respond actively to subject safety issues. 

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9.5 
Post-study Treatment for Subjects 
The investigator shall ensure that a subject who drops out of the study or does not respond to the drug 
can receive other forms of appropriate treatment. 
9.6 
Subject Indemnification 
The sponsor shall compensate the subject in the case of damages caused by AEs of the investigational 
product or in the treatment of AEs, where the investigational product is the direct cause of the damage 
according to Attachment 3. Subject Indemnification. 
Refer to [Attachment 3. Subject Indemnification] 
9.7 
Monitoring 
To protect subject’s rights and welfare, confirm the accuracy, integrity, and verifiability of data 
through comparison between reported study related data and source documents, and check if the 
clinical study has been performed in compliance with the approved protocol and KGCP, the study 
centers shall be monitored.  
The clinical research associate (CRA) from DreamCIS Inc. shall monitor the study, evaluate the study 
progress, and check whether the investigator’s duties are being fulfilled as per the protocol and 
regulations through routine site visits and phone calls. When visiting the center, the CRA shall check 
whether the originals of subject’s records, CRFs, drug management records, and study-related data 
(e.g., investigator’s files) are being kept, and discuss with the investigator upon finding 
inconsistencies or problems in the clinical study records. 
9.8 
Storage of Clinical Study Data 
The investigator shall keep the data and records related to the execution of the study in a safe place, 
maintain their security, and store them for 3 years from the date of product approval in the lastly 
approved country. After the clinical study report has been completed, documents related to the study 
shall be transferred to the data storage manager. If the investigator wishes to discard or to move study 
related records to another place, the investigator shall notify the sponsor in advance. 

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9.9 
Data Safety Monitoring Board and Data Monitoring Committee 
An independent Data Safety Monitoring Board (DSMB) and Data Monitoring Committee (DMC) 
shall perform interim assessments of PK/PD and safety data at the end of each cohort. The DMC 
assesses the PK/PD data while the DSMB accesses the safety data. The DSMB is comprised of 
members independent to the study whom include 1 clinician with expertise regarding the clinical 
aspects of hemophilia (DSMB Chair), 1 clinical pharmacologist, and 1 biostatistician. The DMC is 
comprised of the investigators of this study, the sponsor, PK/PD experts, and etc. 
Upon the termination of each cohort (after the last visit of the final subject), the PK/PD and safety 
data are analyzed before decisions are made regarding the commencement of the next cohort, target 
dose, and blood collection period. In the presence of subject safety concerns, the study may be put on 
hold or terminated, and decisions regarding the necessity of additional subjects as well as 
subject/cohort replacement/suspension may also be made. Ad hoc specialists may be invited to 
participate as non-voting members of DSMB at any time if additional expertise is needed. 
9.10 
Audit and Inspection 
To ensure that the KGCP and all related regulations are observed, the sponsor or a person authorized 
by the sponsor may perform audits while the MFDS may conduct inspections of the study. After the 
relevant notice is given to the investigator, the investigator shall respond to audit or inspection 
requests, allow the auditor or inspector direct access to all clinical study related documents, and 
consent to allocating sufficient time to fully discuss all observations and related issues. 
9.11 
Confidentiality 
All clinical study results and documents shall be kept confidential. The investigator, contract research 
organization, and staff from the sponsor shall not expose any study related information without the 
sponsor’s signed approval. Records that may be used to identify the subject shall be kept confidential, 
and all study related documents will be recorded with the screening number instead of the subject’s 
name. Even if the results of the clinical study are published, the subjects’ identities are to be kept 
confidential. 
The investigator shall be aware of the fact that with the conclusion of the clinical study contract, the 
sponsor, monitor, or auditor may review or copy relevant documents to verify the subjects’ medical 

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records and CRF records. Such information shall be kept confidential, and facilities for confidential 
record keeping shall be established with appropriate management criteria. 

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10 
References 
1) 
Srivastava A, Brewer AK, Mauser-Bunschoten EP et al. Guidelines for the management of 
hemophilia. Haemophilia. 2013;19:e1-47. 
2) 
Roberts HR, Key NS, Escobar MA. Hemophilia A and hemophilia B. In: Lichtman MA, Kipps 
TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 8th ed. New York, NY: 
McGrawHill;2010. 
3) 
Hillyer CD. Blood Banking and Transfusion Medicine: Basic Principles & Practice. Philadelphia 
PA: Elsevier Health Sciences, 2007. 
4) 
Taylor JA, Kruse-Jarres R. A new era for hemophilia B treatment. Blood. 2016;127(14):1734-6. 
5) 
Peyvandi F, Garagiola I. Treatment of hemophilia in the near future. Semin Thromb Hemost. 
2015;41(8):838-48. 
6) 
Stoner KL, Harder H, Fallowfield LJ et al. Intravenous versus subcutaneous drug administration. 
which do patients prefer? a systematic review. Patient. 2015;8:145. 
7) 
McCarthy K, Stewart P, Sigman J et al. Pharmacokinetics of recombinant factor IX after 
intravenous and subcutaneous administration in dogs and cynomolgus monkeys. Thromb 
Haemost. 2002;87(5):824-30. 
8) 
Brooks AR, Sim D, Gritzan U et al. Glycoengineered factor IX variants with improved 
pharmacokinetics and subcutaneous efficacy. J Thromb Haemost. 2013;11(9):1699-706. 
9) 
Liles D, Landen CN, Monroe DM et al. Extravascular administration of factor IX: potential for 
replacement therapy of canine and human hemophilia B. Thromb Haemost. 1997;77(5):944-8. 
10) Food and Drug Administration. Toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials. US Department of Health and Human 
Services, 2007. 
11) Rose EH, Vistnes LM, Ksander GA. (1977). “The panniculus carnosus in the domestic pi
g.” Plast Reconstr Surg. 59(1):94–97.  
12) Richter WF1, Bhansali SG, Morris ME. (2012). “Mechanistic determinants of biotherapeutics 
absorption following SC administration.” AAPS J. 14(3):559-70. 
13) The Guideline for Severity Assessment of Adverse Events in Vaccine Clinical Trials (2011). 
Ministry of Food and Drug Safety 
14) The Guideline for clinical study of blood-clotting preparations (Factor VIII, Factor IX) (2013.09). 
Ministry of Food and Drug Safety 
15) Guideline on clinical investigation of recombinant and human plasma-derived factor IX products 
(2012.02.01). European Medicines Agency 

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11 
Appendix 
Appendix 1. List of Study Centers and Principal Investigators  
Appendix 2. Subject Information Sheet and Informed Consent Form 
Appendix 3. Subject Indemnification  
Appendix 4. Table – Assessment of Local Adverse Events  
Appendix 5. Table – Assessment of Systemic Adverse Events 
 

SOP_DMST_STAT_001_T01 V3 
 
Statistical Analysis Plan 
Version 3.0 
ISU304-001 
 
Confidential 
This document is the property of DreamCIS. It is intended for restricted use only and may not - in full or 
part - be passed on, reproduced, published or used without express permission of DreamCIS.  
Copyright © by DreamCIS. All rights reserved 
 
 
 Effective Date: 2018-10-12 
 
 
Statistical Analysis Plan 
 
 
Protocol Identification No. 
ISU304-001 
Title 
A Phase 1, Open-label, Multi-center, Dose-escalation Study to 
Investigate 
the 
Safety, 
Pharmacokinetics 
and 
Pharmacodynamics of ISU304 in Previously Treated Hemophilia 
B Patients 
Trial Phase 
Phase 1 
Protocol Version 
11-SEP-2018/Version 5.3 
Sponsor 
ISU ABXIS 
Author 
Kyung-Jin You 
Date and Version 
19-MAR-2019/Version 3.0 
 
 
 
 

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History of Revisions 
 
Version 
Date of Approval 
Author Name 
V1.0 
09-FEB-2017 
Kyung-Jin You 
V2.0 
02-JAN-2019 
Kyung-Jin You 
V3.0 
19-MAR-2019 
Kyung-Jin You 
 
 
 
 
 
 
 

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Table of Contents 
Signature Page ............................................................................................................................................................. 2 
History of Revisions .................................................................................................................................................... 3 
Abbreviations ............................................................................................................................................................... 6 
1. Purpose of the Statistical Analysis Plan .............................................................................................................. 7 
2. Study Features ......................................................................................................................................................... 8 
3. Sample Size Calculation ....................................................................................................................................... 12 
4. Sequence of Planned Analyses ........................................................................................................................... 12 
4.1 Interim Analysis .............................................................................................................................................................................. 12 
4.2 Final Analysis ................................................................................................................................................................................... 12 
5. Changes to the Planned Analyses in the Protocol .......................................................................................... 12 
6. Analysis Sets .......................................................................................................................................................... 12 
7. Protocol Deviations .............................................................................................................................................. 13 
8. General Specifications for Statistical Analyses ................................................................................................ 13 
8.1 Analysis Software ........................................................................................................................................................................... 13 
8.2 Multiple Comparison and Multiplicity ................................................................................................................................ 13 
8.3 Planned Subgroup ........................................................................................................................................................................ 13 
8.4 Planned Covariate ......................................................................................................................................................................... 13 
8.5 Summary Statistics ........................................................................................................................................................................ 13 
8.6 Methods for Missing Data and Incomplete Data ......................................................................................................... 14 
8.7 Other Statistical Considerations ............................................................................................................................................. 14 
8.8 Reporting Conventions ............................................................................................................................................................... 14 
9. Evaluation of Study Data ..................................................................................................................................... 15 
9.1 Disposition of Subjects ............................................................................................................................................................... 15 

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9.2 Demographics ................................................................................................................................................................................. 16 
9.3 Medical History .............................................................................................................................................................................. 16 
9.4 Prior and Concomitant Medications .................................................................................................................................... 17 
9.5 Safety Evaluation ........................................................................................................................................................................... 17 
10. Derivation and Categorization for Variable ................................................................................................... 21 
10.1 Derivation ....................................................................................................................................................................................... 21 
10.2 Categorization .............................................................................................................................................................................. 22 
Appendix ..................................................................................................................................................................... 25 

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Abbreviations 
 
Abbreviations 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
CS 
Clinical Significance 
FIX 
Factor IX 
HIV 
Human Immunodeficiency Virus 
IP 
Investigational Products 
IU 
International Unit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Non Clinical Significance 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TLFs 
Tables, Listings, Figures 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 

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1. Purpose of the Statistical Analysis Plan 
 
The purpose of this document is documentation for the details for analyzing the data collected in 
the ISU304-001 study. 
 
This document is based on the statistical analysis method described in protocol, and results of the 
analysis in this document will be included in the clinical study report. 
 
If any additional analysis undescribed in this document is required, it will be written in separate 
document (ex. Additional Analysis Plan). 
 
 
 

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2. Study Features 
 
Study title 
A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate the 
Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in Previously 
Treated Hemophilia B Patients 
Study duration 
Approximately 24 months after the protocol approval from the institutional 
review boards (IRBs) 
Indication 
Previously treated hemophilia B patients 
Study objective 
To investigate the safety, pharmacokinetics and pharmacodynamics of ISU304 
(recombinant factor IX with increased activity) in previously treated 
hemophilia B patients 
Phase and design 
Phase 1, open-label, multi-center, dose-escalation 
Investigational 
products 
• Study drug: ISU304 75, 150IU/kg, intravenous or subcutaneous 
administration 
• Active control: BeneFIX 75 IU/kg, intravenous administration 
• Rescue drug: Treatment currently used by subject to treat hemophilia B 

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Administration 
and 
follow-up 
period 
• Cohort 1 (n=3): 7 days 
Single intravenous administration of BeneFIX (75 IU/kg) with 72 hours of 
observation, followed by single intravenous administration of ISU304 (75 
IU/kg) with 72 hours of observation 
• Cohort 2 (n=3): 7 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 
(75 IU/kg) with 72 hours of observation 
• Cohort 3 (n=3): 9 days 
Single intravenous administration of ISU304 (75 IU/kg) with 72 hours of 
observation, followed by single subcutaneous administration of ISU304 
(150 IU/kg) with 120 hours of observation 
• Cohort 4 (n=5): 10 days  
Single subcutaneous administration of ISU304 (150 IU/kg) per day for 6 
days with 240 hours of observation  
• Cohort 5 (n=minimum 3, maximum 5): 15 days 
Single intravenous administration of ISU304 (75 IU/kg) is followed by 
subcutaneous ISU304 (150 IU/kg) administration for 9 days with 312 
hours of observation 
Planned 
number 
of subjects 
At least 12 subjects (including duplication) 
Inclusion criteria 
1) Previously treated male patients with moderate or severe hemophilia B 
(documented FIX activity ≤ 2% and exposed to any FIX product for ≥ 
150 exposure days (estimated)) 
2) Patients must be 12 to 65 years old at the time of screening 
3) Patients who have discontinued a previously treated FIX product at least 
4 days prior to the administration of investigational product 
4) HIV negative, or if HIV positive with a CD4 count > 200/μL (documented 
< 200 particles/μL or ≤ 400,000 copies/mL) at the time of screening 
5) Voluntary consent to participate in the study 
Exclusion criteria 
1) Patients with a history or a family history of FIX inhibitors 
2) Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from 
inhibitor tests) at the time of screening 
3) Patients who have a history of thromboembolic events (myocardial 
infarction, cerebrovascular disease, venous thrombosis, etc.) 
4) Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX 

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product or hamster protein 
5) Patients receiving treatment with a FIX product or a bypass agent within 
4 half-lives for the agent used (at least 96 hours) prior to the 
administration of the investigational product 
6) Patients who have been exposed to long-term administration(exceeding 
14 days) of immunomodulating agents or immunosuppressants such as 
α-INF or adrenocortical hormones over the past 3 months or who are 
currently receiving or planning to receive such treatment during the study 
period 
7) Patients who have been administered vaccines during the period of 6 
months prior to the administration of the investigational product or plan 
to receive vaccines during the study period  
8) Patients with any other co-existing bleeding disorder (Von Willebrand 
disease, etc.) 
9) Patients with positive D-dimer results (≥ 0.5 μg/mL) at the time of 
screening 
10) Patients with platelet counts less than 100,000/μL at the time of screening 
11) Patients with ALT, AST levels 5 times greater than upper normal limit or 
total bilirubin, serum creatinine levels 2 times greater than upper normal 
limit at the time of screening 
12) Active hepatitis patients who are clinically significant HBs Ag positive or 
anti-HCV Ab positive at the time of screening 
13) Patients scheduled for surgery during the study period 
14) Patients participated in another study within 30 days before screening or 
scheduled to participate in any other study during the study period 
Safety endpoints 
• Adverse events after the administration of investigational products 
(local/systemic/other)  
• Physical examination  
• Vital signs 
• Electrocardiogram 
• Laboratory tests 
• FIX inhibitors (or neutralizing antibodies) and anti-drug antibodies to 
investigational products 
Other endpoints 
Demographic data, hemophilia B status, medical history, medication history 

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Analysis method 
• Analysis population 
- 
Safety analysis set: All subjects who receive at least one dose of 
investigational products 
- 
PK set: Subjects in the safety analysis set who complete all procedures 
planned for the cohort and for whom PK samples have been obtained 
at least 4 times after administration. 
• PK Analysis: Using WinNonlin software (Pharsight, CA, USA)  
• Bioavailability analysis for subcutaneous administration 
• Other statistical analysis 
- 
For each cohort, descriptive statistics will be given for each endpoint 
for each subject using SAS software (SAS Institute Inc, Cary, USA) 
 
 
 

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3. Sample Size Calculation 
 
At least 12 subjects who meet all of the inclusion criteria and none of the exclusion criteria including 
duplication will be enrolled. 
 
 
4. Sequence of Planned Analyses 
 
4.1 Interim Analysis 
 
Interim analysis is not planned in this study. 
 
4.2 Final Analysis 
 
The statistical analysis of this study will be performed after all data is collected and database lock is 
completed. 
 
 
5. Changes to the Planned Analyses in the Protocol 
 
The PK/PD analysis is described in Protocol but PK/PD analysis will be conducted at the designated 
central laboratory (HTI). So this document does not include this analysis. 
 
 
6. Analysis Sets 
 
Safety Analysis Set 
All subjects who receive at least one dose of investigational products 
 
 

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7. Protocol Deviations 
 
The additional protocol deviations other than analysis set criteria described in ‘6. Analysis Sets’ are 
not considered. 
 
 
8. General Specifications for Statistical Analyses 
 
8.1 Analysis Software 
 
All statistical analysis will be carried out with SAS Software (SAS Institute Inc, Cary, USA) version 9.4 
or more recent version. 
 
8.2 Multiple Comparison and Multiplicity 
 
The consideration of multiple comparison and multiplicity is not necessary in this study. 
 
8.3 Planned Subgroup 
 
Subgroup analysis is not planned in this study. 
 
8.4 Planned Covariate 
 
Covariate analysis is not planned in this study. 
 
8.5 Summary Statistics 
 
For the continuous data, descriptive statistics such as mean, standard deviation, 25th percentile, 
median, 75th percentile, minimum and maximum value shall be obtained. For the categorical data, 

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descriptive statistics such as frequency and percentage shall be provided. 
 
8.6 Methods for Missing Data and Incomplete Data 
 
Missing data and incomplete data will not be replaced. 
Exceptionally in laboratory test, if results include incomplete data, it will be converted to numeric 
value and included in the analysis as following example. Also incomplete data will be listed. 
• if data including ‘<number’, it will be replaced 'number - 0.001' (e.g. <2 → 1.999). 
• if data including ‘>number’, it will be replaced 'number + 0.001' (e.g. >100 → 100.001). 
 
8.7 Other Statistical Considerations 
 
The analysis will be carried out according to considerations as follows. If additional considerations 
on each analysis item is required, the corresponding options will be described in ’10.1 Derivation’. 
• In Cohort 1, Cohort 2, Cohort 3, ‘Baseline’ is ‘1st Hospitalization (Before 1st injection)’ visit. And 
in Cohort 4 and Cohort 5, ‘Baseline’ is ‘Before 1st injection’ visit. 
• The criteria for converting day to month are as follows: 1month=30days 
• When calculating percentage for categorical variables except for ‘Analysis Sets’ summary, the 
denominator is the number of subjects in each cohort. Only in case of analysis by type of 
Medical History/Surgical History/Prior Medication/Concomitant Medication, the denominator 
the number of subjects having Medical History/Surgical History/Prior Medication/Concomitant 
Medication in each cohort. 
• The calculating criteria of percentage for ‘Analysis Sets’ summary will be described in 9.1 
Disposition of Subjects’. 
• The 95% confidence interval will be estimated by using exact method. 
 
8.8 Reporting Conventions 
 
• 
The descriptive statistics (mean, standard deviation, 25th percentile, median, 75th percentile, 
minimum, maximum, percentage) rounds to 2 decimal places. 
• 
If the calculated percentage is less than 0.01, it will be presented as ‘<0.01’. 
 
 

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9. Evaluation of Study Data 
 
All analysis will be applied for Safety Analysis Set as follows. 
Analyses 
Safety Analysis Set 
Demographics 
 
Medical History 
 
Prior and Concomitant Medications 
 
Safety Evaluation 
 
 
9.1 Disposition of Subjects 
 
The following ‘Patient disposition’ and ‘Analysis Sets’ will be presented as a figure. 
 
Patient disposition 
• The number of screening subjects 
• The number of screening failure subjects and reason for screening Failure 
• The number of enrolled subjects 
• The number of early withdrawal subjects and reasons for early withdrawal  
• The number of study completion subjects 
 
Analysis Sets 
• The number of enrolled subjects 
• The number of Safety Analysis Set of enrolled subjects 
• The number of subjects excluded from Safety Analysis Set of enrolled subjects and the criterion 
of excluded from Safety Analysis Set 
 
Additionally for ‘Analysis Sets’, the table including the frequency and percentage will be presented. 
 
The following subjects will be listed. 
• Listing of Subjects with early withdrawal  
• Listing of Subjects enrolled in multiple cohorts 
 
 

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9.2 Demographics 
 
For following continuous variable, the descriptive statistics for each cohort will be presented. 
• Age 
• Height 
• Weight 
 
For following categorical variables, the descriptive statistics for each cohort will be presented. 
• Gender 
• Age 
 
The above demographics for each subjects will be listed. 
 
9.3 Medical History 
 
For following continuous variable, the descriptive statistics for each cohort will be presented. 
• Duration of Hemophilia B 
 
For following categorical variables, the descriptive statistics for each cohort will be presented. 
• Duration of Hemophilia B 
• Family History of Hemophilia B 
• History of FIX Inhibitor 
• Family History of FIX Inhibitor 
• FIX activity ≤ 2% before screening visit 
• FIX product 150 exposure days at the time of screening 
• Medical Historya 
• Surgical Historyb 
 
a Medical History: Any past or concomitant disease at screening (last 3months) 
b Surgical History: Any surgical history from prior 3 months ago to screening visit 
 
The medical history and surgical history will be classified as SOC under the classification standard 
of recent version MedDRA. If one subject has 2 or more medical history/surgical history in one 
category (SOC), it will be analyzed as one in the category. Also, the same subject may appear in 

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different category in duplicate. 
 
9.4 Prior and Concomitant Medications 
 
For following categorical variables, the descriptive statistics for each cohort will be presented. 
• Prior Medicationa 
• Concomitant Medicationb 
 
a Prior Medication: any drugs started from 3 months before screening visit to 1st injection 
b Concomitant Medication: any drugs started after 1st injection 
 
The prior and concomitant medication will be classified as Level 1, Level 2 under the classification 
standard of recent version WHODDE. If one subject taken 2 or more medication in one category 
(Level 1, Level 2), it will be analyzed as one in the category. Also, the same subject may appear in 
different category in duplicate. 
 
9.5 Safety Evaluation 
 
9.5.1 Adverse Events 
 
The summary table for the following AE will be presented by each cohort. In the summary table, the 
number and proportion of subjects to whom following AE occurred, and its 95% confidence interval 
and the number of following AEs will be estimated. 
• Adverse Event 
• Adverse Drug Reactiona 
• Serious Adverse Event 
• Serious Adverse Drug Reactiona 
• Early Withdrawal due to AEb 
• Adverse Event of Special Interestc 
 
a Adverse Drug Reaction: AE including whose ‘Causal Relationship with IP’ is assessed “Definitely 
related", "Probably related", "Possibly related", "Unknown" 
b Early Withdrawal due to AE: AE whose 'Reason for discontinuation' of 'Study Conclusion' is 

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'Occurrence of an AE that leads treatment discontinuation' and 'Action taken to IP' is "Interrupted" 
c Adverse Event of Special Interest: It is Thrombosis/embolism, Spontaneous bleeding, Inhibitor 
generation/seroconversion, Anaphylaxis and  collected in other AE only 
 
Additionally, the summary table for the following local1/systemic2/other3 AE will be presented by 
each cohort. In the summary table, the number and proportion of subjects to whom 
local/systemic/other AE occurred, and its 95% confidence interval and the number of following AEs 
will be estimated. 
• Adverse Event 
• Adverse Drug Reaction 
• Serious Adverse Event 
• Serious Adverse Drug Reaction 
• Early Withdrawal due to AE 
 
1 Local AE: AEs occurring within 1 hour after the administration of investigational products including 
pain, tenderness, erythema/redness, urticaria/pruritus, and induration/swelling 
2 Systemic Adverse Event: AEs occurring within 1 hour after the administration of investigational 
products including fever, fatigue/malaise, chill/pyrexia, , headache, myalgia, arthritis(arthralgia),  
decreased appetite/loss of appetite, diarrhea, vomiting, constipation, abdominal pain, mucosal 
skin reaction/rash, vasovagal syncope, dizziness, cough, acute bronchospasm, dyspnea, and 
hypersensitivity 
3 Other Adverse Event: AEs other than local or systemic AEs occurring after the administration of 
investigational products 
 
For following item, the number and proportion of subjects with following local AE and systemic AE 
according to reported term, other AE according to the SOC, PT and its 95% confidence interval and 
the number of following local AE and systemic AE according to reported term, other AE according 
to the SOC, PT will be estimated. If one subject has 2 or more AE in one category, it will be analyzed 
as one in the category. Also, the same subject may appear in different category in duplicate. 
• Adverse Event 
• Adverse Drug Reaction 
• Serious Adverse Event 
• Serious Adverse Drug Reaction 
• Adverse Event of Special Interest 
 
For AE, local/systemic/other AE, AESI, the number of AEs and its percentage (%) by each cohort 

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according to following AE item will be presented.  
• Seriousness 
• Severity 
• Outcome 
• Action Taken to IP 
• Causal Relationship with IP 
• Causal Relationship with others 
• Treatment Given for AE 
 
The following AEs will be listed. 
• Local Adverse Drug Reaction 
• Systemic Adverse Drug Reaction 
• Other Adverse Drug Reaction 
• Local Serious Adverse Event 
• Systemic Serious Adverse Event 
• Other Serious Adverse Event 
• Adverse Event of Special Interest 
• Adverse Event of subjects whose Early Withdrawal due to Adverse Event 
• Other Adverse Event whose reported term is 'Nab positive' or ‘ADA positive’ 
• Other Adverse Event whose PT term include ‘injection site’ 
• Adverse Event (each patient) 
 
9.5.2 Laboratory Tests 
 
For laboratory test, the descriptive statistics for each cohort will be presented in collected visit. And 
the change of baseline and end of cohort will be presented. 
Additionally, the frequency and percentage of ‘Normal/NCS’, ‘CS’ in CD4 count of hematology test 
at screening will be presented. And the frequency and percentage of ‘Normal’, ‘NCS’, ‘CS’ in serology 
test at screening will be presented. 
 
Also, ‘Normal/NCS’, ‘CS’ changes from baseline to end of cohort in hematology test(except for CD4 
count), blood chemistry test, urinalysis and blood coagulation test will be summarized in terms of 
frequency and percentage by cohort. 
 

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9.5.3 Physical Examination 
 
‘Normal/NCS’, ’CS’ changes from baseline to end of cohort in physical examination results will be 
summarized in terms of frequency and percentage by cohort. The subjects with clinically significant 
results in physical examination will be listed. 
 
9.5.4 Vital Signs 
 
For vital signs results, the descriptive statistics for each cohort will be presented in collected visits. 
And the change of baseline and end of cohort will be presented. 
 
9.5.5 Electrocardiogram 
 
For each electrocardiogram results, the descriptive statistics for each cohort will be presented at 
each collected visit. And the change of baseline and end of cohort will be presented. 
‘Normal/NCS’, ’CS’ changes from baseline to end of cohort in electrocardiogram results will be 
summarized in terms of frequency and percentage by cohort. 
 
9.5.6 FIX Inhibitor and Anti-drug Antibody Test 
 
For FIX Inhibitor test and Anti-drug Antibody test, ‘Positive’, ’Negative’ changes from ‘Before injection’ 
to ‘After injection’ in each results will be summarized in terms of frequency and percentage by 
cohort. If ‘Positive’ is confirmed once after injection, the subjects will be included ‘Positive’. 
 
In FIX Inhibitor test, if data is collected as ‘LOQ’, it will be analyzed as ‘Negative’, and if data is 
collected any numeric value, it will be analyzed as ‘Positive’. 
In Anti-drug Antibody test, data is collected as ‘Positive’, ‘Negative’. 
 
Additionally all FIX Inhibitor test and Anti-drug Antibody test results will be listed. 
 
 
 

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10. Derivation and Categorization for Variable 
 
10.1 Derivation 
 
The calculation formulas are as follow. If statistical analysis requires additional calculation formula, 
SAP may not be revised but the calculation formula will be specified in TLFs. 
 
Age 
• In case the date of Informed Consent month/day < Date of Birth month/day: 
Age = (Date of Informed Consent) - (Date of Birth) - 1 
• In case the date of Informed Consent month/day ≥ Date of Birth month/day: 
Age = (Date of Informed Consent) - (Date of Birth) 
 
Duration of Hemophilia B 
• Year of 1st injection - Year of Diagnosis of Hemophilia B 
 
Prior Medication 
• Prior & Concomitant Medication Start Date < Date of 1st injection 
• Prior & Concomitant Medication End date < Date of 1st injection 
• Prior & Concomitant Medication Start Date is missing or unknown 
• The following example will be included in Prior Medication. 
Prior & Concomitant 
Medication Start Date 
Prior & Concomitant 
Medication End date 
Date of 1st injection 
2015-10-06 
Ongoing 
2015-10-15 
2015-10-UK 
2015-10-10 
2015-10-15 
2015-10-UK 
Ongoing 
2015-10-15 
2015-10-UK 
2015-10-UK 
2015-10-15 
UK 
2015-10-20 
2015-10-15 
UK 
UK 
2015-10-15 
 
Concomitant Medication 
• (Prior & Concomitant Medication Start Date < Date of 1st injection) & (Prior & Concomitant 
Medication End Date ≥ Date of 1st injection) 

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• (Prior & Concomitant Medication Start Date < Date of 1st injection) & (Prior & Concomitant 
Medication is ‘Ongoing’) 
• Prior & Concomitant Medication Start Date ≥ Date of 1st injection 
• In case Prior & Concomitant Medication End Date is unknown, it is not defined Concomitant 
Medication. 
• The following example will be included in Concomitant Medication. 
Prior & Concomitant 
Medication Start Date 
Prior & Concomitant 
Medication End date 
Date of 1st injection 
2015-10-20 
2015-10-30 
2015-10-15 
2015-10-06 
Ongoing 
2015-10-15 
2015-11-UK 
2015-11-UK 
2015-10-15 
2016-UK-UK 
2016-UK-UK 
2015-10-15 
2015-10-UK 
2015-10-20 
2015-10-15 
2015-10-UK 
2015-11-UK 
2015-10-15 
2015-UK-UK 
2016-UK-UK 
2015-10-15 
 
10.2 Categorization 
 
Categories for each item are as follows.  
The following defined category for continuous variable can be changed according to the 
distribution of actual collected data.  
 
Item 
Category 
• Gender 
Male 
• Age 
12 years ~ 19 years, 
20 years ~ 29 years, 
30 years ~ 39 years, 
40 years ~ 49 years, 
50 years ~ 59 years, 
60 years ~ 65 years 
• Duration of Hemophilia B 
< Median, ≥ Median 
(Median: median for Duration of Hemophilia B in Safety 
Analysis Set) 
• Family 
History 
of Yes, No 

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Item 
Category 
Hemophilia B 
• History of FIX Inhibitor 
No 
• Family 
History 
of 
FIX 
Inhibitor 
No 
• FIX activity ≤ 2% before 
screening visit 
Yes 
• FIX product 150 exposure 
days 
at 
the 
time 
of 
screening 
Yes 
• Medical History 
Yes, No 
• Surgical History 
Yes, No 
• Prior Medication 
Yes, No 
• Concomitant Medication 
Yes, No 
• AE Seriousness 
Yes, No 
• AE Severity 
Mild, 
Moderate, 
Severe 
• AE Outcome 
Recovered without Sequelae, 
Recovered with Sequelae, 
Continuing, 
Death, 
Unknown 
• Action Taken to IP 
Not Applicable, Interrupted 
• Causal Relationship with IP 
Definitely related, 
Probably related, 
Possibly related, 
Probably not related, 
Definitely not related, 
Unknown 
• Causal Relationship with 
others 
Concomitant Disease, 
Concomitant Medication, 
Other, 
Unknown, 
None 

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Item 
Category 
• Treatment Given for AE 
None, 
Drug Therapy, 
Non-Drug Therapy, 
Drug, Non-Drug Therapy 
• Laboratory 
Tests(Hematology 
test, 
Blood 
Chemistry 
test, 
Urinalysis, 
Blood 
coagulation test) 
Normal/NCS, 
CS 
• 
Laboratory Tests(Serology 
test) 
Normal, 
NCS, 
CS 
• Physical Examination 
Normal/NCS, 
CS 
• Electrocardiogram 
Normal/NCS, 
CS 
 
 

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Appendix 
 
 
Mock up TLFs