Phase 2 Study to Evaluate the Pharmacokinetics, Efficacy and Safety of a Daily Subcutaneous Treatment Regimen With Marzeptacog Alfa (Activated) for Bleeding Prophylaxis in Adult Subjects With Hemophilia A and B Subjects With an Inhibitor
Phase: PHASE2
Conditions: Hemophilia A With Inhibitor, Hemophilia B With Inhibitor
Sponsor: Catalyst Biosciences

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        1 
25 August 2018 
 
Catalyst Biosciences, Inc.
CLINICAL RESEARCH PROTOCOL
Phase 2 Study of Next-Generation Coagulation Factor VIIa, Marzeptacog Alfa (Activated) in 
Adult Subjects with Hemophilia A and B
Protocol Identifying Number:
MAA-201
Official Title:
Phase 2 study to evaluate the pharmacokinetics, 
bioavailability, pharmacodynamics, efficacy and safety of a 
daily subcutaneous treatment regimen with marzeptacog alfa 
(activated) for bleeding prophylaxis in adult subjects with 
hemophilia A and B subjects with an inhibitor
IND/IDE Sponsor: 
Catalyst Biosciences, Inc.
611 Gateway Blvd., Suite 710
South San Francisco, CA  94080
IND Number:
14789
Investigational Product:
Factor VIIa, Marzeptacog Alfa (activated) [MarzAA]
Development Phase:
2
Version Number:
2.0
Amendment 1
Effective Date:
25 August 2018
Sponsor Contact:
Name:
Howard Levy, MD, PhD, MMM
                                    CMO, Catalyst Biosciences, Inc.
Telephone: 
 
+1.650.266.8671
Fax: 
 
 
+1.650.871.2475
E-mail:  
 
hlevy@catbio.com
Prepared by:
Catalyst Biosciences, Inc.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be disclosed unless such disclosure is required 
by applicable law or regulations. In any event, persons to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further 
disclosed by them. These restrictions on disclosure will apply equally to all future information 
supplied to you that is indicated as privileged or confidential.
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        2 
25 August 2018 
 
Compliance Statement:
This study will be conducted in accordance with the clinical 
research guidelines established by the U.S. Code of Federal Regulations (Title 21, Parts 50 
[including Subpart D], 54, 56 and 312), the regulations and guidelines of the Therapeutic 
Goods Administration, and the International Conference on Harmonization (ICH) Guidelines 
for Good Clinical Practice. Study documents will be maintained in accordance with 
applicable regulations.
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        3 
25 August 2018 
 
INVESTIGATOR SIGNATURE PAGE
PROTOCOL TITLE:
Phase 2 study to evaluate the pharmacokinetics, bioavailability, 
pharmacodynamics, efficacy and safety of a daily subcutaneous 
treatment regimen with marzeptacog alfa (activated) for bleeding 
prophylaxis in adult subjects with hemophilia A and B subjects with an 
inhibitor
PROTOCOL No.:
MAA-201
VERSION NUMBER: 
2.0, Amendment 1
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing the Sponsor with complete and timely information, as outlined in the protocol. 
Furthermore, on behalf of the study staff and myself, I agree to conduct the study as 
outlined in the protocol in accordance with the guidelines outlined in the study protocol 
and all applicable government regulations. In addition, I agree to provide all the 
information requested in the CRFs presented to me by the Sponsor in a manner that assures 
legibility and accuracy. I also agree that all information provided to me by the Sponsor, 
including pre-clinical data, protocols, CRFs, verbal and written information, will be kept 
strictly confidential and confined to the clinical personnel involved in conducting the study. 
It is recognized that this information may be relayed in confidence to the IRB/IEC. In 
addition, no reports or information about the study or its progress will be provided to 
anyone who is not involved in the study, other than Sponsor or designee, the IRB/IEC, or the 
appropriate regulatory agencies.
The trial will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), applicable United States (US) Code of Federal 
Regulations (CFR) (Title 21, Parts 50 [including Subpart D], 54, 56 and 312), the regulations 
and guidelines of the Therapeutic Goods Administration. The Principal Investigator will 
assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor, funding agency and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. Study documents will be 
maintained in accordance with applicable regulations.
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments. 
Investigator Signature 
Date
Print Name and Title
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        4 
25 August 2018 
 
SPONSOR SIGNATURE PAGE
Protocol Title:
Phase 2 study to evaluate the pharmacokinetics, bioavailability, 
pharmacodynamics, efficacy and safety of a daily 
subcutaneous treatment regimen with marzeptacog alfa 
(activated) for bleeding prophylaxis in adult subjects with 
hemophilia A and B with an inhibitor 
Protocol Number: 
 
MAA-201
Version Number: 
2.0 (Amendment 1), dated 25 August 2018
_________________________________________________________  
25 August 2018
Howard Levy, MD, PhD, MMM 
 
 
 
 
 
Date
Chief Medical Officer, Catalyst Biosciences, Inc.
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        5 
25 August 2018 
 
DETAILED SUMMARY OF PROTOCOL CHANGES
Protocol Number:
MAA-201
Protocol Title:
Phase 2 study to evaluate the pharmacokinetics, bioavailability, pharmacodynamics, efficacy and safety of a 
daily subcutaneous treatment regimen with marzeptacog alfa (activated) for bleeding prophylaxis in adult 
subjects with hemophilia A and B subjects with an inhibitor
Version Number
Version Date
Current Approved Protocol
1.0
6 June 2017
Amended Protocol
2.0, Amendment 1
25 August 2018
Description of Changes:
Section
Update
Details
Title Page
Addition
Amendment 1 Date: 11 April 2018
Investigator Signature Page
Replacement
VERSION NUMBER:
1.0
With:
VERSION NUMBER:
2.0, Amendment 1
Sponsor Signature Page
Replacement
Version Number: 1.0, dated xx June 2017
With:
Version Number: 2.0 (Amendment 1), dated 25 August 2018
Sponsor Signature Page
Deletion
Jamie Siegel, MD
Senior Medical Lead, Catalyst Biosciences, Inc.
Abbreviations
Updated
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Study MAA-201, Clinical Study Report
IND 14789
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        6 
25 August 2018 
 
1.1 Synopsis; Trial Population;
Exclusion Criteria
Replacement
2. Previous participation in a clinical trial evaluating a modified 
rFVIIa agent (including rFVIIa biosimilars, SC rFVIIa, PEGylated 
rFVIIa, NN1731, BAY86-6150, LR769, rVIIa-FP (CSL689), MOD-
5014).  Note: IV use of NovoSeven® is not an exclusion criteria.
With:
2. Previous participation in a trial involving Subcutaneous 
Administration of rFVIIa (Novo Seven or MOD-5014) or any 
trial using a modified rFVIIa such as: NN1731 or BAY86-6150. 
Prior participation in a trial of LR769 or rFVIIa-FP (CSL689 is 
permissible. 
1.3 Schedule of Activities (SOA)
Deletion
Diary entry of PRO scales at Part 1a Pre-dose
1.3 Schedule of Activities (SOA)
Deletion
Immunogenicity assay at Part 1a Pre-dose
5.2 Exclusion Criteria
Replacement
2. Previous participation in a clinical trial evaluating a modified 
rFVIIa agent (including rFVIIa biosimilars, SC rFVIIa, PEGylated 
rFVIIa, NN1731, BAY86-6150, LR769, rVIIa-FP (CSL689), MOD-
5014).  Note: IV use of NovoSeven® is not an exclusion criteria.
With:
2. Previous participation in a trial involving Subcutaneous 
Administration of rFVIIa (Novo Seven or MOD-5014) or any 
trial using a modified rFVIIa such as: NN1731 or BAY86-6150. 
Prior participation in a trial of LR769 or rFVIIa-FP (CSL689 is 
permissible. 
8.2 Study Procedures
Deletion
Diary entry of PRO scales at Part 1a Pre-dose
8.2 Study Procedures
Deletion
7 hr post-specimen draws at Day 3 and 5: 
MarzAA antigen and activity levels, as well as coagulation 
parameters, will be measured during Part 2 of the study at Day 1 (At 
pre-dose and Hour 7 post-dose, Day 3 (Pre-dose and Post-dose 
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        7 
25 August 2018 
 
Hour 7), Day 5 (Pre-dose and Post-dose Hour 7), Day 7 (Pre-dose 
and Post-dose Hour 7). 
8.2.2.1 Pre-dose evaluations 
Deletion
Immunogenicity assays to FVII, FVIIa, and MarzAA at Part 1a Pre-
dose
8.2.2.1 Pre-dose evaluations
Deletion
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-
QoL; HAL)
APPENDIX B
Updating
Link to HAEM A QoL 
APPENDIX C
Deletion
Diary entry of PRO scales at Pre-dose at Part 1a Pre-dose
APPENDIX C
Deletion
Immunogenicity assays to FVII, FVIIa, and MarzAA at Part 1a Pre-
dose
Administrative changes: Minor changes involving grammar, wordsmithing, punctuation, and other editorial changes have been 
made throughout the document. All are clearly identified in the track-changes version of the amendment.
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Catalyst Biosciences, Inc.

 
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        8 
25 August 2018 
 
ABBREVIATIONS
ABR
Annualized bleeding rate
ADL
Activities of daily living
AE
Adverse event
AICC
Anti-inhibitor coagulant complex
ALT
Alanine aminotransferase
APCC
Activated prothrombin complex concentrates
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI 
Body mass index 
BU
Bethesda Units 
BUN
Blood urea nitrogen
CAD
Coronary artery disease
CBC
Complete blood count
CD4
Cluster of differentiation 4
CFR
Code of Federal Regulations
ClinRO
Clinician reported outcomes
Cmax
Concentration maximum
CMP
Clinical Monitoring Plan
CNS
Central nervous system
Cr
Creatinine
CRF
Case report form
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board
DVT
Deep venous thrombosis
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        9 
25 August 2018 
 
EQAS
External quality assessment scheme 
eCRF 
Electronic Case Report Forms͒
EQ-5D
European Quality of Life-5 Dimensions
F1+2
Prothrombin fragment 1+2
FVII
Factor VII
FVIIa
Factor VII activated
FVIII
Factor VIII
FIX
Factor IX
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GIT
Gastrointestinal Tract
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GS
Gilbert’s syndrome
GWAS
Genome-Wide Association Studies
H0
Null hypothesis
H1
Alternative hypothesis
Haem-A-QoL
Hemophilia A quality of life questionnaire
HAL
Hemophilia Activities List
HIPAA
U.S. Health Insurance Portability and Accountability Act 
Hr
Hour
HTC
Hemophilia Treatment Centre 
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
IDE
Investigational Device Exemption
IEC
Independent Ethics Committee
IMT
Immunomodulatory therapy
IND
Investigational New Drug Application
IP
Investigational product
IRB
Institutional Review Board
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Catalyst Biosciences, Inc.

 
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        10 
25 August 2018 
 
ITI
Immune tolerance induction IV intravenous 
ITT
Intention-To-Treat
IV
Intravenous
LDL
Low-density lipoprotein 
LLN
Lower limit of normal
MarzAA
Marzeptacog alpha (activated)
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minute
MOP
Manual of Procedures
NCT
National Clinical Trial
NDA
New Drug Application
NIH 
National Institutes of Health
OHRP
Office for Human Research Protections
OTC
Over-the-counter
PC
Peak concentration
PCC
Prothrombin complex concentrates 
PD
Pharmacodynamics
PE
Pulmonary embolism
PI
Principal Investigator
PK
Pharmacokinetics
PRO
Patient-reported outcome
PT
Prothrombin time
QA
Quality Assurance
QC
Quality Control
r
Recombinant
rFIX
Recombinant factor IX 
rFVIIa
Recombinant activated factor VIIa 
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SNP
Single nucleotide polymorphisms
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        11 
25 August 2018 
 
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
TEAE
Treatment-emergent adverse event
TAT
Thrombin-antithrombin complexes
TBIL
Total bilirubin level
TE
Thromboembolic event
TGA
Therapeutic Goods Administration
TGT
Thrombin generation time
ULN
Upper limit of normal
UP
Unanticipated Problem
US
United States
VAS
Visual analogue scale
VOD
Volume of distribution
VTE
Venous thromboembolic event
WFH
World Federation of Hemophilia
wt
Wild-type
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        12 
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TABLE OF CONTENTS
Contents
INVESTIGATOR SIGNATURE PAGE .................................................................................................. 3
SPONSOR SIGNATURE PAGE........................................................................................................... 4
ABBREVIATIONS ................................................................................................................................ 8
TABLE OF CONTENTS ......................................................................................................................12
1. 
PROTOCOL SUMMARY..........................................................................................................16
1.1
SYNOPSIS................................................................................................................................................16
1.2
SCHEMA.................................................................................................................................................22
1.3
SCHEDULE OF ACTIVITIES (SOA)...............................................................................................................23
2. INTRODUCTION...........................................................................................................................27
2.1
STUDY RATIONALE........................................................................................................................................27
2.2
BACKGROUND ............................................................................................................................................27
2.2.1
Rationale for Prophylaxis with SC Administration of FVIIa..................................................... 29
2.2.2
Experience with MarzAA in the Clinic ..................................................................................... 30
3. 
OBJECTIVES AND ENDPOINTS ..............................................................................................31
3.1
PRIMARY.................................................................................................................................................31
3.2
SECONDARY ...........................................................................................................................................31
3.3
EXPLORATORY.........................................................................................................................................32
4. 
STUDY DESIGN.........................................................................................................................33
4.1
OVERALL DESIGN ........................................................................................................................................33
4.2
END OF STUDY DEFINITION........................................................................................................................35
5. 
STUDY POPULATION...............................................................................................................36
5.1
INCLUSION CRITERIA.....................................................................................................................................36
5.2
EXCLUSION CRITERIA....................................................................................................................................36
5.3
LIFESTYLE CONSIDERATIONS ......................................................................................................................37
5.4
SCREEN FAILURES.....................................................................................................................................37
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6. 
STUDY INTERVENTION.............................................................................................................38
6.1
STUDY INTERVENTION(S) ADMINISTRATION..................................................................................................38
6.1.1 
Study Intervention Description ................................................................................................. 38
6.1.2 
Dosing and Administration ....................................................................................................... 38
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY .............................................................40
6.2.1 
Acquisition and Accountability ............................................................................................... 40
6.2.2 
Product Storage and Stability.................................................................................................. 41
6.2.3 
Preparation................................................................................................................................. 42
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING...................................................................42
6.4
STUDY INTERVENTION COMPLIANCE ..........................................................................................................42
6.5
CONCOMITANT THERAPY .........................................................................................................................43
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...............................................................................................43
7.1
DISCONTINUATION OF STUDY INTERVENTION...............................................................................................43
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY................................................................. 43
7.3
LOST TO FOLLOW-UP ...............................................................................................................................44
8. 
STUDY ASSESSMENTAND PROCEDURES ..............................................................................46
8.1
EFFICACY ASSESSMENTS ...........................................................................................................................46
8.2
STUDY PROCEDURES ................................................................................................................................47
8.2.1 
Screening.................................................................................................................................... 47
8.2.2 
Part 1a (Duration 24 Hours)....................................................................................................... 48
8.2.3 
Part 1b (Duration: 48 Hours)...................................................................................................... 50
8.2.4 
3DUW'XUDWLRQ'D\V....................................................................................................... 52
8.2.5 
Part 2 – ,I1R6SRQWDQHRXV%OHHGLQJ2FFXUVDIWHUWKHILIWKGDLO\GRVH'XUDWLRQ
Days)  ..................................................................................................................................................... 55
8.2.6 
Part 2 – ,I6SRQWDQHRXV%OHHGLQJ2FFXUVDIWHUWKHILIWKGDLO\GRVH'XUDWLRQ'D\V . 57
8.2.7 
Unscheduled Visit ...................................................................................................................... 61
8.2.8 
End-of-Study Visit (30 Days after Last Dose) ........................................................................... 62
8.3
STUDY ASSESSMENTS ................................................................................................................................63
8.3.1 
Physical Examination................................................................................................................. 63
8.3.2 
Vital signs .................................................................................................................................... 63
8.3.3 
Hematology ............................................................................................................................... 63
8.3.4 
Chemistry.................................................................................................................................... 63
8.3.5 
Coagulation assays................................................................................................................... 63
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MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        14 
25 August 2018 
 
8.3.6 
Thrombogenicity markers ......................................................................................................... 63
8.3.7 
Antibody response and neutralizing antibodies to MarzAA ................................................ 63
8.3.8 
Clinical signs of thrombosis (Appendix A) .............................................................................. 63
8.3.9 
Concomitant medications....................................................................................................... 64
8.3.10 
ECG......................................................................................................................................... 64
8.3.11 
Troponin levels ....................................................................................................................... 64
8.4
SAFETY AND OTHER ASSESSMENTS .............................................................................................................64
8.4.1 
AEs and SAEs .............................................................................................................................. 64
8.4.2 
Injection site reactions .............................................................................................................. 64
8.5
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.......................................................................................65
8.5.1 
Definition of Adverse Events (AE) ............................................................................................ 65
8.5.2 
Definition of Serious Adverse Events (SAE).............................................................................. 65
8.5.3 
Classification of an Adverse Event.......................................................................................... 66
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up...................................... 67
8.5.5 
Adverse Event Reporting.......................................................................................................... 68
8.5.6 
Serious Adverse Event Reporting............................................................................................. 69
8.5.7 
Adverse Events of Special Interest (AESIs) .............................................................................. 70
8.5.8 
Reporting of Pregnancy ........................................................................................................... 71
9. 
STATISTICAL CONSIDERATIONS.............................................................................................72
9.1
STUDY HYPOTHESIS .......................................................................................................................................72
9.2
SAMPLE SIZE DETERMINATION........................................................................................................................74
9.3
POPULATIONS FOR ANALYSES........................................................................................................................74
9.4
STATISTICAL ANALYSIS...................................................................................................................................74
9.4.1
General Approach.................................................................................................................... 74
9.4.2 
Analysis of the Primary Efficacy Endpoint(s)........................................................................... 75
9.4.3 
Analysis of the Secondary Endpoint(s).................................................................................... 75
9.4.4 
Safety Analysis............................................................................................................................ 76
9.4.5 
Baseline Descriptive Statistics................................................................................................... 77
9.4.6 
Planned Interim Analyses.......................................................................................................... 77
9.4.7 
Sub-Group Analyses.................................................................................................................. 77
9.4.8 
Tabulation of Individual Participant Data .............................................................................. 77
9.4.9 
Exploratory Analyses.................................................................................................................. 77
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.......................78
10.1 REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS.....................................................................78
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10.1.1
Informed Consent Process .................................................................................................. 78
10.1.2 Institutional Review Board/Independent Ethics Committee.................................................. 78
10.1.3 
Study Discontinuation and Closure..................................................................................... 79
10.1.4 
Confidentiality and Privacy ................................................................................................. 79
10.1.5 
Future Use of Stored Specimens and Data........................................................................ 80
10.1.6 
Safety Oversight .................................................................................................................... 80
10.1.7 
Clinical Monitoring ................................................................................................................ 80
10.1.8 
Quality Assurance and Quality Control.............................................................................. 81
10.1.9 
Data Handling and Record Keeping.................................................................................. 82
10.1.10 
Protocol Amendments ......................................................................................................... 83
10.1.11 
Publication and Data Sharing Policy.................................................................................. 83
10.2
PROTOCOL AMENDMENT HISTORY ............................................................................................................84
11. 
REFERENCES........................................................................................................................85
APPENDICES....................................................................................................................................90
APPENDIX A – CLINICAL SIGNS OF THROMBOSIS ......................................................................................................90
APPENDIX B – PATIENT REPORTED OUTCOME (PRO) SCALES ....................................................................................98
APPENDIX C – DETAILED STUDY SCHEMA..............................................................................................................110
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25 August 2018 
 
1.  
PROTOCOL SUMMARY
1.1 
SYNOPSIS
Title of Study: Phase 2 study to evaluate the pharmacokinetics, bioavailability, 
pharmacodynamics, efficacy and safety of a daily subcutaneous treatment regimen 
with marzeptacog alfa (activated) for bleeding prophylaxis in adult subjects with 
hemophilia A and B with an inhibitor
Primary Objective: To evaluate the efficacy and safety of a daily subcutaneous (SC)
treatment regimen with MarzAA for bleeding prophylaxis in adult subjects with 
Hemophilia A and B with an inhibitor.
Secondary Objectives: 
x
To determine the pharmacokinetics (PK) of SC MarzAA.
x
To determine the bioavailability of MarzAA when given via SC.
x
To determine the pharmacodynamics (PD) of SC MarzAA.
x
To evaluate and compare the levels of thrombogenicity markers following 
administration of a SC dose of 30 μg /kg MarzAA with the IV dose of 18 μg/kg MarzAA.
x
To evaluate for evidence of the development of antibodies to MarzAA, wild type 
recombinant factor VIIa (wt-rFVIIa), and/or wt-FVII, and to determine if these are 
neutralizing antibodies.
x
To determine the annualized bleeding rate (ABR) during MarzAA treatment compared 
to the rate of historic on-demand treatments.
Study Population: Twelve male subjects, aged 18 or older, with confirmed diagnosis of 
severe congenital hemophilia A or B with an inhibitor and history of frequent spontaneous 
EOHHGLQJHSLVRGHVKLVWRULFDODQQXDOL]HGEOHHGLQJUDWH>$%5@RI
Phase of Development:  Phase 2
Description of Sites: Multinational study conducted at up to approximately 10 centers.
Study Duration: Approximately 1 year
Participant Duration: The minimum duration of treatment for each subject is 
approximately 2 months (if no dose escalation is required) and the maximum duration is 
approximately 7 months (if three dose escalations are required).
Screening: Up to 4 weeks 
Part 1a: 24 hours (single IV dosing and PK/PD/Safety testing)
Part 1b: 48 hours (single SC dosing and PK/PD/safety testing)
Part 2: Up to 197 days of daily SC dosing
Note: Where interruptions to study drug dosing days are observed, study duration may be 
extended to incorporate full dosing schedule.
Follow-up: Two weeks after last dose for PK/PD/safety follow-up and then approximately 
and additional 2 weeks follow-up to study completion.
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CONFIDENTIAL
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___________________________________________________________________
Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        17 
25 August 2018 
 
Subjects must have no spontaneous bleeding for 50 days at any dose level and at least 
50 exposure days and 30 days post-treatment follow-up to complete the study. Subjects 
escalating to 120 μg/kg will continue treatment for 50 exposure days to determine the 
bleed rate.
Study Methodology
This multi-center, open-label Phase 2 study will evaluate the PK, bioavailability, PD, 
efficacy and safety of a daily SC treatment regimen with MarzAA for bleeding 
prophylaxis in adult subjects with hemophilia A and B with an inhibitor. The study will enroll 
and dose, both intravenously and subcutaneously, a total of 12 adult male subjects with 
severe congenital hemophilia A or B with an inhibitor, and history of frequent bleeding 
episodes during the 6 months prior to enrollment, as per the individual’s bleeding and 
treatment records.
At the screening visit and prior to any study procedures, subjects will sign an informed 
consent form (ICF).  Eligibility to participate in the study will be determined by inclusion 
and exclusion criteria elicited from medical history, hemophilia history, physical
examination, laboratory assessments and an electrocardiogram (ECG). At screening, 
subjects will be provided with a diary in which they will be instructed to record any 
adverse events (AEs) and concomitant medication. The screening period duration may 
be up to 4 weeks.
After the first IV dose of MarzAA, subjects will record daily study drug administration (to 
assess compliance), injection site assessment, any AEs they may experience, and 
bleeding episodes (location, inciting event if not spontaneous, and treatment 
administered), and patient reported outcome (PRO) scales. 
Once a subject is enrolled into the trial, the study will be conducted in two phases 
consisting of three parts (occurring consecutively):
Part 1: Single dose administration
Part 1a (24 hours): Single IV administration of MarzAA at 18 μg /kg with assessment of PK, 
PD, and safety for 24 hours post-dose. 
Part 1b (48 hours): Single SC administration of MarzAA at 30 μg /kg with assessment of PK, 
PD, and safety for 48 hours post-dose
Part 2:  Daily SC administration
Daily SC administration of MarzAA at 30 μg /kg with assessment of PK, PD, and safety at 
designated days for 50 treatment days.
If dose escalation is required because of a spontaneous bleeding episode, then 
assessments of PK, PD, and safety will be at designated days for an additional 50 
treatment days.
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        18 
25 August 2018 
 
Study Treatment and Assessments:
Part 1a: Single IV administration
Each subject will receive an IV dose of 18 μg/kg MarzAA. PK, PD, and safety assessments 
will be collected pre-dose and post-dose at 5 and 30 minutes and at Hour 1, 3, 6, 9, 12, 
and 24.
Part 1b: Single SC administration
After the initial 24 hours, the same subject will receive a SC dose of 30 μg/kg MarzAA. PK, 
PD, and safety assessments will be done at pre-dose and repeated at Hour 3, 5, 7, 9, 12, 
24, 30, and 48. At any time during this period, subjects will be trained by appropriate 
study staff to self-administer a SC injection.
Part 2: Daily SC administration 
At Day 1 of daily SC dosing, subjects will begin their self-administered dosing regimen.  
MarzAA will be self-administered by subjects daily (at approximately the same time every 
day), starting with a SC dose of 30 μg/kg MarzAA.  At each dose, subjects will record the 
day and time of the SC injections in their diary. If a spontaneous bleeding episode 
(defined as one that is precipitated by normal activities of daily living [ADL]) occurs 
before the fifth daily dose, subjects will continue at the current dosing level. If a 
spontaneous bleeding episode occurs after the fifth daily dose, the MarzAA dose will be 
escalated to the next dose level. Three dose escalations are allowed during part 2: 60, 90, 
and 120 μg/kg (maximum dose). At each dose level escalation, safety and PK/PD will be 
monitored to ensure that dose escalation to a higher dose level is appropriate. If a 
subject requires a third dose escalation to the fourth dose level, then they will continue 
treatment with that dose for 50 days and complete the study, regardless if a spontaneous 
bleeding episode occurs during the highest treatment dose level.
Treatment of a spontaneous bleeding episode: Subjects will use their current bypass 
regimen for any spontaneous or traumatic bleed that occurs while on study drug. If 
treatment for a breakthrough bleeding episode is needed, then subjects will contact the 
clinical investigative team immediately to report the event; treatment dose administered; 
and determine follow-up plans for that event, including to arrange for a blood specimen 
to be drawn (if feasible) before further administration of either study drug or bypassing 
agent used for treatment.  This information will also be recorded in the subjects’ diary.
Dose interruption and surgery: Daily SC study injections will be interrupted, as needed, if 
there is a need for a surgical procedure; an event requiring extended (>48 hours) 
hospitalization; a thrombotic event; clinical evidence of inhibitor formation; or laboratory 
results suggesting an antibody may be developing.
Measurements:
MarzAA antigen and activity levels, as well as coagulation parameters, will be measured 
during Part 2 of the study at Day 1 (At pre-dose and Hour 7 post-dose, Day 3 (Pre-dose), 
Day 5 (Pre-dose), Day 7 (Pre-dose and Post-dose Hour 7). 
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CONFIDENTIAL
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___________________________________________________________________
Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        19 
25 August 2018 
 
If no spontaneous bleeding occurs at the first dose level in part 2 of the study, trough 
antigen and activity, as well as coagulation parameters, will be measured on days 14, 21, 
28, and 50 after starting their dosing regimen. 
If spontaneous bleeding occurs after the fifth daily dose at any dose level, MarzAA 
antigen and activity levels will be measured within 6 hours of the spontaneous bleed (if 
feasible).  Specimens for coagulation and immunogenicity testing will also be drawn.
Once it is determined to escalate to the next dose level, a pre-dose and Hour 7 post-
dose specimen, will be drawn for PK, coagulation, and thrombogenicity markers on Day 
7 after the dose has been escalated to estimate the new trough and peak 
concentrations (PCs) and PD.  MarzAA antigen and activity levels, as well as coagulation 
parameters, will then be measured (pre-dose) at Day 14, 21, 28, and 50 after dose 
escalation.  
Immunogenicity assays: Specimens for immunogenicity testing (antibody to MarzAA, 
neutralizing activity, cross reactivity) will be drawn at screening, Part 1a pre-dose, Part 1b 
pre-dose, and during part 2 pre-dose on Day 1, 7, 14, 21, 28, and 42, and then every two 
weeks until end of study.
Number of planned subjects: 12
Trial population:
Inclusion criteria: 
1.
Confirmed diagnosis of severe congenital hemophilia A or B with an inhibitor. 
2.
History of frequent spontaneous bleeding episodes (historical annualized bleeding 
rate [ABR] of 12).
3.
Male, age 18 or older.
4.  
Agreement to use highly effective birth control throughout the study.  
5. 
Affirmation of informed consent with signature confirmation before any trial-
related activities. (Trial related activities are any procedure that would not have 
been performed during normal clinical management of the subject).
6.         Stated willingness to comply with all study procedures and availability for the 
duration of the study. 
Exclusion criteria: 
1.
Receiving prophylaxis treatment. 
2.
Previous participation in a trial involving Subcutaneous Administration of rFVIIa 
(Novo Seven or MOD-5014) or any trial using a modified rFVIIa such as: NN1731 or 
BAY86-6150. Prior participation in a trial of LR769 or rFVIIa-FP (CSL689) is permissible.  
3.
Previous participation in and subsequent treatment in a clinical trial within the 
previous 30 days or 3-half-lives or absence of clinical effect, whichever is longer.
4. 
Known positive antibody to FVII or FVIIa detected by central laboratory at 
screening. 
5. 
History of clinically relevant coagulation disorders other than congenital 
hemophilia A or B.
6.
Platelet count <100,000 based on screening laboratory assessments.
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        20 
25 August 2018 
 
7.
Advanced atherosclerotic disease (i.e. known history of coronary artery disease 
(CAD), ischemic stroke, etc.), or known deep venous thrombosis (DVT) or 
considered to be at a high risk of venous thromboembolic event (VTE) as judged 
by the Investigator.
8. 
Known or suspected allergy to trial product or related products.
9. 
Absolute cluster of differentiation 4 (CD4) count <200 cellsǍ/
10. 
Receiving immunomodulatory therapy (IMT). 
11. 
Compromised hepatic or renal function:
o
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 
WLPHVWKHXSSHUOLPLWRIQRUPDO8/1
o
Total bilirubin level (TBIL) PJG/!ǍPRO/XQOHVVWKHUHLVDNQRZQ
history of Gilbert’s syndrome (GS)
o
6HUXPDOEXPLQWKHORZHUOLPLWRIQRUPDO//1
o
Serum creatinine (Cr) level >1.25 x ULN  
12. 
Inability or medical, psychosocial, or familial issues that might prevent full 
participation and cooperation with the procedures and requirements of the 
clinical trial as determined by the potential subject and physician investigator.
Investigational product, dose, and mode of administration: 
Investigational Product: Recombinant Factor VII variant, Marzeptacog alfa (activated) 
[MarzAA]  
Dosage and mode of administration: Single IV dose at 18 μg/kg and then an initial SC
doses at 30 μg/kg.  Dose levels may increase to 60, 90, or 120 μg/kg, as required
Reference therapy: None
Concomitant Medications: In the event of spontaneous or traumatic bleeding, treatment 
for a bleeding episode will be permitted using the subject’s current treatment regimen 
which could be FEIBA® (anti-inhibitor coagulant complex [AICC]), NovoSeven®
(recombinant wild-type factor VII activated [wt-rFVIIa]), or a high dose regimen utilizing a 
FVIII or FIX product.
Efficacy and Safety Evaluations
Primary endpoints:
x
Annualized bleed (spontaneous and total) rate (ABR) during Part 2 when on final 
MarzAA dose level versus recorded historical ABR.  
Secondary endpoints:
x
Occurrence of breakthrough bleeds requiring escalation to higher dose level.
x
Safety parameters: Occurrence of clinical thrombotic event not attributable to 
another cause, and occurrence of antibody formation resulting in a decreased 
endogenous level of FVII or FVIIa.
x
Change in coagulation parameters (prothrombin time [PT], activated partial 
thromboplastin time [aPTT], fibrinogen, MarzAA antigen and activity levels, and 
thrombin generation time [TGT]) from pre-dose.
x
Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-
reactive to wild-type recombinant FVIIa (wt-rFVIIa) or wt-FVII.
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        21 
25 August 2018 
 
x
Clinically significant levels of thrombogenicity markers resulting from daily SC 
administration of MarzAA.  
x
Feasibility and ease of use of daily SC self-administration by subject as measured by 
compliance with treatment. 
Exploratory endpoints
x
Identification of biomarker(s) such as antigen levels, activity levels, or global 
thrombosis assay evaluation that can be used to predict or correlate with a subject’s 
lack of spontaneous bleeding.
x
Identification of biomarker(s) such as D-dimer, F1+2, or a functional assay of the FVIIa 
activity that will identify or predict clinical thrombogenicity with the daily SC
administration of MarzAA.
x
Identification of biomarker(s) such as D-dimer, F1+2, or a functional assay of the FVIIa 
activity that will identify or predict clinical thrombogenicity of daily SC administration 
of MarzAA when use of rescue medication is required.
x
PRO measures: European Quality of Life-5 Dimensions(EQ-5D), Visual analogue scale 
(VAS); Hemophilia A quality of life questionnaire(Haem-A-QoL); Hemophilia Activities 
List (HAL) 
Statistics
Primary Analysis Plan: 
Standard pharmacokinetic parameters, such as terminal half-life, AUC0-t, clearance, 
mean residence time and volume of distribution will be calculated. In addition, the 
bioavailability of the SC administration will be computed. Descriptive statistics for these 
parameters will be reported. The number of subjects requiring dose escalation will be 
reported. 
The analysis of the primary endpoint (ABR) of the final dose used to treat a subject will be 
based on the evaluation of the ABR of MarzAA compared to a rate for on-demand 
therapy. The latter is assumed to be 12, ie, 1 bleed per month, as our null hypothesis (H0). 
The comparison of the actual ABR for MarzAA either pooled across all doses used or 
evaluated at the highest dose for an individual will be compared to this null hypothesized 
value using the one-sample test for a Poisson rate (using an exact calculation of the p-
value). Because this will be a one-tailed test (the alternative hypothesis [H1] is the ABR for 
MarzAA will be < 12), a one-tailed 2.5% significance level will be used.
Rationale for Number of Subjects:
With a total of 12 subjects and assuming a null hypothesis of an ABR of 12, then the 
demonstration of a reduction to an ABR of 6 or less with a one-tailed 2.5% significance 
level would be accomplished with near 100% power using a one sample Poisson test of 
the null hypothesis. Even if only 6 subjects were available to be pooled for this analysis, 
the power would still be in excess of 99%.
Name of sponsor: Catalyst Biosciences
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CONFIDENTIAL
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        22 
25 August 2018 
 
1.2 
SCHEMA
Figure 1. Schematic of Study Design (see Appendix D for a more detailed schema)
Screening
Part 1a
Part 1b
Part 2
x Eligibility criteria
x Medical + hemophilia history
x Concomitant medications
x Vital signs
x Weight
x Physical examination
x Clinical signs of thrombosis
x Hematology and chemistry
x Coagulation assays
x Thrombogenicity assays
x PK sampling
x Immunologenicity assays
x Tropinin level
x ECG
x Diary entry of PRO scales 
x Diary entry of bleeding 
episodes, AEs, injection site 
assessment
x Adverse events
x Administration of MarzAA IV
x Informed consent
x Demographic parameters
x Eligibility criteria
x Medical + hemophilia history
x Concomitant medications
x Vital signs
x Height and weight
x Physical examination
x Clinical signs of thrombosis
x Hematology and chemistry
x Coagulation assays
x Thrombogenicity assays
x PK sampling
x Immunologenicity assays
x Tropinin level
x ECG
x Participant training
x PRO scales diary entry
x Adverse events
x Medical + hemophilia history
x Concomitant medications
x Vital signs
x Weight
x Physical examination
x Clinical signs of thrombosis
x Hematology and chemistry
x Coagulation assays
x Thrombogenicity assays
x PK sampling
x Immunologenicity assays
x Tropinin level
x ECG (only for Phase 1b)
x Diary entry of PRO scales 
x Diary entry of bleeding episodes, AEs, injection site 
assessment
x Adverse events
x Administration of MarzAA SC
x Participant training on SC administration and proficiency 
confirmation (Phase 1b)
x IP compliance and proficiency confirmation; IP 
dispensing, inventory and accountability (Phase 2)
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CONFIDENTIAL
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___________________________________________________________________
Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        23 
25 August 2018 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA)
Table 1. Part D6LQJOHGRVHDGPLQLVWUDWLRQRI0DU]$$ǍJNJ,9
Study Period
Screening
Treatment
Study Day/Hour
(Up to 4 
weeks
prior)
Pre-
dose
(- 5 min)
Dosing
(Hr 0) 
Post-dose (at 
5 and 30 min)
(+ 2 m)
Hr 1
(+ 10 m)
Hr 3
(+ 10 m)
Hr 6
(+ 10 m)
Hr 9
(+ 30 m)
Hr 12
(+ 30 m)
Hr 24
(+ 1.5 hr)
Informed Consent
X
Demographic Parameters
X
Inclusion and Exclusion Criteria review
X
X
Medical and Hemophilia History1
X
X
X
Concomitant Medications1
X
X
X
Vital Signs
X
X
X
Height (screening only) & Weight
X
X
X
Physical Examination1
X
X
X
Clinical Signs of Thrombosis2
X
X
X
Hematology and Chemistry3
X
X
X
Coagulation Assays4
X
X
X
X
X
X
X
X
X
Thrombogenicity markers4
X
X
X
X
X
X
X
X
X
Pharmacokinetic (PK) sampling4
X
X
X
X
X
X
X
X
Immunogenicity assays4
X
Troponin level3
X
X
X
ECG
X
X
Study Subject Training5
X
Diary entry of PRO scales6
X
X
Diary entry of bleeding episodes, AEs, injection site assessment
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
MarzAA administration
X
1.
Complete evaluation at Screening followed by interim targeted evaluation, per Investigator’s discretion, as indicated on presentation of subject at study visit and review of diary entries (including PRO scales).
2.
Clinical Signs of Thrombosis – See Appendix A. 
3.
Local Laboratory: Hematology - CBC and platelet count, CD4.  Chemistry - Sodium, potassium, chloride, bicarbonate, hepatic enzymes (ALT, AST, GGT), bilirubin, albumin, BUN, creatinine.  Troponin Level.
4.
Central Laboratory:  Coagulation assays – PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT.  Thrombogenicity markers – D-dimer, F1+2, and TAT.  Pharmacokinetics – MarzAA antigen and activity. Immunogenicity assays – to FVII, FVIIa, 
and MarzAA.
5.
  Training of investigational drug administration & injection site assessment, spontaneous or traumatic bleeding episodes & treatment, evaluation & diary entry of AEs, & patient reported outcome (PRO) scales.
6.
PRO scales (Appendix B):  EQ-5D, VAS; Haem-A-QoL; HAL.
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CONFIDENTIAL
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        24 
25 August 2018 
 
Table 2. Part E6LQJOHGRVHDGPLQLVWUDWLRQRI0DU]$$ǍJNJ6&LPPHGLDWHO\IROORZLQJPart 1a)
Study Period
Treatment
Study Day/Hour
Pre-dose*
(- 5 min)
Dosing
(Hr 0) 
Hr 3
(+ 10 m)
Hr 5
(+ 10 m)
Hr 7
(+ 10 m)
Hr 9
(+ 30 m)
Hr 12
(+ 30 m)
Hr 24
(+ 1.5 hr)
Hr 30
(+ 1.5 hr)
Hr 48
(+ 1.5 hr)
Medical and Hemophilia History1
X
X
X
Concomitant Medications1
X
X
X
Vital Signs
X
X
X
Weight
X
X
X
Physical Examination1
X
X
X
Clinical Signs of Thrombosis2
X
X
X
Hematology and Chemistry3
X
X
X
Coagulation Assays4
X
X
X
X
X
X
X
X
X
Thrombogenicity markers4
X
X
X
X
X
X
X
X
X
Pharmacokinetic (PK) sampling4
X
X
X
X
X
X
X
X
X
Immunogenicity assays4
X
Troponin level3
X
X
ECG
X
Diary entry of PRO scales5
X
X
X
Diary entry of bleeding episodes, AEs, injection site assessment
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
MarzAA administration
X
SC administration training & proficiency confirmation
X
X
X
*NOTE: Assessments required for Pre-dose in Part 1b that have been completed at Hour 24 in Part 1a do not have to be repeated if within 2 days.  
1.
Complete evaluation at Screening followed by interim targeted evaluation, per Investigator’s discretion, as indicated on presentation of subject at study visit and review of diary entries (including PRO scales).
2.
Clinical Signs of Thrombosis – See Appendix A. 
3.
Local Laboratory: Hematology - CBC and platelet count, CD4.  Chemistry - Sodium, potassium, chloride, bicarbonate, hepatic enzymes (ALT, AST, GGT), bilirubin, albumin, BUN, creatinine.  Troponin Level.
4.
Central Laboratory:  Coagulation assays – PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT.  Thrombogenicity markers – D-dimer, F1+2, and TAT.  Pharmacokinetics – MarzAA antigen and activity.  Immunogenicity assays – to FVII, FVIIa, 
and MarzAA.
5.
PRO scales (Appendix B):  EQ-5D, VAS; Haem-A-QoL; HAL.
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CONFIDENTIAL
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        25 
25 August 2018 
 
Table 3. Part 2: Daily SC administUDWLRQRI0DU]$$ǍJNJ6&IROORZLQJPart 1b), no spontaneous bleeding occurs after the fifth daily dose. 
Study Period
Treatment
Study Day/Hour
Day 1*
Day 3
(+1d)
Day 5 
(+1d)
Day 7 
(+1d)
Day 14 
(+2d)
Day 21 
(+2d)
Day 28 
(+2d)
Day 42 
(+3d)
Day 50 
(+3d)
Un-
sched-
uled9
End of 
Study10
Medical and Hemophilia History1
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Clinical Signs of Thrombosis2
X
X
X
X
X
X
X
X
X
X
X
Hematology and Chemistry3
X
X
X
X
X
X
X
X
Coagulation Assays4,5
X
X
X
X
X
X
X
X
X
X
Thrombogenicity markers4,5
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic (PK) sampling4,5
X
X
X
X
X
X
X
X
X
X
Immunogenicity assays4,6
X
X
X
X
X
X6
X6
X
Troponin level3
X
X
Diary entry of PRO scales7
X
X
X
X
X
X
X
X
X
Diary entry of IP, bleeding episodes and treatment, 
AEs, injection site assessment
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
SC Daily MarzAA administration8
IP compliance & proficiency confirmation
X
X
X
X
X
X
X
X
X
X
IP dispensing, inventory and accountability
X
X
X
X
X
X
X
X
X
X
X
*NOTE: Assessments required for Day 1 that have been completed at Hour 48 in Part 1b do not have to be repeated if within 2 days.  
** Assessments performed on Day 3, 5, 7, 14, 21, 28, 42, and 50 will be done pre-dose, unless otherwise specified.
1.
Interim targeted evaluation, per Investigator’s discretion, as indicated on presentation of subject at study visit and review of diary entries (including PRO scales).
2.
Clinical Signs of Thrombosis – See Appendix A. 
3.
Local Laboratory: Hematology - CBC and platelet count, CD4.  Chemistry - Sodium, potassium, chloride, bicarbonate, hepatic enzymes (ALT, AST, GGT), bilirubin, albumin, BUN, creatinine.  Troponin Level.
4.
Central Laboratory:  Coagulation assays – PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT.  Thrombogenicity markers – D-dimer, F1+2, and TAT.  Pharmacokinetics – MarzAA antigen and activity.  Immunogenicity assays – to FVII, FVIIa, 
and MarzAA.
5.
Days 1, 3, 5, 7, 14, 21, 28, 50: Sampling is done predose and predose at 7 hours. MarzAA antigen and activity levels, as well as coagulation parameters, will be measured during Part 2 of the study at Day 1 (at predose and Hour 7 predose; 
Day 3 (Predose only), Day 5 (Predose only), and Day 7 (Predose only)
6.
After Day 42, sampling will be done every two (2) weeks until the End of Study visit.
7.
PRO scales (Appendix B):  EQ-5D, VAS; Ham-A-QoL; HAL.
8.
Subjects must have been at the same dose level for 50 days to complete the study.
9.
At an Unscheduled Visit, perform only the assessments as appropriate to the reason for the visit.
10.
End of Study Visit will occur 30 days after the last dose.
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25 August 2018 
 
Table 4. Part 2: If spontaneous bleeding occurs after the fifth daily dose (only if necessary)
Study Period
Treatment
Study Day/Hour
Day 0*
Day 7 
(+1d)
Day 14 
(+ 2d)
Day 21 
(+ 2d)
Day 28 
(+ 2d)
Day 42 
(+ 3d)
Day 50 
(+3d)
Un-
scheduled10
End of 
Study11
Medical and Hemophilia History1
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
Clinical Signs of Thrombosis2
X
X
X
X
X
X
X
X
X
Hematology and Chemistry3
X
X
X
X
X
X
X
Coagulation Assays4,6
X5
X
X
X
X
X
X
X
Thrombogenicity markers4,6
X
X
X
X
X
X
X
Pharmacokinetic (PK) sampling4,6
X5
X
X
X
X
X
X
X
Immunogenicity assays4,7
X5
X
X
X7
X7
X
Troponin level3
X
X
X
Diary entry of PRO scales8
X
X
X
X
X
X
X
X
Diary entry of IP, bleeding episodes and treatment, AEs, injection site assessment
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
SC Daily MarzAA administration9
IP compliance & proficiency confirmation
X
X
X
X
X
X
X
IP dispensing, inventory and accountability
X
X
X
X
X
X
X
X
X
* NOTE: When a spontaneous bleeding episode and dose escalation occurs, the “day count” is reset to zero.  The day the spontaneous bleeding episode occurs and 
subsequent time until treatment resolution is considered Day 0.  Dose escalation starts the next day (Day 1).  
**Assessments performed on Day 7, 14, 21, 28, 42, and 50 will be done pre-dose, unless otherwise specified.
1.
Interim targeted evaluation, per Investigator’s discretion, as indicated on presentation of subject at study visit and review of diary entries (including PRO scales).
2.
Clinical Signs of Thrombosis – See Appendix A. 
3.
Local Laboratory: Hematology - CBC and platelet count, CD4.  Chemistry - Sodium, potassium, chloride, bicarbonate, hepatic enzymes (ALT, AST, GGT), bilirubin, albumin, BUN, creatinine.  Troponin Level.
4.
Central Laboratory:  Coagulation assays – PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT.  Thrombogenicity markers – D-dimer, F1+2, and TAT.  Pharmacokinetics – MarzAA antigen and activity.  Immunogenicity assays – to FVII, FVIIa, 
and MarzAA.
5.
Day 0 PK sampling should occur within 6 hours of spontaneous bleed, if feasible.
6.
Days 7, 14, 21, 28, 50:  Sampling will be done Pre- and Post-dose at 7 hours.
7.
After Day 42, sampling will be done every two (2) weeks until the End of Study visit.
8.
PRO scales (Appendix B):  EQ-5D, VAS; Haem-A-QoL; HAL.
9.
Subjects must have been at the same dose level for 50 days to complete the study.
10.
At an Unscheduled Visit, perform only the assessments as appropriate to the reason for the visit.
11.
End of Study Visit will occur 30 days after the last dose.
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        27 
25 August 2018 
2. INTRODUCTION
2.1 STUDY RATIONALE
A significant number of patients with hemophilia A develop neutralizing 
antibodies (“inhibitors”) against factor VIII and become refractory to standard 
factor replacement treatment.1-4 Hemophilia A is four times as common as 
hemophilia B.5 Patients with Hemophilia B can also develop neutralizing 
antibodies and become refractory to factor replacement therapy.6-8 Currently, 
available treatment for patients with hemophilia A and B with inhibitors is with 
rFVIIa or with APCCs. The prevention of bleeding episodes, referred to as 
prophylaxis, requires frequent intravenous dosing.9 Catalyst Biosciences has 
created a FVIIa variant with pre-clinical properties that suggest increased 
potency and duration and the ability to be administered subcutaneously for 
daily use as prophylaxis. 
2.2 BACKGROUND
Hemophilia A and B are X-linked, recessive, hereditary bleeding disorders caused 
by an impaired deficiency of coagulation factor VIII (FVIII) (hemophilia A) or factor 
IX (FIX) (hemophilia B).10 The prevalence of Hemophilia A is 1 in 5000 live male births 
and hemophilia B is 1 in 30,000 (hemophilia A is four times as common as 
hemophilia B).5 Disease classification of mild (>5 and <40%), moderate (1 to 5%) 
or severe (<1%) is based on plasma FVIII and FIX levels.11 Bleeding is the main 
clinical manifestation, which can occur spontaneously, especially in severe 
hemophilia. Bleeding most often affects the joints, causing arthropathy with 
significant impairment of mobility and quality of life. Other sites can include the 
soft tissue, gastrointestinal tract (GIT) and central nervous system (CNS).12,13
Treatment of hemophilia A or hemophilia B typically involves factor replacement 
therapy by IV injection of FVIII or FIX concentrate respectively to treat or provide 
prophylaxis against bleeding episodes.10 Factor replacement therapy is also used 
for surgical hemostasis and to maintain hemostasis during the post-operative 
wound healing period.  Neutralizing antibodies (inhibitors) to the injected FVIII or 
FIX are a complication of factor replacement therapy that develops in 
approximately one-third of hemophilia A patients and in up to 5% of hemophilia B 
patients14-17 Inhibitors can occur at high or low titer (quantitated in Bethesda Units 
[BU]), can neutralize the activity of the replacement therapy, and can make 
treatment of bleeding episodes unsuccessful, resulting in potentially catastrophic 
clinical consequences for the patient, including an increased morbidity and 
mortality risk.10,17
For hemophilia patients with high titer inhibitors to FVIII or FIX and for hemophilia 
patients with low titer inhibitors in whom it is not possible to achieve hemostasis 
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25 August 2018 
using FVIII or FIX replacement therapy, respectively, the current standard of care
includes treatment with wt-rFVIIa (NovoSeven® or NovoSeven® RT, Novo Nordisk) 
or activated prothrombin complex concentrates (APCCs), including AICC,
(FEIBA®, Baxalta Incorporated).4,18-22 These agents fall in the category of bypass 
agents and effect hemostasis by achieving conversion of prothrombin to thrombin 
via the tissue factor pathway (extrinsic pathway) of coagulation or via a 
combination of the tissue factor pathway and the final common pathway of 
coagulation respectively.23 NovoSeven®, a wt-rFVIIa, was approved by the Food 
and Drug Administration (FDA) in March 1999, for the treatment of bleeding 
episodes in hemophilia A (FVIII-deficient) or hemophilia B (FIX-deficient) patients 
with inhibitors, and in patients with congenital FVII deficiency.  It is also approved 
for prevention of bleeding prior to surgery or invasive procedures in these patients 
with inhibitors or FVII deficiency. Based on its very short (2.3 hours) half-life,
administration of NovoSeven® is repeated approximately every 2 hours to control 
hemorrhage in patients with hemophilia A or B with inhibitors. 4,18-22 Often, multiple 
doses (3 or more) are required to complete treatment of a bleeding episode.9
Activated prothrombin complex concentrates (APCCs) were introduced for 
treatment of inhibitors in patients with hemophilia in the 1970s.24 The only APCC 
currently available on a commercial basis is FEIBA® which was first marketed in 
1977 and was first licensed in the US as FEIBA VH® (vapor heat-treated FEIBA). FEIBA 
VH® was manufactured via vapor heat treatment to inactivate lipid-enveloped 
RNA and DNA viruses and non-enveloped RNA viruses. In 2006 Baxter introduced 
nanofiltration to the manufacturing process of FEIBA VH® to create FEIBA NF®.
During 2010, FEIBA VH® was completely replaced by FEIBA NF® on a worldwide 
basis.24 FEIBA VH® and FEIBA NF® and is now available as FEIBA®. FEIBA® and FEIBA 
NF® are identical in formulation to FEIBA VH®. 24-26 FEIBA® is indicated for the control 
and prevention of bleeding episodes, routine prophylaxis to prevent or reduce the 
frequency of bleeding episodes and to cover surgical interventions in hemophilia 
A and hemophilia B patients with inhibitors. For treatment of bleeding episodes in 
hemophilia patients with inhibitors, FEIBA® is typically administered in doses of 50 to 
100 units/kg, determined by the type of bleeding episode.  Repeat administration, 
if required, is typically administered at 6-12-hour intervals until resolution of bleed 
or alleviation of symptoms. For prophylaxis, the approved dose of FEIBA® is 85 
units/kg administered every other day.25
Treatment of inhibitor patients with wt-rFVIIa or with APCCs has limitations with 
regard to efficacy, safety, and/or convenience27-29, and therefore presents 
opportunities for development of improved or alternative biotherapeutics to 
satisfy an unmet medical need in this patient population.  Efficacy of wt-rFVIIa or 
APCCs in patients with inhibitors is suboptimal in terms of ability to control bleeds 
and with regard to duration of action. These therapies fall short of the efficacy 
achieved with conventional factor replacement therapies in patients without 
inhibitors.10,30,31 Because efficacy is suboptimal with either of the currently licensed 
products, elective surgical procedures may be deferred for patients with inhibitors 
who may need such procedures.32 Pathogen transmission, thromboembolic 
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25 August 2018 
events, hypersensitivity and anamnestic response resulting in an increase in 
inhibitory antibody titers have been the main safety concerns when treating 
patients with hemophilia with inhibitors.20,25 Thrombotic events in association with 
NovoSeven® treatment in hemophilia patients with inhibitors have been reported 
in up to 4% of patients.20,33-35 Reported incidence of thrombotic events in 
association with FEIBA® use ranges from 4-8.24/100,000 infusions.25,36-38 NovoSeven®
is not approved for prophylaxis and its use for that purpose is not generally feasible 
for many reasons, including short duration of action that precludes administration 
schedules practical for routine use.20,39 The percent reduction in annual bleed rate 
during prophylaxis of hemophilia patients with inhibitors with FEIBA®40 is less than 
that reported for factor replacement therapy in hemophilia patients without 
inhibitors.41 FEIBA® also contains small amounts of FVIII and has the potential to 
boost inhibitor titers in hemophilia A patients with inhibitors.4 
2.2.1
Rationale for Prophylaxis with SC Administration of FVIIa
There is currently no cure for hemophilia.42 The prevention of bleeding episodes in 
hemophilia patients requires life-long prophylaxis.42,43 Due to the short half-life of 
wt-rFVIIa and APCC products, prophylaxis and treatment for bleeding episodes 
requires frequent IV dosing (daily for wt-rFVIIa or every other day for APCCs).20,25 IV
dosing often requires a medical professional or family member to perform the 
venipuncture, making home prophylaxis cumbersome, particularly for pediatric 
patients.43,44 Other challenges include patient adherence, and reliable IV 
access.45,45 IV administration requires direct venipuncture or sterile entry into a 
central venous access device on a regular basis, which makes it time-consuming 
and negatively influences adherence.45
SC administration presents a major advantage over IV administration because it 
enables at-home injection, improves quality of life, and reduces health care 
costs.46 While home IV administration has been essential to the provision of 
comprehensive hemophilia care, it nonetheless remains a significant barrier.45 SC 
dosing allows improved ease of self-administration and obviates the need for 
home nursing or a visit to a hemophilia center to provide an IV infusion when a 
patient or a family member has not been able to do so.46 Compared with the IV 
route, SC administration of wt-rFVIIa has been shown to extend half-life (12.4 hours 
vs 2.7 hours) and significantly reduces the large daily fluctuations of systemic drug 
concentrations, though with a reduced bioavailability (21-30% vs 100%).47
Consequently, there is a clear need for the development of rFVIIa variants with 
greater bioavailability and extended effect for SC administration to facilitate 
effective bleeding prophylaxis in hemophilia patients with inhibitors.
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        30 
25 August 2018 
MarzAA, a novel rFVIIa variant, is being developed by Catalyst Biosciences (the 
Sponsor) to address the unmet need for medical management of hemophilia A 
and B patients with inhibitors.  MarzAA was developed using a structure-based 
rational protein design approach intended to enhance the biological properties 
of wt-rFVIIa and contains a total of 4 amino acid substitutions.  The 2 amino acid 
substitutions in the protease domain (Q286R and M298Q) increase catalytic 
activity for factor X activation in both a tissue factor dependent and tissue factor 
independent manner.  The 2 others are in the light chain (T128N and P129A) and 
yield an additional N-linked glycosylation site designed to provide an extended 
duration of effect.  These qualities are expected to prolong the interval between 
doses, improve convenience of treatment, and facilitate use of the product for 
bleeding prophylaxis.
2.2.2
Experience with MarzAA in the Clinic
To date, the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
MarzAA IV administration has been evaluated in one clinical study (B3051001) 
which recruited 25 adult subjects with hemophilia A or B (all male) with or without 
inhibLWRUVZLWKVXEMHFWLQWKHǍJNJGRVHJURXSDQGVXEMHFWVLQHDFKRIWKH
DQGǍJNJGRVHJURXSV48 Cmax was reached at 5-15 minutes after IV 
bolus administration. Both clearance and volume of distribution (VOD) were similar 
at 18 to 30 ǍJNJGRVHOHYHOEXWGHFUHDVHGDFURVVWKHORZHUGRVHVWR
ǍJNJ 0DU]$$ WHUPLQDO KDOI-life (~3.5 hours) was similar across all doses. The 
MarzAA PK profile observed in study B3051001 was consistent with projections 
based on preclinical data. All hemophilia and non-hemophilia AEs were mild or 
moderate in severity; there were no severe treatment-emergent adverse events 
(TEAEs), no serious adverse events (SAEs) and no AEs leading to treatment 
discontinuation. Overall, the most common non-hemophilia-related AEs were 
dizziness, headache, and oropharyngeal pain (2 subjects each).  Hemophilia-
related AEs consisted of 3 AEs of arthralgia, and 1 AE each of flank pain, 
hemarthrosis, joint swelling, muscle swelling, and limb injury. MarzAA demonstrated 
good PD effects, with treatment-related (most often dose-related) changes 
observed for a variety of coagulation parameters. Thus, MarzAA showed an 
acceptable safety profile and promising PD effects in the phase 1 study. 
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25 August 2018 
3. 
OBJECTIVES AND ENDPOINTS
3.1  
PRIMARY  
x
To evaluate the efficacy and safety of marzeptacog alfa (activated) for 
bleeding prophylaxis in adult subjects with hemophilia A and B with an 
inhibitor
o
To evaluate the ABR (spontaneous and total) during Part 2 when on 
final MarzAA dose level versus recorded historical ABR 
o
To evaluate spontaneous bleeding requiring escalation to higher 
dose level
o
Note: A spontaneous bleeding episode is defined as one that is 
precipitated by normal ADL.
3.2 
SECONDARY
x
To determine the PK and PD, of SC administration of MarzAA in patients 
with hemophilia with inhibitors and compare IV versus SC administration of 
MarzAA regarding PK, PD, and safety parameters.
x
To find the optimal dose of MarzAA for each subject, ie, the dose that
prevents spontaneous bleeding*; and determine the PK, PD, and safety of 
daily SC administration of MarzAA at the optimal dose for each subject for 
an extended duration, mimicking the intended SC prophylactic use of 
MarzAA in patients with hemophilia.
x
To determine occurrence of and categorize breakthrough bleeds 
requiring escalation to higher dose level as follows: 
o
Number of bleeds that are life threatening 
o
Number that require hospitalization and/or blood transfusion 
o
Number of muscle bleeds
o
Median time to resolution (and interquartile range) of bleeds 
*A spontaneous bleeding episode is defined as one that is precipitated by 
normal ADL.
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25 August 2018 
3.3  
EXPLORATORY
x
To identify potential biomarkers and determine the effect of SC 
administration of MarzAA of the quality of life of patients with hemophilia 
with inhibitors
o
Identification of biomarker(s) such as antigen levels, activity levels, 
or global thrombosis assay evaluation that can be used to predict 
or correlate with a subject’s lack of spontaneous bleeding. 
o
Identification of biomarker(s) such as D-dimer, F1+2, or a functional 
assay of the FVIIa activity that will identify or predict clinical 
thrombogenicity with the daily SC administration of MarzAA.
o
Identification of biomarker(s) such as D-dimer, F1+2, or a functional 
assay of the FVIIa activity that will identify or predict clinical 
thrombogenicity of daily SC administration of MarzAA when use of 
rescue medication is required.
o
PRO measures: European Quality of Life-5 Dimensions(EQ-5D), 
Visual analogue scale (VAS); Hemophilia A quality of life 
questionnaire(Haem-A-QoL); Hemophilia Activities List (HAL)
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        33 
25 August 2018 
4. 
STUDY DESIGN
  
4.1
OVERALL DESIGN
This is a Phase 2 study designed to evaluate the pharmacokinetics, 
bioavailability, pharmacodynamics, efficacy and safety of a daily SC treatment 
regimen with MarzAA for bleeding prophylaxis in adult subjects with hemophilia A 
and B with an inhibitor. It is an open-label study, so subjects and members of the 
clinical study team will not be blinded to treatment. It is estimated that it will take 
approximately one year from when the study opens enrollment until completion 
of data analyses. The study will enroll a total of 12 adult male subjects with severe 
congenital hemophilia A or B with an inhibitor, and history of frequent 
spontaneous bleeding episodes (historical annualized bleeding rate [ABR] of 
DVSHUWKHLQGLYLGXDO·VEOHHGLQJDQGWUHDWPHQWUecords. Participants will be 
given a sLQJOH,9DGPLQLVWUDWLRQRI0DU]$$DWǍJNJIROORZHGE\VLQJOHGDLO\6&
DGPLQLVWUDWLRQRI0DU]$$DWǍJNJ.  Dose levels may increase to 60, 90, or 120 
μg/kg as required. The H0 is that the ABR (for MarzAA) = 12 versus H1: ABR (for 
MarzAA) < 12. 
Each subject will participate in all three phases (occurring consecutively):  
Part 1a (24 hours) is intended to compare IV versus SC administration of MarzAA 
regarding PK, PD, and safety parameters. Each subject will receive a single IV 
dose of 18 μg/kg MarzAA. PK, PD, and safety assessments will be collected pre-
dose and post-dose at 5 and 30 minutes and Hour 1, 3, 6, 9, 12, and 24.
Part 1b (48 hours) is intended to compare IV versus SC administration of MarzAA 
regarding PK, PD, and safety parameters. After the initial 24 hours, subjects will 
receive a single SC dose of 30 μg/kg MarzAA. PK, PD, and safety assessments will 
be done at pre-dose and repeated at Hour 3, 5, 7, 9, 12, 24, 30, and 48. During 
this period, subjects will be trained by appropriate study staff to self-administer a 
SC injection.
Part 2 is intended to (i) find the optimal dose of MarzAA for each subject, ie, the 
dose that prevents spontaneous bleeding; and (ii) determine the PK, PD, and 
safety of daily SC administration of MarzAA at the optimal dose for each subject 
for an extended duration, mimicking the intended SC prophylactic use of 
MarzAA in patients with hemophilia.  
Subjects will sign an informed consent form (ICF) at the Screening Visit, prior to 
any study procedures. Eligibility to participate in the study will be determined by 
inclusion and exclusion criteria from medical history, hemophilia history, 
laboratory investigations and ECG. At screening, subjects will receive training 
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25 August 2018 
and diary entry of investigational drug administration & injection site assessment, 
bleeding episodes & treatment, evaluation & entry of AEs & entry of PRO scales.  
The screening period duration may be up to 4 weeks. 
At Day 1 of daily SC dosing, subjects will begin their self-administered dosing 
regimen.  MarzAA will be self-administered by subjects daily (at approximately 
the same time every day), starting with a SC dose of 30 μg/kg MarzAA.  At each 
dose, subjects will record the day and time of the SC injections in their diary. If a 
spontaneous bleeding episode (defined as one that is precipitated by normal 
ADL) occurs before the fifth daily dose, subjects will continue at the current 
dosing level. If a spontaneous bleeding episode occurs after the fifth daily dose, 
the MarzAA dose will be escalated to the next dose level. Three dose escalations 
are allowed during Part 2: 60, 90, and 120 μg/kg (maximum dose). At each dose 
level escalation, safety and PK/PD will be monitored to ensure that dose 
escalation to a higher dose level is appropriate.  If a subject requires a third dose 
escalation to the fourth dose level, he will continue treatment with that dose for 
50 days and complete the study, regardless if a spontaneous bleeding episode 
occurs during the highest treatment dose level.
The participation of each subject to all three phases is intended to reduce the 
number of subjects enrolled in this study.  
Treatment of a spontaneous or traumatic bleeding episode: Subjects will use 
their current bypass regimen for any spontaneous or traumatic bleed that occurs 
while on study drug. If treatment for a spontaneous or traumatic bleeding 
episode is needed, then subjects will contact the clinical investigative team 
immediately to report the event, treatment dose administered, and determine 
follow-up plans for that event including whether to arrange for a blood 
specimen to be drawn (if feasible) before further administration of either study 
drug or the bypassing agent used for treatment.  Decision whether to continue 
daily study drug administration will also be determined by the clinical study team 
after discussion with the Sponsor. See Section 6.1.2, Dosing and Administration,
for details on dose escalation, dose de-escalation, and treatment interruption. 
This information will also be recorded in the subjects’ diary.
Dose interruption and surgery: Daily SC study injections will be interrupted if there 
is a need for a surgical procedure; an event requiring extended (>48 hours)
hospitalization; a thrombotic event; clinical evidence of inhibitor formation; or 
laboratory results suggesting an antibody may be developing.
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25 August 2018 
Measurements:  
MarzAA antigen and activity levels and coagulation parameters will be 
measured at Day 1 (Pre-dose and Post-dose Hour 7), Day 3 (Pre-dose), Day 5 
(Pre-dose), Day 7 (Pre-dose and Post-dose Hour 7).  
If no spontaneous bleeding occurs at the first dose level in Part 2 of the study, 
trough antigen and activity and coagulation parameters will be measured on 
days 14, 21, 28, and 50 after starting their dosing regimen. 
If spontaneous bleeding occurs after the fifth daily dose on a dose level, MarzAA 
antigen and activity levels will be measured within 6 hours of the spontaneous 
bleed (if feasible).  Specimens for coagulation and immunogenicity testing will 
also be drawn.
Once it is determined to escalate to the next dose level, a pre- and 7 hours post-
dose specimen will be drawn for PK, coagulation, and thrombogenicity markers 
on Day 7 after the dose has been escalated to estimate the new trough and 
peak concentrations and PD.  MarzAA antigen and activity levels and 
coagulation parameters will then be measured (pre-dose) at Day 14, 21, 28, and 
50 after dose escalation. 
Immunogenicity assays: Specimens for immunogenicity testing (antibody to 
MarzAA, neutralizing activity, cross reactivity) will be drawn at screening, Part 1a 
pre-dose, Part 1b pre-dose, and during Part 2 pre-dose on Day 1, 7, 14, 21, 28, 
and 42, and then every two weeks until end of study.
4.2  
END OF STUDY DEFINITION
The minimum duration of treatment for each subject is approximately 2 months 
(if no dose escalation is required) and the maximum duration is approximately 7
months (if three dose escalations are required).
Up to 4 weeks for screening period; 24 hours for the part 1a (single IV dosing and 
PK/PD/Safety testing); 48 hours for the Part 1b (single SC dosing and PK/PD/safety 
testing); and up to 197 days of daily SC dosing and a PK/PD/safety follow-up 
assessment 30 days after last dose. Subjects must have no spontaneous bleeding 
for 50 days if on the first three dose levels or complete 50 days of treatment on 
the fourth dose level.  The end of study visit will be 30 days after the last dose of 
study drug treatment in Part 2. 
A participant is considered to have completed the study if he has completed all 
phases of the study, including treatment at the same dose level for 50 days, and 
returned for procedures listed under end of study visit as shown in the SOA.
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5. 
STUDY POPULATION
5.1
INCLUSION CRITERIA
An individual must meet all of the following criteria to be eligible to participate in 
this study: 
1.
Confirmed diagnosis of severe congenital hemophilia A or B with an 
inhibitor.
2.
+LVWRU\RIIUHTXHQWVSRQWDQHRXVEOHHGLQJHSLVRGHVKLVWRULFDO$%5
3.
Male, age 18 or older.
4.
Agreement to use highly effective birth control throughout the study. 
5.
Affirmation of informed consent with signature confirmation before any 
trial-related activities. (Trial related activities are any procedure that 
would not have been performed during normal clinical management of 
the subject).
6.
Stated willingness to comply with all study procedures and availability for 
the duration of the study. 
5.2
EXCLUSION CRITERIA  
An individual who meets any of the following criteria will be excluded from 
participation in this study:
1.
Receiving prophylaxis treatment.
2.
Previous participation in a trial involving Subcutaneous Administration of
rFVIIa (Novo Seven or MOD-5014) or any trial using a modified rFVIIa such 
as: NN1731 or BAY86-6150. Prior participation in a trial of LR769 or rFVIIa-FP 
(CSL689) is permissible.
3.
Previous participation in and subsequent treatment in a clinical trial within 
the previous 30 days or 3-half-lives or absence of clinical effect, whichever 
is longer. 
4.
Known positive antibody to FVII or FVIIa detected by central laboratory at 
screening. 
5.
History of clinically relevant coagulation disorders other than congenital 
hemophilia A or B.
6.
Platelet count <100,000 based on screening laboratory assessments.
7.
Advanced atherosclerotic disease (i.e. known history of CAD, ischemic 
stroke, etc.), or known DVT or considered to be at a high risk of VTE as 
judged by the Investigator.
8.
Known or suspected allergy to trial product or related products.
9.
$EVROXWH&'FRXQWFHOOVǍL.
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        37 
25 August 2018 
10. Receiving IMT. 
11. Compromised hepatic or renal function:
a. ALT and $67OHYHOV5 times ULN
b. TBIL OHYHOPJG/!Ǎmol/L) unless there is a known history of 
GS
c. 6HUXPDOEXPLQ//1
d. Serum Cr level >1.25 x ULN  
12. Inability or medical, psychosocial, or familial issues that might prevent full 
participation and cooperation with the procedures and requirements of 
the clinical trial as determined by the potential subject and physician 
investigator. 
5.3 
LIFESTYLE CONSIDERATIONS
There are no specific lifestyle considerations.
5.4 
SCREEN FAILURES
An individual who does not meet the criteria for participation in this trial (screen 
failure) because of an out of range laboratory parameter may be rescreened. 
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        38 
25 August 2018 
6.  
STUDY INTERVENTION
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 Study Intervention Description
Description and Composition of the Drug Product
MarzAA will be provided as a powder for injection, at a 4.62 mg/vial dosage 
strength. The drug product is supplied in a 5-mL vial that is sealed with a 20mm 
lyophile stopper and 20mm aluminum over-seal. To manufacture the drug 
product, 2.2 ml of formulated bulk drug product is filled in each vial and 
lyophilized. The lyophilized drug product will be reconstituted for IV and SC 
injection.
6.1.2 Dosing and Administration
This is an open-label study. Each subject will receive the study drug according to 
three phases occurring consecutively:
x
In Part 1a (24 hours), subjects will receive a single IV administration of MarzAA 
at 18 μg /kg with assessment of PK, PD, and safety for 24 hours post-dose. 
x
In Part 1b (48 hours), subjects will receive a single SC administration of MarzAA 
at 30 μg /kg with assessment of PK, PD, and safety for 48 hours post-dose
x
In Part VXEMHFWVZLOOUHFHLYHGDLO\6&DGPLQLVWUDWLRQRI0DU]$$DWǍJNJ
with assessment of PK, PD, and safety at designated days for 50 treatment 
days. During Part 2, dose may be escalated to 60, 90, or 120 μg/kg, if required 
because of spontaneous bleeding, with assessment of PK, PD, and safety at 
designated days for an additional 50 treatment days.
Each subject will participate in each phase of the study.
For Part 1a and 1b, investigational product will be administered at the study site 
by qualified study personnel.  
During Part 1b, subjects will be trained to reconstitute and self-administer the 
study drug. Once proficiency in drug reconstitution and SC administration has 
been confirmed the subject can then proceed with home administration of 
study treatment. 
On Day 1 of Part 2 daily SC dosing, subjects will begin their self-administered 
dosing regimen.  MarzAA will be self-administered in the morning by the subjects 
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        39 
25 August 2018 
daily (at approximately the same time), starting with a SC dose of 30 μg/kg 
MarzAA.  Subjects will record the day and time of the SC injections in their diary. 
If a spontaneous bleeding episode (defined as one that is precipitated by 
normal ADL) occurs before the fifth daily dose, the subject will continue at the 
current dosing level. 
If a spontaneous bleeding episode occurs after the fifth daily dose, the MarzAA 
dose will be escalated to the next dose level. Three dose escalations are allowed 
during Part 2: 60, 90, and 120 μg/kg (maximum dose).
On those days that the subject is required to present for a study visit during which 
laboratory evaluations are scheduled, he will bring his study drug for self-
administration of his daily dose under observation by study team staff after pre-
dose assessments are completed.   
6.1.2.1 
Guidelines for Dose Escalation
An escalation to the next dose level is required if a spontaneous bleeding event 
occurs after the fifth daily dose on a dose level.  A dose escalation will not occur 
if the subject is on the maximum dose level of 120 μg/kg.  A spontaneous 
bleeding episode is defined as one that is precipitated by normal activities of 
daily living (ADL).  Subjects will use their current bypass regimen for any 
spontaneous or traumatic bleed that occurs while on study drug.
Three dose escalations are allowed during Part 2: 60, 90, and 120 μg/kg 
(maximum dose).  
Safety parameters and PK/PD assessments at each dose level will be monitored 
to ensure that dose escalation to a higher dose level is appropriate. 
The spontaneous bleeding episode must be reported to the clinical team 
immediately and determination of a dose escalation will be made on review of 
available clinical information related to the spontaneous bleeding episode and 
may require subsequent treatment and laboratory data, including available 
results from the PK/PD/safety assessments.  
A decision to proceed with dose escalation will be made by the principal 
investigator in agreement with personnel who have Sponsor, or designee, 
medical oversight responsibility. 
If there is disagreement amongst any of those individuals, the decision will be 
reviewed on an urgent basis by an independent Medical Consultant for Safety 
Oversight. 
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        40 
25 August 2018 
6.1.2.2 
Guidelines for Dose De-escalation 
While it is not expected that there will be a need for dose de-escalation in this 
trial, if there is evidence of drug accumulation based on rising peak and trough 
levels of MarzAA or other laboratory parameters, then the subject’s dose level 
will be reviewed by the PI and Sponsor, or designee, and a determination to hold 
treatment at the current dose level or decrease to the lower dose level will be 
made.  This determination will be made in conjunction with the independent 
Medical Consultant for Safety Oversight.  
6.1.2.3  
Guidelines for Treatment Interruption 
Daily SC study injections will be interrupted, as needed, when:
x
A surgical procedure is needed
x
There is a medical event requiring extended (>48 hours) hospitalization
x
If there is a thrombotic event
x
If there is clinical evidence of inhibitor formation
x
If there are laboratory results suggesting an antibody may be developing
Daily SC study injections may be interrupted, as needed, when:
x
A spontaneous bleeding event occurs
x
A traumatic bleeding event occurs 
Subjects will use their current treatment regimen for any spontaneous or 
traumatic bleed that occurs while on study.   If treatment for a spontaneous or 
traumatic bleeding episode is needed, then subjects will contact the clinical 
investigative team immediately to report the event; treatment dose 
administered; and determine follow-up plans for that event, including to arrange 
for a blood specimen to be drawn (if feasible) before further administration of 
either study drug or bypassing agent used for treatment.  This information will also 
be recorded in the subjects’ diary.
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
6.2.1 Acquisition and Accountability
Upon receipt of the MarzAA shipment, the pharmacist, or a designee, will 
conduct an inventory and return an acknowledgement that all IP was received 
frozen and undamaged, thereby maintaining the Good Manufacturing Practice 
(GMP) status of the product during shipment.
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Study MAA-201, Clinical Study Report
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        41 
25 August 2018 
All used and unused investigational product must be returned by the subject to 
the study site. Subjects must return all investigational product packages and vials 
(including used, empty, and unused vials) for reconciliation of IP. 
The investigator, or approved representative (eg, pharmacist) must maintain 
adequate records documenting the receipt, use, loss, or other disposition of the 
investigational product. The sponsor will supply drug accountability forms to be 
used in this study.
The sponsor or designee will arrange for the return of unused investigational 
product. The IP destruction procedure for used vials is to be decided locally to 
comply with local regulations and procedures.
Drug accountability will be reviewed by the monitor during routine monitoring 
visits.  No IP can be destroyed or returned until the study monitor has reconciled 
all vials of IP.
6.2.2  Product Storage and Stability
The investigator, or an approved representative, eg, pharmacist, will ensure that 
all investigational products are stored in a secured area with controlled access 
under recommended storage conditions and in accordance with applicable 
regulatory requirements.  The IP and its storage and preparation requirements will 
be provided by the Sponsor, or designee.
Investigational product should be stored in its original container and in 
accordance with the drug label. The Sponsor will provide the Investigator with 
packaged IP in accordance with specific country label requirements. 
Site systems must be capable of measuring and documenting (for example, via 
a log), at a minimum, daily minimum and maximum temperatures for all site 
storage locations (as applicable, including frozen, refrigerated and/or room 
temperature products). This should be captured from the time of investigational 
product receipt throughout study. Even for continuous monitoring systems, a log 
or site procedure which ensures active daily evaluation for excursions should be 
available. The operation of the temperature monitoring device and storage unit 
(for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product storage conditions should be reported upon 
discovery. The site should actively pursue options for returning the product to 
appropriate storage conditions, as soon as possible. Deviations from the storage 
requirements, including any actions taken, must be documented and reported 
to the Sponsor, or designee.
Once an excursion is identified, the investigational product must be quarantined 
and not used until the Sponsor, or designee, provides documentation of 
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        42 
25 August 2018 
permission to use the investigational product. Specific details regarding 
information the site should report for each excursion will be provided to the site. 
Receipt of materials, door opening and closing, and other routine handling 
operations where the product(s) are briefly out of labeled temperature range 
are not considered excursions. Site staff will instruct subjects on the storage 
requirements for take home medications including how to report temperature 
excursions.  
6.2.3  Preparation 
MarzAA will be provided as a powder for injection, at a 4.62 mg/vial dosage 
strength, and is supplied in a 5-mL vial.  The lyophilized drug product will be 
reconstituted for IV and SC injection.
Details regarding the dosing administration, both at the study site and in the 
homecare setting, will be provided by the Sponsor, or designee.
At the study site, both the MarzAA IV dose and SC dose will be prepared and 
administered by an appropriately qualified and experienced member of the 
study staff (eg, physician, nurse, physician assistant, nurse practitioner, or 
pharmacist) as allowed by local, state, and institutional guidance.   
In the homecare setting, the MarzAA SC dose will be prepared and administered 
by the study subject or subject caregiver/guardian. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
The study is an open-label study; subjects and members of the clinical study 
team will not be blinded to treatment. 
6.4 
STUDY INTERVENTION COMPLIANCE
Reasonable efforts should be made to ensure that study drug administration is 
administered daily in the morning.  However, if an unavoidable disruption of the 
daily administration occurs and a dose is not administered then the subject 
should be instructed to continue beginning the following day in the morning. 
If the subject misses two or more daily doses, then a spontaneous bleeding event 
will result in a dose escalation only if it occurs 4 days or longer after resumption of 
the daily administration.
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        43 
25 August 2018 
6.5 
CONCOMITANT THERAPY
Enrolled subjects will record all concomitant medications administered from the 
Screening Visit to Study termination (including the date and time of 
administration) in their diary.
For this protocol, a prescription medication is defined as a medication that can 
be prescribed only by a properly authorized/licensed clinician. Medications to 
be reported in the electronic Case Report Form (eCRF) are concomitant 
prescription medications, over-the-counter (OTC) medications and 
supplements.] 
There are no concomitant medication restrictions.  However, individuals are 
excluded if they have been on a prophylactic treatment regimen with a FVIII or 
FIX replacement factor or a bypassing agent prior to enrollment.   
If an individual has previously been enrolled on a clinical trial evaluating a 
treatment for prophylaxis other than a modified rFVIIa (as specified in exclusion 
criteria #2) or Emicizumab (ACE910)49, Fitusiran (ALN-AT3SC)50,51, or one of the 
anti-TFPI agents (Concizumab [mAb2021]52, BAY109388453, PF-0674108654) in 
clinical investigation he will be permitted to enroll onto this study, provided it is 
greater than 30 days since exposure to that study drug.
The following medications will be permitted during the study:
x
In the event of spontaneous or traumatic bleeding, treatment for a 
spontaneous or traumatic bleeding episode will be permitted using the 
subject’s current treatment regimen which could be FEIBA®, NovoSeven®, or 
a high dose regimen utilizing a FVIII or FIX product.
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1 
DISCONTINUATION OF STUDY INTERVENTION
Discontinuation from study intervention does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by 
the study protocol. 
Any new clinically relevant finding will be reported as an AE.
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Subjects are free to withdraw from participation in the study at any time upon 
request.
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        44 
25 August 2018 
An investigator may discontinue or withdraw a participant from the study for the 
following reasons:
x
Significant study intervention non-compliance 
x
If any clinical AE, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be 
in the best interest of the participant
x
If the participant meets a criterion (either newly developed or not previously 
recognized) that precludes further study participation
x
Decision by Investigator or Sponsor
The reason for participant discontinuation or withdrawal from the study and the 
date will be recorded on the electronic case report form͒(eCRF).
Replacement of a subject occurs for the following reason:
x
If a subject does not complete the study as defined in the protocol (ie, 
before receiving study drug for 50 days at the same dose level), another 
subject will need to be enrolled.
If the subject withdraws from the study and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to 
use any data collected before such withdrawal of consent.
7.3 
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he fails to return for two 
consecutive scheduled visits and is unable to be contacted by the study site 
staff.  
The following actions must be taken if a participant fails to return to the clinic for 
a required study visit:
The site will attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study.
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file. 
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        45 
25 August 2018 
Should the participant continue to be unreachable, he or she will be considered 
to have withdrawn from the study with a primary reason of lost to follow-up.]
In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request the subject to return all used and unused investigational 
product(s), request the subject to return for a final visit, if applicable, and follow 
up with the subject regarding any unresolved AEs.
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        46 
25 August 2018 
8. 
STUDY ASSESSMENTAND PROCEDURES
8.1 
EFFICACY ASSESSMENTS
Subjects will be asked to record all spontaneous or traumatic bleeding episodes 
and concomitant medications administered into the eDiary, including (but not 
limited to) the following: 
x
Bleeding episode (date/time of onset and date/time of resolution)
x
Cause of bleeding (spontaneous or traumatic)
x
Bleeding site: joint (ankle, knee, elbow, other [right or left]); muscle (iliopsoas, 
calf, forearm, other [right or left]); mucous membranes (mouth, gums, nose, 
genitourinary tract); gastrointestinal (gastric ulcer, fissure, other [requiring 
transfusion – yes, no]), neck/throat, intracranial.
x
Hemostatic drugs used for treatment of bleeding episodes (time/date of 
administration, type, amount [international units or mg and/or number of 
infusions])
A spontaneous bleeding episode is defined as one that is precipitated by normal 
ADL.
Investigators will document: 
x
Subject demographics (sex, age, race and ethnicity) will be recorded at the 
screening visit. 
x
All ongoing conditions and relevant medical history (including all major 
hospitalizations and surgeries) as well as the subject’s current medical status 
will be recorded at the screening visit.  
x
Diagnosis of severe congenital hemophilia A or B with an inhibitor will be 
documented including the frequency of spontaneous or traumatic bleeding 
episodes in the past 6 months.  
x
Notation will be made regarding history of orthopedic procedures including 
joint aspiration, synovectomy, fusion, or joint replacements or other 
complications of hemophilia including pseudotumors.
x
Concomitant medication use including treatment used for control of 
spontaneous or traumatic bleeding events (infusion therapies, anti-fibrinolytic 
agents, local agents) and for management of pain and other complications 
related to hemophilia.
x
Vital signs, height, weight, general physical examination will be performed at 
screening. 
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Study MAA-201, Clinical Study Report
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        47 
25 August 2018 
Evaluations related to PK and PD will include:
x
MarzAA antigen and activity levels over time post-dose and calculation of 
standard PK parameters and bioavailability. These evaluations will be 
performed at a central laboratory.
x
Coagulation parameters: prothrombin time (PT), activated partial 
thromboplastin time (aPTT), fibrinogen, FVII, FVIIa activity, and thrombin 
generation time (TGT).  These evaluations will be performed at a central 
laboratory. 
x
Thrombogenicity markers: D-dimer, F1+2, and thrombin-antithrombin 
complexes (TAT). These evaluations will be performed at a central laboratory.
8.2 
STUDY PROCEDURES 
Study procedures and evaluations to be done as part of the study. Please refer 
to Section 1.3, Schedule of Activities (SOA) for the sequence of events.  
8.2.1  Screening 
Please refer to Section 1.3, Schedule of Activities (SOA) and specifically Table 1 
for the sequence of events that should occur during the screening process.  
Screening should occur within 4 weeks prior to enrollment.  
x
Informed consent
x
Demographic parameters
x
Inclusion and Exclusion Criteria review
x
Medical and hemophilia history
x
Concomitant medications
x
Vital signs
x
Height and weight
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry: (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities)
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT 
x
Immunogenicity assays: to FVII, FVIIa, and MarzAA 
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        48 
25 August 2018 
x
Troponin level 
x
ECG
x
Study Subject training on drug administration and injection site 
assessment; evaluation and diary entry of AEs, spontaneous or traumatic 
bleeding episodes and treatment, and PRO scales 
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Adverse events 
8.2.2  Part 1a (Duration 24 Hours)
Please refer to Section 1.3, Schedule of Activities (SOA) and specifically Table 1 
for the sequence of events that should occur during the Part 1a process.  
8.2.2.1 
Pre-dose evaluations 
x
Inclusion and Exclusion Criteria review
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Troponin level
x
Adverse events
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        49 
25 August 2018 
8.2.2.2 
MarzAA administration (Hr 0) 
x
Subjects will receive a EROXV,9GRVHRI0DU]$$DWǍJNJ
8.2.2.3 
Post-dose evaluations 
Blood will be collected at 5 and 30 minutes and 1, 3, 6, 9, and 12 hours (on Day 
1) post-dose for the following evaluations:
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
8.2.2.4 
Post-dose evaluations (24 hours)
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity 
x
Troponin level
x
ECG
x
Adverse events (from Hr 0 to 24 hours)
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MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        50 
25 August 2018 
8.2.3  Part 1b (Duration: 48 Hours)
Please refer to Section 1.3, Schedule of Activities (SOA) and specifically Table 2 
for the sequence of events that should occur during the Part 1b process.  
Assessments required for pre-dose in Part 1b that have been completed at Hour 
24 in Part 1a do not have to be repeated (if done within 2 days).
8.2.3.1 
Pre-dose evaluations 
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Troponin level
x
Adverse events  
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Study MAA-201, Clinical Study Report
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Catalyst Biosciences, Inc.

 
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CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        51 
25 August 2018 
8.2.3.2 
MarzAA administration (Hr 0)  
x
6XEMHFWVZLOOUHFHLYHD6&GRVHRI0DU]$$DWǍJNJ
x
SC administration training and proficiency confirmation
8.2.3.3 
Post-dose evaluations
Blood will be collected at 3, 5, 7, 9, and 12 hours post-dose for the following 
evaluations: 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
8.2.3.4 
Post-dose evaluations (24 hours)
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Troponin level
x
ECG
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        52 
25 August 2018 
x
SC administration training and proficiency confirmation 
x
Adverse events (Hr 0 to Hr 24)
8.2.3.5 
Post-dose evaluations (30 hours)
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
8.2.3.6 
Post-dose evaluations (48 hours)
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
SC administration training and proficiency confirmation
x
Adverse events (Hr 24 to Hr 48)
8.2.4  Part 2 (Duration: ı50 Days)
Please refer to Section 1.3, Schedule of Activities (SOA) and specifically Table 3 
and 4 for the sequence of events that should occur during the Part 2 process.  
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        53 
25 August 2018 
Part 2 procedures will be the same for all subjects; there are modifications in the 
schedule of follow-up visits and assays drawn for those subjects who have no 
spontaneous bleeding occurrence after the fifth daily dose, as shown in Section 
1.3, Schedule of Activities and specifically Table 3 and for those who have an 
interim spontaneous bleeding event requiring dose escalation as shown in 
Section 1.3, Schedule of Activities and specifically Table 4. 
Day 1 of Part 2 will start the next morning right after Part 1b is completed. During 
Part 2, subjects will self-administer MarzAA SC daily in the morning DWǍJNJ
Subjects will record daily in their diary: the injection day/time, dose, spontaneous 
or traumatic bleeding episodes that may occur and whether bypassing 
treatment is administered, which agent, and what dose, AEs that may occur, 
and injection site assessment. 
Subjects will return to the clinic the day after Part 1b for the Part 2, Day 1 
assessments.  
8.2.4.1 
Day 1 Visit 
The following procedures will be performed. 
Assessments required on Part 2, Day 1 that have been completed at Part 1b, do 
not have to be repeated (if done within 2 days). 
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
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Study MAA-201, Clinical Study Report
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Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        54 
25 August 2018 
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
8.2.4.2 
Day 3 and Day 5 Visits 
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Injection compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        55 
25 August 2018 
8.2.4.3 
Day 7 Visit
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Troponin level
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability 
x
Adverse events 
8.2.5  Part 2 – If No Spontaneous Bleeding Occurs after the fifth daily dose, 
(Duration: ı50 Days)
If No Spontaneous Bleeding Occurs after the fifth daily dose, the following 
procedures will be performed on the Days 14, 21, and 28 Visits: 
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        56 
25 August 2018 
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
8.2.5.1 
Day 42 Visit
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        57 
25 August 2018 
8.2.5.2 
Day 50 Visit
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
8.2.6  Part 2 – If Spontaneous Bleeding Occurs after the fifth daily dose 
(Duration: ı50 Days)
If a spontaneous bleeding episode occurs in Part 2 after the fifth daily dose, 
necessitating a dose escalation, the “day count” will be reset to zero. The day a 
spontaneous bleeding event occurs (and subsequent days until the event is 
resolved) is considered Day 0. Dose escalation starts on the next day (Day 1).  
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        58 
25 August 2018 
8.2.6.1 
Day 0 Visit
If a breakthrough bleed event occurs, subjects are instructed to use their current 
bypass regimen for treatment and to then immediately contact the clinical 
investigative team to report the event, what treatment and dose was utilized, 
arrange for immediate follow-up, if feasible and determine follow-up plans for 
that event.  The Day 0 Visit begins when a breakthrough bleed event occurs and 
includes the subsequent time until treatment resolution.
The following procedures will be performed on the Day 0 Visit:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Troponin level
x
Study drug dispensing, inventory and accountability
x
Dispense study drug at the escalated dose to the subject to use once the 
spontaneous bleeding episode has resolved.  Reschedule subjects’ visits 
for Days 7, 14, 21, 28, and 50 after dose escalation. 
x
Adverse events 
Once the spontaneous bleeding episode has resolved, the subject will be 
LQVWUXFWHGWRLQMHFW0DU]$$DWWKHQH[WGRVHOHYHORUǍJP/
beginning in the morning on Day 1.  
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        59 
25 August 2018 
8.2.6.2 
Day 7 Visit After Spontaneous Bleeding Event Reset and Day 0 
evaluations 
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)  
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Troponin level
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events  
8.2.6.3 
Day 14, 21, 28 Visits After Spontaneous Bleeding Event Reset and 
Day 0 evaluations
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        60 
25 August 2018 
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA (Day 14 and 28 only)
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
8.3.6.4 
Day 42 Visit After Spontaneous Bleeding Event Reset and Day 0 
evaluations 
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        61 
25 August 2018 
8.2.6.5 
Day 50 Visit After Spontaneous Bleeding Event Reset and Day 0 
evaluations 
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications 
x
Vital signs
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events  
8.2.7 Unscheduled Visit 
Should a subject need to be seen at any time while enrolled onto the trial, and 
not on a study scheduled visit, the following assessments may need to be 
conducted based on the judgement of the clinical study team.
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Weight
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL; 
HAL)
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        62 
25 August 2018 
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Troponin level
x
IP compliance and proficiency confirmation
x
Study drug dispensing, inventory and accountability
x
Adverse events 
8.2.8 End-of-Study Visit (30 Days after Last Dose)
The following procedures will be performed:
x
Medical and Hemophilia History (including that obtained from review of 
diary entries of bleeding episodes and treatment, AEs, and PRO scales)
x
Concomitant medications
x
Vital signs
x
Diary entry of PRO scales (see Appendix B – EQ-5D, VAS; Haem-A-QoL;
HAL)
x
Physical examination
x
Clinical signs of thrombosis (see Appendix A) 
x
Hematology and chemistry (see Footnote 3 for Table 1 in Section 1.3, 
Schedule of Activities) 
x
Coagulation assays: PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT
x
Thrombogenicity markers: D-dimer, F1+2, and TAT
x
PK: MarzAA antigen and activity
x
Immunogenicity assays to FVII, FVIIa, and MarzAA
x
Study drug dispensing, inventory and accountability
x
Adverse events 
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        63 
25 August 2018 
8.3 
STUDY ASSESSMENTS
8.3.1 Physical Examination
A full physical assessment of the major body systems will be recorded.
8.3.2 Vital signs 
One measurement of blood pressure, heart rate, respiratory rate, and body 
temperature will be taken after the subject has been sitting quietly for at least 5 
minutes.
8.3.3  Hematology  
Complete blood cell count (CBC), platelet counts, and CD4 count will be will be 
measured using standard laboratory testing methods at a local laboratory.
8.3.4  Chemistry 
Sodium, potassium, chloride, bicarbonate, hepatic enzymes (ALT and AST), 
bilirubin, albumin, blood urea nitrogen (BUN), and Cr will be measured using 
standard laboratory testing methods at a local laboratory.
8.3.5 Coagulation assays 
PT, aPTT, fibrinogen, FVII, FVIIa activity, and TGT. These evaluations will be 
performed at a central laboratory.
8.3.6  Thrombogenicity markers 
D-dimer, F1+2, and thrombin-antithrombin complexes (TAT). These evaluations will 
be performed at a central laboratory.
8.3.7 Antibody response and neutralizing antibodies to MarzAA 
These evaluations will be performed and tested at a central laboratory.
8.3.8 Clinical signs of thrombosis (Appendix A)
This assessment will be included as part of the study subject training, provided as 
a reference on the eDiary device, and will be a scheduled evaluation at clinical 
study visits.  
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IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        64 
25 August 2018 
8.3.9 Concomitant medications 
Subjects will record concomitant medications (including name of medication, 
dose taken, day and time) they may be taking in their daily diaries. Diaries will be 
reviewed by the clinical staff at each visit. 
8.3.10 ECG
A12-lead ECG will be performed using local standard methods. 
8.3.11 Troponin levels
Blood troponin levels will be measured using standard laboratory testing methods 
at a local laboratory. 
For participants that may discontinue or withdraw early, it is important to capture 
the rationale during the final visit. See Section 7, Study Intervention 
Discontinuation and Participant Discontinuation/Withdrawal, for details.
8.4  
SAFETY AND OTHER ASSESSMENTS
Evaluations related to safety will include:
8.4.1 AEs and SAEs
Subjects will record any AEs that occur during the study in their daily diaries. 
Diaries will be reviewed by the clinical staff at each visit.  
8.4.2 Injection site reactions
Subjects will record site injection reactions in their daily diaries. Diaries will be 
reviewed by the clinical staff at each visit.  
Evaluations that are related to the exploratory endpoints will include the 
following PRO and clinician reported outcomes (ClinRO) measures: 
PRO:
x
Health status with the use of the EQ-5D questionnaire.55 This is a health utility 
measure that includes assessment of 5 dimensions of health (mobility, self-
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Marzeptacog alfa (activated), (MarzAA) 
Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        65 
25 August 2018 
care, usual activities, pain/discomfort, anxiety/depression) along with a 0-100 
VAS.
x
Haem-A-QoL, which measures the quality of life in patients with hemophilia.56  
x
Hemophilia Activities List (HAL), a self-assessment which measures the 
perceived functional status of patients with hemophilia.57
8.5  
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
8.5.1 Definition of Adverse Events (AE)
Definition of an AE: An AE is any untoward medical occurrence in a patient or 
clinical trial subject administered a medicinal product that may not necessarily 
have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant laboratory 
abnormality, for example), symptom, or disease temporarily associated with the 
use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
Pre-existing conditions, diseases or disorders are not considered AEs unless there 
is a change in the intensity, frequency or quality.
  
8.5.2 Definition of Serious Adverse Events (SAE)
Definition of a SAE: Definition of a SAE:  An AE or suspected adverse reaction is 
considered "serious" if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may 
jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
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Study MAA-201, Clinical Study Report
IND 14789 
Catalyst Biosciences, Inc.

 
MAA-201 VERSION 2.0 
CONFIDENTIAL CATALYST BIOSCIENCES, INC.                        66 
25 August 2018 
8.5.3 Classification of an Adverse Event
8.5.3.1 
Severity of Event
All AEs will be assessed by the study clinician using the CTCAE v4.0 where 
applicable.59
For those AEs that are not included under the CTCAE v4.0, the following 
guidelines will be used to describe severity. 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning.
Severe – Events interrupt a participant’s usual ADL and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”.
8.5.3.2  
Relationship to Study Drug
All AEs must have their relationship to study drug assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below. In a clinical trial, the study product must always be 
suspect.  
Related – The AE is known to occur with the study intervention, there is a 
reasonable possibility that the study intervention caused the AE, or there is a 
temporal relationship between the study intervention and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between 
the study intervention and the AE.
Not Related – There is not a reasonable possibility that the administration of the 
study intervention caused the event, there is no temporal relationship between 
the study intervention and event onset, or an alternate etiology has been 
established. 
8.5.3.3  
Action Taken  
None: No changes were made to Study Drug administration and dose 
Permanently discontinued: Study drug was discontinued and not restarted
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Temporarily interrupted, restarted same dose: Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the same dose without 
unblinding to treatment group
8.5.3.4  
Expectedness 
The Principle Investigator (or Co-PI) will be responsible for determining whether 
an AE is expected or unexpected.  An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
8.5.4 Time Period and Frequency for Event Assessment and Follow-Up
Subjects will be instructed regarding direct reporting and diary entries of AEs; 
diaries will be reviewed at each visit and subjects queried if evidence of an AE 
recorded. 
The occurrence of an AE or SAE may come to the attention of study personnel 
during study visits and interviews of a study participant presenting for medical 
care, or upon review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for SAEs will 
be captured on the appropriate CRF. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be 
recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of 
the duration of the event at each level of severity to be performed. AEs 
characterized as intermittent require documentation of onset and duration of 
each episode.
Subject Withdrawal from the Study Due to an Adverse Event: 
Every reasonable effort should be made to maintain subject compliance and 
participation in the study. All enrolled subjects who received the study drug must 
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be followed through the Follow-Up visit, regardless of the reason for withdrawal. If 
a subject who has a clinically significant laboratory abnormality or AE withdraws 
from the study, every effort must be made to follow these events until satisfactory 
resolution. 
8.5.5 Adverse Event Reporting
Members of the study team will record all reportable events with start dates 
occurring any time after informed consent is obtained until study completion, or 
discharge, for non-serious AEs.  At each study visit, the investigator will inquire 
about the occurrence of AE since the last visit.  Events will be followed for 
outcome information until resolution or stabilization.
The Investigator will categorize the outcome of each AE according to the 
definitions below:
Resolved: 
 
The subject recovered from the AE.  
Ongoing:
At the time of the last assessment, the event is ongoing, with 
an undetermined outcome.  Note: Ongoing AEs are not 
considered resolved as a result of death. No AE stop date 
should be recorded with an AE that is ongoing.
Chronic/Stable: 
At the time of the last assessment, the event is ongoing and 
stabilized, with no change to the event outcome 
anticipated.  
Unknown:
There is an inability to access the subject or the subject’s 
records to determine the outcome (i.e., subject withdraws 
consent or is lost to follow-up).
All protocol-defined adverse events will be reported from the time a patient is 
enrolled in the study until the end of study visit.
Spontaneous or traumatic bleeding events will not be reported as an AE unless 
considered serious and should then be reported per the standard process for 
reporting.  
All bleeds should be reported via the ePRO device including spontaneous 
bleeds, traumatic bleeds or bleeds related to procedure/surgery (see Section 
7.4). Only bleeds (spontaneous bleeds, traumatic bleeds or bleeds related to 
procedure/surgery) that are considered serious as per definition (see Section 
9.1.2) should be reported as an SAE in the CRF. Non-serious bleeds are not 
considered adverse events for the purpose of this protocol and should not be 
reported as adverse event in the eCRF. 
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The study drug has the potential risk of causing the following AEs based on 
information associated with other drugs in the same category, ie, bypassing 
agents for treatment of hemophilia; these are:
Thrombotic events (see Appendix A)
The study drug has the potential risk of causing thrombotic events based on 
information associated with other drugs for treatment of hemophilia.  See 
Appendix A for signs and symptoms listed for the subjects and the study team 
personnel as those requiring urgent reporting and attention. 
Development of Drug Antibodies and Inhibitors
There is a risk with the study drug of developing an immune response resulting in 
antibody formation and potentially an inhibitory antibody response.  This will also 
be monitored for throughout the study.   
Skin injection site may become reddened or painful. 
Risks associated with blood collection: 
A blood draw may cause faintness, inflammation of the vein, pain, bruising, or 
bleeding at the site of puncture.  There is also a slight chance of infection.
8.5.6 Serious Adverse Event Reporting
Members of the study team will record all reportable events within 24 hours of 
knowledge of the SAE with start dates occurring any time after informed consent 
is obtained until 30 days after the last day of study participation.  At each study 
visit, the investigator will inquire about the occurrence of SAEs since the last visit.  
Events will be followed for outcome information until resolution or stabilization.
The Investigator will categorize the outcome of each SAE according to the 
definitions below:
Resolved: 
 
The subject recovered from the AE.  
Ongoing:
At the time of the last assessment, the event is ongoing, with 
an undetermined outcome.  Note: Ongoing AEs are not 
considered resolved as a result of death. No AE stop date 
should be recorded with an AE that is ongoing.
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Chronic/Stable: 
At the time of the last assessment, the event is ongoing and 
stabilized, with no change to the event outcome 
anticipated.  
Death:  
 
The AE directly caused death.
Unknown:
There is an inability to access the subject or the subject’s 
records to determine the outcome (i.e., subject withdraws 
consent or is lost to follow-up).
Definitions:
Death: Any event resulting in a subject’s death must be reported as an SAE.  
However, death, in and of itself, is not an AE; it is only an outcome.  The cause of 
death is the AE.  Therefore, the investigator should make every effort to obtain 
and document the cause of death for all subjects who die during the study.  If, 
despite all efforts, the cause of death remains unknown, the AE should be 
documented as an “unspecified fatal event”.
Life threatening AE:  Any AE that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred (i.e., it 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death).
Hospitalization:  It should be noted that hospitalization, in and of itself, does not 
represent an SAE.  It is the AE leading to the subject’s hospitalization that 
becomes “serious” when it requires inpatient care.  Consequently, an SAE should 
not be reported in the case of pre-planned hospitalizations for pre-existing 
conditions that did not worsen during the study.
Disability: A substantial disruption of a person’s ability to conduct normal life 
functions.
8.5.7  Adverse Events of Special Interest (AESIs)
The study drug has the potential risk of causing the following AESIs based on 
information associated with other drugs in the same category. These are:
1. Thromboembolic events (TEs) based on information associated with other 
drugs for treatment of hemophilia. TEs include myocardial infarction (MI); 
venous thrombosis, and pulmonary embolism (PE); and stroke. See 
Appendix A for signs and symptoms listed for the subjects and the study 
team personnel as those requiring urgent reporting and attention. 
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2. Immune response resulting in antibody formation and potentially an 
inhibitory antibody response. This will also be monitored for throughout the 
study. 
8.5.8  Reporting of Pregnancy
Although pregnancy itself is not considered an adverse event or a serious 
adverse event, the partner of a male participant should be followed until 
termination or to term to ensure absence of congenital anomaly or birth defect 
that may have resulted from maternal exposure or transmission of the study drug 
via semen following paternal exposure.
Please advise all participants to use a highly effective method of birth control 
from the first dose of study drug through 28 days after dosing to protect the 
health and safety of the mother and/or child. Despite the warnings provided 
and precautions taken, pregnancy may occur during research participation. 
Investigators must be aware of the requirements related to reporting and follow-
up in the event a research participant’s partner becomes pregnant.
If a participant’s partner becomes pregnant during this study, please provide an 
authorization form to present to the partner. If she is in agreement, that 
authorization will function as consent to approve the study doctor’s access to 
medical information to allow the regulatory required monitoring of the 
pregnancy, and the birth and the health of the child. 
Please report the pregnancy of a participant’s partner to Catalyst Biosciences, or 
it’s designee, and the IRB, and include the following information: expected date 
of delivery, last menstruation, estimated conception date and pregnancy result 
(if known).  
Pregnancy should be reported as “Information” (not as an “Adverse Event” or 
“Other Problem or Event”).
x
Pregnancy does NOT have to be reported to the IRB if the subject is receiving 
follow-up only, and conception occurred outside of the time period that the 
study protocol requires contraception (ie, 28 days after the last dose of the 
study drug and the pregnancy occurred after that time).
x
Subsequent reports containing follow-up information regarding a pregnancy 
is not required unless the pregnancy results in a congenital anomaly. The 
congenital anomaly should be promptly reported.  
x
NOTE: If you suspect that exposure to a medical product prior to conception 
or during pregnancy may have resulted in an adverse outcome in the child, it 
must be reported to the FDA.
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9. 
STATISTICAL CONSIDERATIONS 
With a total of 12 subjects and assuming a null hypothesis of an ABR of 12, then if
the true ABR for MarzAA is 6 or less, with a one-tailed 2.5% significance level there 
is near 100% power to demonstrate this using a one sample Poisson test of the 
null hypothesis. Even if only 6 subjects were available to be pooled for this 
analysis, the power would still be in excess of 99%. Thus, a sample of 12 subjects is 
expected to provide sufficient power for the primary endpoint analysis in this 
study. 
9.1
STUDY HYPOTHESIS
The null hypothesis (H0) is that the ABR in all subjects treated with daily SC 
administration of MarzAA will result in an ABR of 12 as compared to the historical 
control rate of 12, i.e. H0: ABR (for MarzAA) = 12. The alternative hypothesis (H1): 
ABR (for MarzAA) < 12.
Primary Endpoint
The primary endpoint will include:
•
ABR (spontaneous and total) during Part 2 when on final MarzAA dose level 
versus recorded historical ABR 
Bleeding events will be evaluated as follows:
x
Spontaneous vs Traumatic
A spontaneous bleeding episode is defined as one that is precipitated by normal 
ADL.
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Secondary Endpoints
The secondary endpoints will include:
x
Occurrence of breakthrough bleeds requiring escalation to higher dose level.
x
Safety parameters: Occurrence of clinical thrombotic event not attributable 
to another cause, and occurrence of antibody formation resulting in a 
decreased endogenous level of FVII or FVIIa.
x
Change in coagulation parameters (PT, aPTT, fibrinogen, MarzAA antigen 
and activity levels, and TGT) from pre-dose.
x
Occurrence of an antibody response to MarzAA and whether it is inhibitory 
and cross-reactive to wt-rFVIIa or wt-FVII.
x
Clinically significant levels of thrombogenicity markers resulting from daily SC 
administration of MarzAA 
x
Feasibility and ease of use of daily SC self-administration by patient as 
measured by compliance with treatment 
x
Breakthrough bleeding events will be categorized as follows:
x
Number of bleeds that are life threatening 
x
Number that require hospitalization and/or blood transfusion 
x
Number of muscle bleeds
x
Median time to resolution (and interquartile range) of bleeds 
Exploratory Endpoints
x
Identification of biomarker(s) such as antigen levels, activity levels, or global 
thrombosis assay evaluation that can be used to predict or correlate with a 
subject’s lack of spontaneous bleeding.
x
Identification of biomarker(s) such as D-dimer, F1+2, or a functional assay of 
the FVIIa activity that will identify or predict clinical thrombogenicity with the 
daily SC administration of MarzAA.
x
Identification of biomarker(s) such as D-dimer, F1+2, or a functional assay of 
the FVIIa activity that will identify or predict clinical thrombogenicity of daily 
SC administration of MarzAA when use of rescue medication is required.
x
PRO measures: EQ-5D, VAS; Haem-A-QoL; Hemophilia Activities List (HAL)
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9.2
SAMPLE SIZE DETERMINATION
With a total of 12 subjects and assuming a null hypothesis of an ABR of 12, then if
the true ABR for MarzAA is 6 or less, with a one-tailed 2.5% significance level there 
is near 100% power to demonstrate this using a one sample Poisson test of the 
null hypothesis. Even if only 6 subjects were available to be pooled for this 
analysis, the power would still be in excess of 99%. Thus, a sample of 12 subjects is 
expected to provide sufficient power for the primary endpoint analysis in this 
study. 
12 subjects were chosen to increase the size of the safety data set.
9.3
POPULATIONS FOR ANALYSES
Safety population: any patient who receives at least one dose
Efficacy/PD ITT population: any patient who receives at least one dose
Efficacy/PD modified ITT population: any patient who receives at least 7 SC doses 
DWǍJNJ
Efficacy/PD per protocol population: any patient who completes at least 50 
exposure days (SC product)
If a subject does not complete the study as defined in the protocol (i.e., before 
receiving study drug for 50 days at the same dose level) another subject will 
need to be enrolled in replacement.
9.4
STATISTICAL ANALYSIS
9.4.1
General Approach
Standard PK parameters such as terminal half-life, AUC0-t and AUC0-inf, 
clearance, volume of distribution, mean residence time and bioavailability (of 
the subcutaneous versus the intravenous administration) will be calculated. A 
semi-parametric model described by Lee et all (1990, 1997) will be used to 
calculate the terminal half-life. A noncompartmental approach based on the 
trapezoidal rule will be used to compute the AUCs and the parameters derived 
from them. Descriptive statistics will be reported for each parameter and will 
include mean ± standard deviation and median ± interquartile range. The 
number of subjects requiring dose escalation will be reported.
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The analysis of the primary endpoint (annualized bleeding rate) of the final dose 
used to treat a subject will be based on the evaluation of the ABR of MarzAA 
compared to a rate seen with on-demand therapy. The latter is assumed to be 
12 (or one bleed per month) as our null hypothesis (H0). The comparison of the 
actual ABR for MarzAA either pooled across all doses used or evaluated at the 
highest dose for an individual will be compared to this null hypothesized value 
using the one-sample test for a Poisson rate (using an exact calculation of the p-
value based on the program StatXact 11, Cytel, Inc., 2015). Because this will be a 
one-tailed test (the alternative hypothesis is the ABR for MarzAA will be < 12), a 
one-tailed 2.5% significance level will be used.
All other statistical tests will be performed at the 0.05 significance level using two-
sided tests.
There will be a formal Statistical Analysis Plan (SAP) completed prior to database 
lock and unblinding of the study data. 
9.4.2 Analysis of the Primary Efficacy Endpoint(s)
The analysis of the primary endpoint (annualized bleeding rate) of the final dose 
used to treat a subject will be based on the evaluation of the ABR of MarzAA 
compared to a rate seen with on-demand therapy. The latter is assumed to be 
12 (or one bleed per month) as our null hypothesis (H0). The comparison of the 
actual ABR for MarzAA either pooled across all doses used or evaluated at the 
highest dose for an individual will be compared to this null hypothesized value 
using the one-sample test for a Poisson rate (using an exact calculation of the p-
value based on the program StatXact 11, Cytel, Inc., 2015). Because this will be a 
one-tailed test (the alternative hypothesis is the ABR for MarzAA will be < 12), a 
one-tailed 2.5% significance level will be used. 
To calculate the ABR for subjects who do not have a total of 12 months of follow 
up, the ABR will be calculated as: 
(number of bleeds/number of months on study) x 12
9.4.3 Analysis of the Secondary Endpoint(s)
Study drug exposure and compliance will be provided for both phases, and by 
treatment group for the Treatment Phase. 
The following parameters will be documented:
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25 August 2018 
x
Occurrence of clinical thrombotic event not attributable to another cause, 
and occurrence of antibody formation resulting in a decreased endogenous 
level of FVII or FVIIa.
x
Change in coagulation parameters (PT, aPTT, fibrinogen, MarzAA antigen 
and activity levels, and TGT) from pre-dose.
x
Occurrence of an antibody response to MarzAA and whether it is inhibitory 
and cross-reactive to wt-rFVIIa or wt-FVII.
x
Clinically significant levels of thrombogenicity markers resulting from daily SC 
administration of MarzAA 
The frequencies of these events will be summarized as proportions and counts.
Protocol deviations will be listed.  All major protocol deviations (in particular 
those regarding entry criteria) will be summarized in the study report. 
9.4.4 Safety Analysis 
Adverse Events
All AEs will be listed, documenting the course, outcome, severity, and causality 
to study drug. Verbatim terms on CRFs will be mapped to preferred terms and 
related system organ class using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Incidence rates of AEs and the proportion of subjects prematurely withdrawn 
from the study due to AEs will be shown for. Incidence rates will also be displayed 
based on severity and relationship to study drug. AEs with a relationship of 
“possibly” or “probably” related will be considered by the Sponsor as “related” 
to the study drug. Events assessed as “unrelated”, “unlikely” related, or where the 
relationship was not reported will be considered by the Sponsor as “not related” 
to the study drug. The incidence of SAEs will be provided for each phase. All 
incidence rates will be categorized and displayed by system organ class and 
preferred term.
Vital Signs 
Safety analyses will include descriptive statistical summaries of shifts in vital signs 
(blood pressure, heart rate, respiratory rate) and in laboratory values for each 
phase. 
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9.4.5 Baseline Descriptive Statistics 
Demographic and baseline measurement variables will be summarized using 
descriptive statistics. 
9.4.6 Planned Interim Analyses
Not applicable to this study.
9.4.7 Sub-Group Analyses
Not applicable to this study.
9.4.8 Tabulation of Individual Participant Data
Individual participant data will be listed by measure and time point.
9.4.9 Exploratory Analyses
The following will be documented:
x
Biomarker(s) such as antigen levels, activity levels, or global thrombosis assay 
evaluation that can be used to predict or correlate with a subject’s lack of 
spontaneous bleeding.
x
Biomarker(s) such as D-dimer, F1+2, or a functional assay of the FVIIa activity 
that will identify or predict clinical thrombogenicity with the daily SC 
administration of MarzAA.
x
Biomarker(s) such as D-dimer, F1+2, or a functional assay of the FVIIa activity 
that will identify or predict clinical thrombogenicity of daily SC administration 
of MarzAA when use of rescue medication is required.
x
PRO measures: EQ-5D, VAS; Haem-A-QoL; Hemophilia Activities List (HAL)
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS
10.1.1  
Informed Consent Process
The written informed consent documents will be prepared in the language(s) of 
the potential subject population, based on an English version provided by the 
Sponsor and should be easy to understand.  
Before a subject’s participation in the trial, the investigator is responsible for 
obtaining written information consent from the subject after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of 
the study and before any protocol specific screening procedures or any study 
drugs are administered. Sufficient time must be given to consider whether to 
participate in the study.
The informed consent form should be signed and personally dated by the 
subject and by the study person who conducted the informed consent 
discussion. The original signed informed consent form should be retained in the 
Study Master File and in any other locations required by institutional policy, and a 
copy of the signed consent form should be provided to the subject.
10.1.2 Institutional Review Board/Independent Ethics Committee
Before initiation of the study, the investigator must submit for approval the 
protocol, ICF, Investigator’s Brochure, and any advertisements to an IRB/IEC for 
written approval. The Investigator must ensure IRB/IEC compliance with the 
applicable regulations. A copy of written IRB/IEC approval of the protocol, ICF,
and all advertisements must be provided to Sponsor or designee prior to initiation 
of the study and shipment of study drug. The Investigator is responsible for 
obtaining continued review of the clinical research at intervals not exceeding 
one year or at more frequent intervals if specified by the IRB/IEC. The Investigator 
must supply Sponsor or designee with written documentation of continued 
review of the clinical research.
The Investigator is responsible for reporting the following to the IRB/IEC:
x
All SAEs (including deaths) regardless of cause and whether anticipated or 
unanticipated (reported immediately)
x
Significant findings that become known in the course of the study that might 
affect the willingness of subjects to continue to participate 
x
Protocol, or consent amendments prior to the implementation of the change
x
Study progress reports at least once a year, if applicable
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x
Notification of study completion or termination.
Sponsor may amend the protocol as needed to ensure that the clinical 
investigation is being conducted as intended. Sponsor will initiate protocol 
amendments in writing if any change significantly affects the safety of subjects, 
the scope of the investigation, or the scientific quality of the study. Protocol 
changes must be submitted to the IRB/IEC as a protocol amendment. If 
necessary, the ICF will be revised to reflect the changes in the amendment and 
will be submitted to the IRB/IEC for review and approval. A copy of the 
amendment must be signed by the Investigator and returned to Sponsor or 
designee. Written documentation of IRB/IEC approval is required before the 
amendment is implemented. Investigators may not perform study-specific 
assessments that are not included in the protocol unless agreed to by Sponsor. 
10.1.3  Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause.  Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or 
terminating party to study subjects, investigator, and regulatory authorities.  If the 
study is prematurely terminated or suspended, the PI will promptly inform study 
participants, the IRB/IEC, and sponsor and will provide the reason(s) for the 
termination or suspension.  Study subjects will be contacted, as applicable, and 
be informed of changes to study visit schedule.
When a study is prematurely terminated, refer to Section 7, Study Intervention 
Discontinuation and Participant Discontinuation/Withdrawal, for handling of 
enrolled study participants.
10.1.4  Confidentiality and Privacy
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor, or designee. The study protocol, 
documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to 
any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, 
representatives of the IRB/IEC, or regulatory agencies may inspect all documents 
and records required to be maintained by the investigator, including but not 
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limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study. The clinical study site will permit access to such 
records.
The study participant’s contact information will be securely stored at each 
clinical site for internal use during the study. At the end of the study, all records 
will continue to be kept in a secure location for as long a period as dictated by 
the reviewing IRB/IEC, Institutional policies, or sponsor requirements.
10.1.5  Future Use of Stored Specimens and Data
There is no genetic testing performed in relation to this study.
10.1.6  Safety Oversight
There will be an Independent Safety Consultant for review of dose escalation 
and dose de-escalation decisions as outlined in Section 6.1.2.1, Guidelines for 
Dose Escalation and Section 6.1.2.2 Guidelines for Dose De-escalation. 
10.1.7  Clinical Monitoring
Clinical site monitoring is conducted to ensure that the rights and well-being of 
trial participants are protected, that the reported trial data are accurate, 
complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable 
regulatory requirement(s). 
The Sponsor, or its designee, and regulatory authority inspectors are responsible 
for contacting and visiting the Investigator for the purpose of inspecting the 
facilities and, upon request, inspecting the various records of the trial (e.g., CRFs 
and other pertinent data) provided that subject confidentiality is respected. The 
Sponsor monitor is responsible for inspecting the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, 
accuracy, and consistency of the data; and adherence to local regulations on 
the conduct of clinical research. The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on 
the CRFs. The Investigator agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits, including delays 
in completing CRFs, are resolved.
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To ensure the quality of clinical data a clinical data management review will be 
performed on subject data received by the Sponsor. During this review, subject 
data will be checked for consistency, omissions, and any apparent 
discrepancies. In addition, the data will be reviewed for adherence to the 
protocol and GCP. 
Independent audits may be conducted by the Sponsor, or designee, or 
regulatory authority inspectors to inspection the Study Center facilities (e.g., 
pharmacy, drug storage areas, laboratories) and review of study related records 
to evaluate the trial conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements.
The Principal Investigator will sign and date the indicated places on the CRF. 
These signatures will indicate that the principal Investigator inspected or 
reviewed the data on the CRF, the data queries, and the Study Center 
notifications, and agrees with the content.
10.1.8  Quality Assurance and Quality Control
The Sponsor, or designee, will be responsible for data management of this study, 
including quality checking of the data. Sites will be responsible for data entry into 
the electronic data capture (EDC) system (eCRFs). In the event of data 
discrepancy, the Sponsor, or designee, will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system. 
The eCRFs and correction documentation will be maintained in the EDC system 
audit trail. 
The ePRO data will be collected with the use of an electronic device provided 
by an ePRO vendor. The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with FDA and European 
regulations for electronic records (21 CFR, Part 11). The ePRO device data are 
available for view access only via secure access to a Web server. Only identified 
and trained users may view the data, and their actions become part of the audit 
trail. The Sponsor will have view access only. 
Following written Standard Operating Procedures (SOPs), the monitors will verify 
that the clinical trial is conducted, and data are generated, and biological 
specimens are collected, documented (recorded), and reported in compliance 
with the protocol, ICH GCP, and applicable regulatory requirements (e.g., Good 
Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. 
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10.1.9  Data Handling and Record Keeping
10.1.9.1 
Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site investigator. The investigator is responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported.
All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  
Clinical data (including AEs, concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Medidata Rave 
EDC, a 21 CFR Part 11-compliant data capture system. The data system includes 
password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents.]
10.1.9.2 
Study Records Retention
Study documents should be retained as required by local regulations. No records 
will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained
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10.1.10  
Protocol Amendments
Sponsor may amend the protocol as needed to ensure that the clinical 
investigation is being conducted as intended. Sponsor will initiate protocol 
amendments in writing if any change significantly affects the safety of subjects, 
the scope of the investigation, or the scientific quality of the study. Protocol 
changes must be submitted to the IRB/IEC as a protocol amendment. If 
necessary, the ICF and assent form will be revised to reflect the changes in the 
amendment and will be submitted to the IRB/IEC for review and approval. A 
copy of the amendment must be signed by the Investigator and returned to 
Sponsor or designee. Written documentation of IRB/IEC approval is required
before the amendment is implemented. Investigators may not perform study-
specific assessments that are not included in the protocol unless agreed to by 
Sponsor. Additionally, a site-specific amendment and revised ICF and assent 
form must be generated and submitted for approval to the IRB/IEC.
10.1.11  
Publication and Data Sharing Policy
The final clinical study report is also intended to form the basis for a manuscript 
intended for publication in a peer-reviewed scientific journal. The authorship, 
timetable and any arrangements for review by the participating investigators will 
be coordinated by Catalyst Biosciences.  No partial subset of data from 
individual investigational sites can be presented or published until after the 
primary manuscript for the entire study has been accepted for publication in a 
peer reviewed scientific journal.
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10.2 
PROTOCOL AMENDMENT HISTORY
Version
Date
Description of Change
Brief Rationale
1.0
June 2017
2.0
25 August 2018
Outlined in Detailed 
Summary of Protocol
Changes 
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11. 
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55. Gusi N, Olivares PR, Rajendram R. The EQ-5D Health-Related Quality of Life 
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ï
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APPENDICES
APPENDIX A – CLINICAL SIGNS OF THROMBOSIS
  
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Symptoms and Signs of Venous Thromboembolism – Deep Vein Thrombosis (DVT) 
and Pulmonary Embolism (PE):
Leg pain or tenderness of the thigh or calf
Leg swelling (edema)
Skin that feels warm to the touch
Reddish discoloration or red streaks
Unexplained shortness of breath
Rapid breathing
Chest pain anywhere under the rib cage (may be worse with deep breathing)
Fast heart rate
Light headedness or passing out
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Common Heart Attack Warning Signs
Pain or discomfort in the chest
Lightheadedness, nausea, or vomiting
Jaw, neck, or back pain
Discomfort or pain in arm or shoulder
Shortness of breath
Stroke Signs
Face Drooping
Arm Weakness
Speech Difficulty
Sudden confusion, trouble speaking or understanding speech
Sudden numbness or weakness of face, arm or leg.  Especially on one side of the 
body.
Sudden trouble seeing in one or both eyes.
Sudden trouble walking, dizziness, loss of balance or coordination.
Sudden severe headache with no known cause.
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Signs and Symptoms of Thrombosis
The clinical spectrum of venous thromboembolism (VTE) ranges from deep vein thrombosis (DVT) to pulmonary 
embolism (PE). The symptoms of VTE depend on the location of the affected vessel and whether the vessel is totally or 
partially occluded by the clot. 
Table. Clinical Spectrum of VTE
Type
Signs and Symptoms
Physical Examination
Deep vein thrombosis (DVT)
•Blood clots may form in the deep blood 
vessels, most commonly in the legs and groin, 
and can block normal blood flow returning from 
the legs to the heart.
•Venous clots that form in regions of slow to 
moderate flow are composed of a mixture of 
red cells, platelets, and fibrin and are known as 
mixed platelet fibrin thrombi.
•Partially occlusive venous thrombosis of the 
deep veins in the legs or abdomen may present 
with subtle symptoms and sometimes may not 
present until significant collateral circulation* 
has developed.
x
Pain
x
Swelling of the affected 
extremity/area with 
erythema and warmth over 
the vicinity of the clot
x
Discoloration including a 
bluish or suffused color
x
Positive Homan’s sign: pain with 
dorsiflexion of the foot
x
Swelling
x
Pain on palpation
x
Presence of a palpable cord
x
Evidence of collateral circulation, 
usually manifested by increased 
prominence of superficial veins
x
Some people with a DVT may be 
asymptomatic 
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Pulmonary Embolism (PE)
•PE results from a piece or all of a blood clot 
that breaks off and is carried by the blood 
stream to the lung where it obstructs the blood 
vessel. 
•The size of the clot and the site of the 
obstruction of blood flow in the vessel 
determine the extent and severity of the 
pulmonary embolus.
•Proximal vein thrombosis is more likely to lead 
to fatal PE as compared to calf vein thrombosis.
•The incidence of fatal PE can be markedly 
reduced if DVT is treated with anticoagulant 
therapy.  
Pulmonary emboli may present 
subtly with the following 
complaints listed in order of 
frequency: 
x
Dyspnea 
x
Rapid breathing, fast 
heartbeat and chest pain 
especially with inhalation
x
Pleural pain: Some patients 
notice only a dull ache in 
their chest
x
Apprehension, anxiety
x
Cough
x
Hemoptysis 
x
Sweats 
x
Syncope
x
Fatigue
x
Tachypnea
x
Tachycardia
x
Rales 
x
Fever 
x
Sweating 
x
Thrombophlebitis
x
Accentuation of the pulmonary 
closure sound
x
Gallop heart sound
x
Cyanosis 
x
Some people with a PE may be 
asymptomatic 
Superficial Thrombophlebitis
•Superficial thrombophlebitis is due to blood 
clots that form in veins that are closer to the 
surface of the skin and are associated with 
inflammation.
x
These clots often partially block blood flow in affected veins and may 
cause pain and irritation.
x
Redness and inflammation along the vein may occur; if hard and 
erythematous, the affected vein is often visible and most commonly 
occurs in the legs or arms. 
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•Superficial thrombophlebitis is often observed 
in individuals who are heterozygous or 
homozygous for the factor V Leiden mutation.
x
Other associated symptoms include warmth and tenderness, 
surrounding purities and swelling.
x
Pain along the vein: patients may report a throbbing or burning 
sensation beneath the skin’s surface; these symptoms may interfere 
with sleep as they progress.
Fever: Patients with venous inflammation may develop an elevated 
temperature associated with an episode of thrombophlebitis.
Adapted from IHTC. Signs and Symptoms of Thrombosis. Available at http://www.ihtc.org/payors/conditions-we-
treat/clotting-disorders/signs-and-symptoms-of-thrombosis.
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APPENDIX B – PATIENT REPORTED OUTCOME (PRO) SCALES  
EQ-5D: http://www.euroqol.org/eq-5d-products/how-to-obtain-eq-5d.html
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HAEM-A-QoL: https://eprovide.mapi-trust.org/instruments/haemophilia-quality-of-life-
questionnaire-for-adults HAL: http://elearning.wfh.org/resource/hemophilia-activities-list-
hal/
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APPENDIX C – DETAILED STUDY SCHEMA
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If spontaneous bleed occurs after the fifth daily dose  
If no spontaneous bleed occurs after the fifth daily dose  
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