Clinical trial NCT03650413
Conditions: Ulcerative Colitis Crohn's Disease
Sponsor: Genentech, Inc.
Start date: 2019-01-14; Completion date: 2022-07-12
Enrollment: 143 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the long-term safety and tolerability of UTTR1147A in participants with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD), enrolling up to 320 participants from the parent studies: Phase Ib Study GA29469 (NCT02749630) and Phase II Study GA39925 (NCT03558152).

Detailed description:

Arms: arm 1: All participants will have the opportunity to receive treatment with UTTR1147A until clinical remission is achieved. Participants will either receive treatment with UTTR1147A or undergo observation depending on disease status, as described in the protocol.
Interventions: intervention 1: UTTR1147A
Intervention descriptions: intervention 1: UTTR1147A will be administered based on disease status, as described in the protocol.

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Efmarodocokin Alfa—Genentech, Inc.
Protocol GA40209, Version 7
PROTOCOL
TITLE:
A PHASE II OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND
TOLERABILITY OF UTTR1147A IN PATIENTS WITH 
MODERATE TO SEVERE ULCERATIVE COLITIS
OR CROHN'S DISEASE
PROTOCOL NUMBER:
GA40209
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004997-32
IND NUMBER:
136180
NCT NUMBER:
NCT03650413
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
26-Jul-2021 20:28:59


Efmarodocokin Alfa—Genentech, Inc.
2/ Protocol GA40209, Version 7
PROTOCOL HISTORY
Protocol
Associated Country- or Region-Specific Protocols
Version
Date Final
Country or Region
Version
Date Final
7
See electronic date 
stamp on title page.
China Version 4 protocol has not been amended.
China will not be activated for this study.
6
15 December 2020
5
9 April 2020
3
6 April 2018
China
4
11 April 2019
VHP
4
21 November 2018
VHP/UK
3
24 August 2018
2
2 March 2018



1
19 December 2017





Efmarodocokin Alfa—Genentech, Inc.
3/ Protocol GA40209, Version 7
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol GA40209 has been amended to align with the Investigator Brochure update 
(Version 8, April 2021) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Efmarodocokin Alfa—Genentech, Inc.
4/ Protocol GA40209, Version 7
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol.


Efmarodocokin Alfa—Genentech, Inc.
5/ Protocol GA40209, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 22
1.1
Background on Inflammatory bowel disease ......................... 22
1.2
Background on Efmarodocokin Alfa ...................................... 22
1.2.1
Summary of Nonclinical Studies............................................ 23
1.2.2
Summary of Clinical Studies.................................................. 23
1.3
Study Rationale and Benefit-Risk Assessment...................... 25
2.
OBJECTIVES AND ENDPOINTS ............................................................... 27
3.
STUDY DESIGN......................................................................................... 29
3.1
Description of the Study......................................................... 29
3.1.1
Overview of Study Design ..................................................... 29
3.1.2
Efmarodocokin Alfa Administration........................................ 29
3.1.3
Study Participation during Year 2 .......................................... 30
3.1.4
Key Definitions for the Study ................................................. 31
3.1.4.1
Definitions for Clinical Response during Study 
GA29469 ............................................................................... 31
3.1.4.2
Definitions for Clinical Response during the 
Extension Study..................................................................... 32
3.1.4.3
Definitions for Clinical Remission during the 
Extension Study..................................................................... 32
3.1.4.4
Definitions for Disease Flare during the 
Extension Study..................................................................... 33
3.1.5
Disease Evaluation Visits ...................................................... 33
3.1.6
Safety Follow-Up Visit and Early Termination 
Visit........................................................................................ 34
3.1.7
Corticosteroids....................................................................... 34
3.1.8
Internal Monitoring Committee............................................... 35
3.2
End of Study and Length of Study......................................... 36
3.3
Rationale for Study Design.................................................... 36
3.3.1
Rationale for Efmarodocokin Alfa Dose and 
Schedule................................................................................ 36


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3.3.2
Rationale for Pharmacokinetic Sample Collection................. 36
3.3.3
Rationale for Biomarker Assessments................................... 36
4.
MATERIALS AND METHODS .................................................................... 36
4.1
Patients.................................................................................. 36
4.1.1
Inclusion Criteria.................................................................... 37
4.1.1.1
Inclusion Criteria for Study Entry ........................................... 37
4.1.1.2
Inclusion Criteria for Study Entry and Study Re-
Entry ...................................................................................... 37
4.1.2
Exclusion Criteria................................................................... 38
4.1.2.1
Exclusion Criteria for Study Entry.......................................... 38
4.1.2.2
Exclusion Criteria for Study Entry and Study Re-
Entry ...................................................................................... 38
4.1.2.3
Exclusion Criterion for Study Re-Entry .................................. 39
4.2
Method of Treatment Assignment and Blinding..................... 39
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 39
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 39
4.3.1.1
Efmarodocokin Alfa ............................................................... 39
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 39
4.3.2.1
Efmarodocokin Alfa ............................................................... 40
4.3.3
Investigational Medicinal Product Accountability ................... 40
4.3.4
Continued Access to Efmarodocokin Alfa.............................. 41
4.4
Concomitant Therapy and Additional Restrictions................. 41
4.4.1
Rescue Therapy .................................................................... 42
4.4.2
Other Concomitant Therapy .................................................. 42
4.4.2.1
Permitted Concomitant Therapy............................................ 42
4.4.2.2
Prohibited Concomitant Therapy ........................................... 43
4.4.3
Additional Restrictions ........................................................... 43
4.5
Study Assessments ............................................................... 43
4.5.1
Informed Consent Forms and Screening Log........................ 44
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 44


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4.5.3
Physical Examinations........................................................... 44
4.5.4
Vital Signs.............................................................................. 45
4.5.5
Clinical Outcome Assessments ............................................. 45
4.5.5.1
Mayo Clinic Score, Modified Mayo Clinic Score, 
and Partial Mayo Clinic Score................................................ 45
4.5.5.2
Crohn's Disease Activity Index and Patient-
Reported Outcome-2 Score................................................... 45
4.5.5.3
Simple Endoscopic Score for Crohn's Disease ..................... 46
4.5.5.4
Patient-Reported Outcomes .................................................. 46
4.5.5.5
Physician's Global Assessment............................................. 47
4.5.5.6
Endoscopy with Biopsies....................................................... 47
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 48
4.5.7
Electrocardiograms................................................................ 50
4.5.8
Optional Samples for Research Biosample 
Repository ............................................................................. 51
4.5.8.1
Overview of the Research Biosample Repository.................. 51
4.5.8.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 51
4.5.8.3
Sample Collection.................................................................. 52
4.5.8.4
Confidentiality........................................................................ 52
4.5.8.5
Consent to Participate in the Research 
Biosample Repository............................................................ 53
4.5.8.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 53
4.5.8.7
Monitoring and Oversight....................................................... 54
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 54
4.6.1
Study Treatment Discontinuation........................................... 54
4.6.2
Patient Discontinuation from Study........................................ 55
4.6.3
Study Discontinuation............................................................ 55
4.6.4
Site Discontinuation............................................................... 55
5.
ASSESSMENT OF SAFETY....................................................................... 56
5.1
Safety Plan ............................................................................ 56
5.1.1
Risks Associated with Efmarodocokin Alfa............................ 56


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8/ Protocol GA40209, Version 7
5.1.1.1
Dermatologic Reactions......................................................... 56
5.1.1.2
Infusion-Related Reactions.................................................... 57
5.1.1.3
Epithelial Tumor Promotion ................................................... 57
5.1.1.4
Neutralization of Endogenous IL-22 by Anti-Drug 
Antibodies.............................................................................. 58
5.1.1.5
Worsening of Clotting/Coagulation Dysfunction in 
High-Risk Populations due to Increased 
Fibrinogen.............................................................................. 58
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 59
5.1.2.1
Dose Modifications ................................................................ 59
5.1.2.2
Treatment Interruption ........................................................... 60
5.1.2.3
Management Guidelines........................................................ 60
5.2
Safety Parameters and Definitions ........................................ 66
5.2.1
Adverse Events ..................................................................... 67
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 67
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 68
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 69
5.3.2
Eliciting Adverse Event Information....................................... 69
5.3.3
Assessment of Severity of Adverse Events ........................... 70
5.3.4
Assessment of Causality of Adverse Events ......................... 70
5.3.5
Procedures for Recording Adverse Events............................ 71
5.3.5.1
Infusion-Related Reactions.................................................... 71
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 72
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 72
5.3.5.4
Persistent or Recurrent Adverse Events................................ 72
5.3.5.5
Abnormal Laboratory Values ................................................. 73
5.3.5.6
Abnormal Vital Sign Values ................................................... 74
5.3.5.7
Abnormal ECG Findings........................................................ 74
5.3.5.8
Abnormal Liver Function Tests.............................................. 75


Efmarodocokin Alfa—Genentech, Inc.
9/ Protocol GA40209, Version 7
5.3.5.9
Deaths ................................................................................... 75
5.3.5.10
Preexisting Medical Conditions.............................................. 76
5.3.5.11
Lack of Efficacy or Worsening of Ulcerative 
Colitis or Crohn's Disease ..................................................... 76
5.3.5.12
Hospitalization or Prolonged Hospitalization.......................... 76
5.3.5.13
Patient-Reported Outcome Data ........................................... 77
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 77
5.4.1
Emergency Medical Contacts................................................ 78
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 78
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 78
5.4.2.2
Events That Occur after Study Drug Initiation........................ 78
5.4.3
Reporting Requirements for Pregnancies.............................. 79
5.4.3.1
Pregnancies in Female Patients............................................ 79
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 79
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 80
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 80
5.5
Follow-Up of Patients after Adverse Events .......................... 81
5.5.1
Investigator Follow-Up........................................................... 81
5.5.2
Sponsor Follow-Up ................................................................ 82
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 82
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 82
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 83
6.1
Determination of Sample Size ............................................... 83
6.2
Summaries of Conduct of Study............................................ 84
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 84
6.4
Safety Analyses..................................................................... 84
6.5
Exploratory Efficacy Analyses ............................................... 85


Efmarodocokin Alfa—Genentech, Inc.
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6.6
Exploratory Pharmacokinetic Analyses.................................. 85
6.7
Exploratory Immunogenicity Analyses................................... 85
6.8
Exploratory Biomarker Analyses............................................ 86
7.
DATA COLLECTION AND MANAGEMENT ............................................... 86
7.1
Data Quality Assurance......................................................... 86
7.2
Electronic Case Report Forms............................................... 86
7.3
Source Data Documentation.................................................. 87
7.4
Use of Computerized Systems .............................................. 87
7.5
Retention of Records............................................................. 88
8.
ETHICAL CONSIDERATIONS.................................................................... 88
8.1
Compliance with Laws and Regulations ................................ 88
8.2
Informed Consent.................................................................. 89
8.3
Institutional Review Board or Ethics Committee.................... 90
8.4
Confidentiality........................................................................ 90
8.5
Financial Disclosure .............................................................. 91
8.6
Patient Recruitment ............................................................... 91
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 92
9.1
Study Documentation ............................................................ 92
9.2
Protocol Deviations................................................................ 92
9.3
Site Inspections ..................................................................... 92
9.4
Administrative Structure......................................................... 92
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 93
9.6
Protocol Amendments ........................................................... 94
10. REFERENCES ........................................................................................... 95
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 28
Table 2
Efmarodocokin Alfa Treatment Algorithm ................................... 30
Table 3
Algorithm for Continued Study Participation during Year 2 ......... 31
Table 4
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 63


Efmarodocokin Alfa—Genentech, Inc.
11/ Protocol GA40209, Version 7
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 70
Table 6
Causal Attribution Guidance ....................................................... 71
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 97
Appendix 2
Mayo Clinic Score..................................................................... 103
Appendix 3
Modified Mayo Clinic Score....................................................... 104
Appendix 4
Partial Mayo Clinic Score.......................................................... 105
Appendix 5
Signs and Symptoms in Ulcerative Colitis Daily Diary:  
Stool Frequency and Rectal Bleeding....................................... 106
Appendix 6
Crohn's Disease Activity Index 
(Includes Patient-Reported Outcome-2 Score) ......................... 107
Appendix 7
Simple Endoscopic Score for Crohn's Disease......................... 108
Appendix 8
Bristol Stool Form Scale ........................................................... 109
Appendix 9
Anaphylaxis Precautions........................................................... 110


Efmarodocokin Alfa—Genentech, Inc.
12/Protocol GA40209, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND
TOLERABILITY OF UTTR1147A IN PATIENTS WITH 
MODERATE TO SEVERE ULCERATIVE COLITIS
OR CROHN'S DISEASE
PROTOCOL NUMBER:
GA40209
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004997-32
IND NUMBER:
136180
NCT NUMBER:
NCT03650413
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO.


Efmarodocokin Alfa—Genentech, Inc.
13/Protocol GA40209, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE II OPEN-LABEL EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND TOLERABILITY OF UTTR1147A 
IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE 
COLITIS OR CROHN'S DISEASE
PROTOCOL NUMBER:
GA40209
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004997-32
IND NUMBER:
136180
NCT NUMBER:
NCT03650413
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
PHASE:
II
INDICATION:
Ulcerative colitis and Crohn's disease
SPONSOR:
Genentech, Inc.
OBJECTIVES AND ENDPOINTS
This study will evaluate the long-term safety and tolerability of efmarodocokin alfa in patients 
with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD).  In addition, the study 
will obtain long-term data on the efficacy, immunogenicity, and exposure of efmarodocokin alfa.  
Specific objectives and corresponding endpoints for the study are outlined below.  For endpoint 
determination, endoscopic scores will be based on interpretation by a central reader.
Objectives and Corresponding Endpoints
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability 
of efmarodocokin alfa
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE scale
Change in targeted vital signs, physical findings, and 
clinical laboratory test results during and following 
efmarodocokin alfa administration
ADAanti-drug antibody; NCI CTCAE National Cancer Institute Common Terminology Criteria 
for Adverse Events; PKpharmacokinetic; PRO2Patient-Reported Outcome-2.
Note:  For endpoint determination, endoscopic scores will be based on interpretation by a central 
reader.
a Clinical response during the extension study, as defined in the protocol.
b Clinical remission during the extension study, as defined in the protocol.
c Efmarodocokin alfa 60 g/kg IV Q4W.


Efmarodocokin Alfa—Genentech, Inc.
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Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
efmarodocokin alfa
Clinical response a at Weeks 28, 52, 80, and 104
Clinical remission b at Weeks 28, 52, 80, and 104
Durability of clinical remission, defined as time from 
achieving clinical remission b to loss of clinical 
remission b
Change from baseline (i.e., either the baseline score 
in the parent study or the last score prior to initiation 
of the most recent course c of efmarodocokin alfa
during the extension study, whichever score is the 
most recent) in PRO2 in patients with Crohn's 
disease
Exploratory Pharmacokinetic 
Objective
Corresponding Endpoints
To evaluate potential relationships 
between long-term drug exposure and 
the safety and efficacy of 
efmarodocokin alfa
Relationship between serum concentration or PK 
parameters for efmarodocokin alfa and exploratory 
efficacy endpoints
Relationship between serum concentration or PK 
parameters for efmarodocokin alfa and safety 
endpoints
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate the immune response to 
efmarodocokin alfa
Presence of ADAs to efmarodocokin alfa during the 
study relative to the presence of ADAs at baseline 
(Study Week 0)
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers that can 
increase the knowledge and 
understanding of disease biology
Relationship between biomarkers in stool and 
colonic tissue and efficacy, safety, or 
immunogenicity endpoints
ADAanti-drug antibody; NCI CTCAE National Cancer Institute Common Terminology Criteria 
for Adverse Events; PKpharmacokinetic; PRO2Patient-Reported Outcome-2.
Note:  For endpoint determination, endoscopic scores will be based on interpretation by a central 
reader.
a Clinical response during the extension study, as defined in the protocol.
b Clinical remission during the extension study, as defined in the protocol.
c Efmarodocokin alfa 60 g/kg IV Q4W.
STUDY DESIGN
DESCRIPTION OF STUDY
This open-label extension study (GA40209) will evaluate the long-term safety and tolerability of 
efmarodocokin alfa in patients with moderate to severe UC or CD.  In addition, the study will 
obtain long-term data on the efficacy, immunogenicity, and exposure of efmarodocokin alfa.  
Patients enrolled in the extension study will receive efmarodocokin alfa treatment or undergo 
observation for up to approximately 2 years (through Week 104), as determined on the basis of 
the patient's disease status.  Upon entry into the extension study, patients will receive 
efmarodocokin alfa 60 g/kg IV every 4 weeks (Q4W) or undergo observation, depending on 
their disease status at the time of their last endoscopy in the parent study.  The first dose of 


Efmarodocokin Alfa—Genentech, Inc.
15/ Protocol GA40209, Version 7
efmarodocokin alfa in the extension study may not be administered less than 2 weeks after last 
dose of study drug in parent study.  During the extension study, patients will receive 
efmarodocokin alfa 60 g/kg IV Q4W or undergo observation, depending on their disease status 
at a scheduled visit or a disease evaluation visit.
Efmarodocokin Alfa Treatment Algorithm
Patient's Disease Status
Action to Be Taken
Meets criteria for clinical remission. a

Discontinue efmarodocokin alfa (if 
applicable)

Undergo observation and assessments per 
schedule of activities
Does not meet criteria for clinical remission. a 

Receive efmarodocokin alfa 60 g/kg IV 
Q4W until clinical remission is achieved b

Undergo assessments per schedule of 
activities 
Meets criteria for disease flare c (off treatment)
after entry into the study

Consult with Medical Monitor to determine 
appropriate course of action prior to 
administration of efmarodocokin alfa (if 
applicable)
Experiences disease worsening as a result of 
efmarodocokin alfa treatment, in the 
investigator's judgment, or disease flare while 
receiving efmarodocokin alfa c

Permanently discontinue efmarodocokin 
alfa

Initiate rescue therapy at discretion of 
investigator

Undergo safety follow-up assessments  
8 weeks after final dose of efmarodocokin 
alfa
Q4W every 4 weeks.
a Clinical remission during the extension study, as defined in the protocol.
b First dose of efmarodocokin alfa in the extension study to be administered no less than 2 
weeks after last dose of study drug in parent study
c Disease flare during the extension study, as defined in the protocol.
The duration of the study has been extended from 1 year to 2 years with the implementation of 
Protocol Version 6.  Patients who completed the study through Week 52 (Year 1) prior to the 
implementation of Protocol Version 6 may still be eligible for an additional year of treatment 
and/or observation, provided that certain criteria are met, as outlined in the algorithm below.  
Participation during Year 2 is not required for such patients, and those who do not participate 
will be considered to have completed the study per protocol, provided required safety follow-up 
assessments have been completed.


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Algorithm for Continued Study Participation during Year 2
Patient Disposition Status at Time of 
Implementation of Protocol Version 6
Action to Be Taken
Has not yet reached Week 52

Patient will continue study drug treatment or 
observation through Week 104 per 
efmarodocokin alfa treatment algorithm above.
Has completed Week 52 visit but has 
not yet completed required safety 
follow-up assessments

Patient may resume study drug treatment or 
observation through Week 104 per 
efmarodocokin alfa treatment algorithm above.  
If resuming study treatment, there must be a 
minimum of 2 weeks since the last dose of 
efmarodocokin alfa. a
Has completed Week 52 visit and 
required safety follow-up assessments b

Re-consent patient within 8 weeks of 
implementation of Protocol Version 6.

Conduct study re-entry screening assessments 
(including endoscopy) over a 3-week period to 
confirm study eligibility and evaluate disease 
status.  Daily diary recording will be re-initiated 
to enable collection of patient-reported outcome 
data for MCS, CDAI, and PRO2 assessments.

If eligible for study re-entry, patient will resume 
study drug treatment (within 1 week of 
establishing eligibility) or undergo observation 
through Week 104 per efmarodocokin alfa
treatment algorithm above. 
CDAICrohn's Disease Activity Index; MCSMayo Clinic Score; PRO2Patient-Reported
Outcome-2.
a If resuming study treatment, there will be no visit window deviation if there is a minimum of 
2 weeks since the last dose of efmarodocokin alfa.
b Also includes patients who have completed Week 52 visit but do not require safety 
follow-up assessments because they did not receive efmarodocokin alfa during the study.
NUMBER OF PATIENTS
This study will enroll up to approximately 320 patients from Phase Ib Study GA29469 and 
Phase II Study GA39925 (parent studies).  Enrollment numbers may be less based on the 
actual number of patients who rollover into Study GA40209.  
TARGET POPULATION
Inclusion Criteria
Inclusion Criteria for Study Entry
Patients must meet the following criteria for study entry:

Prior enrollment in Study GA29469 or Study GA39925, with one of the following having 
occurred during that study:
Patients previously enrolled in Study GA29469

Unable to achieve clinical response during the study and completion of the study 
through at least Day 85

Initiation of protocol-defined rescue therapy during the study and completion of the 
study through at least Day 85

Completion of the study through Day 134


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Patients previously enrolled in Study GA39925

Unable to achieve protocol-defined clinical response by Week 8 

Initiation of protocol-defined rescue therapy during the study and completion of the 
study through at least Week 8

Protocol-defined disease flare after Week 8

Completion of the study through Week 30

Age 1880 years, inclusive, at time of signing Informed Consent Form
Inclusion Criteria for Study Entry and Study Re-Entry
Patients must meet the following criteria for study entry and study re-entry:

Signed Informed Consent Form (at time of initial entry and again at time of study re-entry)

Ability to comply with requirements of the study, in the investigator's judgment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for 8 weeks after the final dose of study drug or 18 weeks 
after final dose of study drug from Study GA39925 (due to the possibility of receiving 
vedolizumab), whichever is longer
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices 
(recommendations related to contraception and pregnancy testing in clinical trials, 
Clinical Trial Facilitation Group, final version, dated 2014-09-15, Section 4.1).
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for 8 weeks after 
the final dose of study drug or 18 weeks after final dose of study drug from 
Study GA39925, whichever is longer, to avoid exposing the embryo.  Men must refrain 
from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.
Exclusion Criteria
Exclusion Criteria for Study Entry
Patients who meet any of the following criteria will be excluded from study entry:

Withdrawal of consent from parent study

Discontinuation of study drug as required by the parent study protocol 

Discontinuation of study drug and withdrawal from Study GA29469 prior to Day 85 or from 
Study GA39925 prior to Week 8

Non-compliance in the parent study, specifically defined as missing scheduled visits or 
non-adherence with background medications and concomitant medications


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Exclusion Criteria for Study Entry and Study Re-Entry
Patients who meet any of the following criteria will be excluded from study entry and study 
re-entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
8 weeks after the final dose of study drug or 18 weeks after final dose of study drug from 
Study GA39925 (due to the possibility of receiving vedolizumab), whichever is longer

Any new malignancy since enrolling in the parent study

Any new significant uncontrolled comorbidity, such as cardiac, pulmonary, renal, hepatic, 
endocrine, or gastrointestinal disorders, since enrolling in the parent study

Any new signs or symptoms of infection judged by the investigator to be clinically significant 
since enrolling in the parent study

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) since enrolling 
in the parent study

Prior treatment with etrolizumab, natalizumab, efalizumab, or any other anti-integrin agents 
(other than vedolizumab)

Use of IV corticosteroid or topical corticosteroid (i.e., enemas or suppositories) at the time 
of entry into this study

Abnormal laboratory value recorded at the last visit in the parent study, as defined below:
−
Hemoglobin 90 g/L (9 g/dL)
−
Serum creatinine 1.5upper limit of normal (ULN)
−
ALT, AST, or ALP 2.5ULN, total bilirubin 1.5ULN, or presence of abnormalities in 
synthetic function tests judged to be clinically significant by the investigator
Patients with known Gilbert syndrome who have unconjugated hyperbilirubinemia 
will not be excluded.
−
Platelet count 100109/L (100,000/L)
−
ANC 1.5109/L (1500/L)
−
Absolute lymphocyte count 0.5109/L (500/L)
Exclusion Criterion for Study Re-Entry
Patients who meet the following criterion will be excluded from study re-entry:

Use of prohibited concomitant therapy since enrolling in the extension study
END OF STUDY
The end of the study is defined as the date when the last patient completes his or her final study
visit.
LENGTH OF STUDY
Patients in this study will receive treatment or undergo observation for up to approximately 
2 years.
INVESTIGATIONAL MEDICINAL PRODUCTS
The investigational medicinal product for this study is efmarodocokin alfa.
Treatment with efmarodocokin alfa 60 g/kg Q4W will be administered by IV infusion.
STATISTICAL METHODS
Data collected from the final visit of the parent study will serve as baseline (Study Week 0) data 
for the extension study.  
PRIMARY ANALYSIS
The safety analysis population will consist of all patients who received at least one dose of 
study drug. 
Safety will be assessed through descriptive summaries of adverse events and laboratory test 
results.


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DETERMINATION OF SAMPLE SIZE
Approximately 48 patients will be enrolled in parent study GA29469, and approximately 
270 patients will be enrolled in parent study GA39925.  These patients will be potentially eligible 
for this extension study.
The purpose of this study is to evaluate the long-term safety and tolerability of efmarodocokin 
alfa; no formal hypothesis testing will be performed.  Assumptions for sample size determination 
are based on a 52-week study period, in line with the study duration prior to the implementation 
of Protocol Version 6.  Assuming approximately 50% of patients from parent study GA39925 will 
enter this open-label extension study as non-responders (approximately 135 patients) and 20% 
of those patients will have sustained clinical remission at the end of the 52-week study period, a 
total of 135 evaluable patients will provide a 95% confidence interval of 13.3% to 26.7% for the 
point estimate of 20%.  In two different 52-week maintenance Phase III studies in patients with 
moderate to severely active UC, the percentage of patients randomly assigned to the placebo 
arm and who had at least one severe adverse event was 6.6% (13/198) and 13.5% (37/275) 
respectively. Assuming a 52-week serious adverse event rate of 6.6% or 13.5% for 
efmarodocokin alfa in Study GA40209, 135 evaluable patients will provide a 95% confidence 
interval of 3% to 12% or a 95% confidence interval of 8% to 20%, respectively.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
ADA
anti-drug antibody, also known as anti-therapeutic 
antibody
AIS
adenocarcinoma in situ
AZA
azathioprine
CD
Crohn's disease
CDAI
Crohn's Disease Activity Index
CIN
cervical intraepithelial neoplasia
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DE
disease evaluation (visit)
DLT
dose-limiting toxicity
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
Food and Drug Administration
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesion
HV
healthy volunteer
IBD
inflammatory bowel disease
ICH
International Council for Harmonisation
IL-22
interleukin-22
IL-22R
interleukin-22 receptor
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LFT
liver function test
MCS
Mayo Clinic Score
mMCS
modified Mayo Clinic Score
MMF
mycophenolate mofetil
MTX
methotrexate
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug


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Abbreviation
Definition
PD
pharmacodynamic
PGA
Physician's Global Assessment
PK
pharmacokinetic
pMCS
partial Mayo Clinic Score
PRO
patient-reported outcome
PRO2
Patient-Reported Outcome-2 
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected through use of Fridericia’s 
formula
RBR
Research Biosample Repository
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SES-CD
Simple Endoscopic Score for Crohn's Disease
SUSAR
suspected unexpected serious adverse reaction
TNF
tumor necrosis factor
UC
ulcerative colitis
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON INFLAMMATORY BOWEL DISEASE
Ulcerative colitis (UC) and Crohn's disease (CD), the two most common types of 
inflammatory bowel disease (IBD), are chronic inflammatory conditions of the colon and 
gastrointestinal (GI) tract, respectively.  Both diseases have the potential for 
extra-intestinal complications.  Although there are many risk factors associated with the 
development of UC and CD, these diseases fundamentally represent dysregulation of 
the mucosal immune system in a genetically susceptible individual in response to 
commensal microbiota and other environmental triggers.  UC is characterized by 
mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain and may be 
complicated by severe bloody diarrhea and toxic megacolon, requiring major and 
sometimes urgent surgery.  CD is characterized by patchy, transmural inflammation of 
the GI tract with areas of normal mucosa between diseased areas.  Patients with CD can 
present with a variety of symptoms, including nausea, vomiting, abdominal pain, and 
diarrhea.  In addition, patients can present with intestinal obstructions, fistulas, or 
abscesses.  The incidence of UC ranges globally from 6.3 to 24.3 cases per 
100,000 persons per year, and the prevalence ranges globally from 4.9 to 505.0 cases 
per 100,000 persons.  The incidence of CD ranges globally from 0.0 to 20.2 cases per
100,000 persons per year, and the prevalence ranges globally from 0.6 to 322.0 cases 
per 100,000 persons (Molodecky et al. 2012).  The incidence and prevalence vary 
among regions of the world, with the highest estimates occurring in European and 
Northern American populations. This rise may be due in part to better detection and 
diagnosis as well as environmental factors such as improved hygiene and Western diet.  
The disease can affect any age group, but occurrence peaks between the ages of 15 
and 35 years.
Pharmacologic management of IBD currently includes anti-inflammatory drugs 
(corticosteroids and aminosalicylates such as 5-aminosalicylic acid [5-ASA]), tumor 
necrosis factor (TNF) inhibitors and other immunosuppressants (such as azathioprine 
[AZA], 6-mercaptopurine [6-MP], and methotrexate [MTX]), and anti-47 integrin 
agents (such as vedolizumab).  Newer therapies aim to modify the disease by inducing 
mucosal healing, decrease dependence on corticosteroids, and reduce the probability of 
progression to surgery, without significantly compromising immune competence. 
1.2
BACKGROUND ON EFMARODOCOKIN ALFA
Efmarodocokin alfa (also known as UTTR1147A) is a human interleukin-22 (IL-22) 
fusion protein in which the cytokine IL-22 is linked with the Fc portion of IgG4 to improve 
the cytokine's pharmacokinetic (PK) characteristics.  The Fc portion of the fusion protein 
incorporates a mutation that minimizes the potential for Fc effector function.


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IL-22 belongs to the IL-10 cytokine family (Ouyang et al. 2011) and binds specifically to 
the IL-22 receptor (IL-22R) heterodimer, which is expressed on a variety of epithelial 
tissues, including the GI tract epithelium, epidermal keratinocytes, liver hepatocytes, 
pancreatic acinar epithelium, and renal tubular epithelium (Gurney 2004).  IL-22 
modulates innate immunity in epithelial tissues (Wolk et al. 2004), including the GI tract 
mucosal epithelium, by upregulating antimicrobial peptides, increasing mucin production, 
and stimulating epithelial barrier repair (Sugimoto et al. 2008; Zheng et al. 2008).  In 
murine models of UC, IL-22 has demonstrated efficacy through these epithelial 
protective mechanisms (Sugimoto et al. 2008).  Therefore, efmarodocokin alfa is being 
developed as a therapeutic for IBDs such as CD and UC on the basis of IL-22's 
demonstrated biology.
1.2.1
Summary of Nonclinical Studies 
Extensive in vitro and in vivo nonclinical studies have been conducted to characterize 
the pharmacologic activity, safety, PK, and pharmacodynamic (PD) profiles of 
efmarodocokin alfa.  These studies define the pharmacologic activities and PK/PD 
relationships and provide a safety profile supporting IV dosing in humans. 
In an in vivo model of dextran sulfate sodiuminduced mouse colitis, muIL-22 Fc, a 
mouse surrogate for efmarodocokin alfa with full-length mouse IL-22 and the Fc portion 
of mouse IgG2a, was efficacious in a dose-dependent manner.  At the lowest efficacious 
dose of 1.25 g (efficacy assessed by colon histologic score), the corresponding 
minimum serum concentration of muIL-22 Fc was approximately 10 ng/mL.  These 
results are consistent with the conclusions reported by other investigators
(Sugimoto et al. 2008; Pickert et al. 2009; Neufert et al. 2010).
REG3A was evaluated as a PD biomarker in cynomolgus monkeys (Studies 12-2623, 
13-2601, and 15-0279).  Results in these studies suggest that elevations in REG3A are 
likely a maximum concentration (Cmax)driven event (i.e., associated with peak exposure 
levels) and that this response is reversible and not sustainable in the absence of 
exposure, making REG3A a PD biomarker suggestive of IL-22R target engagement. 
Toxicology studies of up to 6 month's duration have been conducted in rats, cynomolgus 
monkeys, and Yucatan minipigs.  These studies have identified a transient acute phase 
inflammatory response and epidermal hyperplasia with skin reddening as clinical safety 
risks.  These risks are considered predictable, manageable, monitorable, and reversible 
in the clinic.
Refer to the Efmarodocokin Alfa Investigator's Brochure for details on nonclinical studies.
1.2.2
Summary of Clinical Studies
Results from Study GA29468, a Phase Ia, placebo-controlled, single-dose, 
dose-escalation study in healthy volunteers (HVs), showed that efmarodocokin alfa
had acceptable tolerability at single IV doses of up to 90 g/kg and SC doses of 


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up to 60 g/kg. Starting at 30 g/kg IV, dose-dependent reversible increases in the 
number and intensity of skin events (e.g., dry skin, patchy erythema, and subjective 
skin-related complaints such as skin discomfort) were reported (see Section 5.1.1 for 
additional details).  At the highest IV dose (120 g/kg), 3 of 4 HVs experienced 
protocol-defined dermatologic dose-limiting toxicities (DLTs).
Mild to moderate elevations in C-reactive protein (CRP) (which were predicted on the 
basis of nonclinical studies) were reported and were assessed by the investigator as 
related to efmarodocokin alfa in some subjects.  All other abnormal clinical laboratory 
results reported as treatment-emergent adverse events were assessed by the 
investigator as mild or moderate in intensity and not related to efmarodocokin alfa.  No 
clinically significant changes or findings were noted from vital signs measurements, 
12-lead ECGs, or body weight measurements for this study.
Dose-dependent increases in serum levels of PD biomarkers SAA, REG3A, and CRP, 
indicative of IL-22R engagement by efmarodocokin alfa, were observed following 
treatment with efmarodocokin alfa compared with placebo.  Transient increases in CRP 
were consistent with data from nonclinical studies and importantly occurred in the 
absence of symptoms of inflammation (fever, leukocytosis, vital sign changes).
Anti-drug antibodies (ADAs) occurred in 1 of 44 subjects (2.3%).  This subject was in the 
low-dose (3 g/kg) SC treatment group.  A positive ADA result for this subject was first 
observed at Day 57 (study completion); ADAs were not detected at earlier timepoints.  
The safety and tolerability profile for this subject was similar to that for other subjects in 
the cohort.
In the Phase Ib, placebo-controlled, multiple-dose, dose-escalation study in HVs, 
patients with UC, and patients with CD (Study GA29469), efmarodocokin alfa was 
adequately tolerated at IV doses up to 60 g/kg IV Q2W in HVs and patients in the 
only CD cohort evaluated, and up to 90 g/kg IV Q2W in patients with UC.  In HVs, a 
dose regimen of 90 g/kg Q2W was not tolerated, as two HVs in this dose cohort 
experienced dermatologic dose-limiting adverse events at this dose (severe skin 
discomfort and severe dry skin) that occurred after the second dose of blinded 
efmarodocokin alfa or placebo.  Topical emollients and topical corticosteroids provided 
minimal relief.  Skin effects were fully reversible.  PK exposures were approximately dose 
proportional within HVs and within patients with UC. Patients with UC or CD had 
relatively low drug exposures as compared to HVs when dosed at the same level. Two 
participants had ADAs at baseline, and no participants were found to have treatment-
emergent ADAs. The observed increases trending upwards with increasing 
efmarodocokin alfa dose levels returned to baseline levels for CRP and SAA, whereas 
REG3A levels returned to near baseline level by study completion suggestive of 
sustained pathway activation though considerable variability was observed in the 
different cohorts.


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Refer to the Efmarodocokin Alfa Investigator's Brochure for details on clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Study GA40209 is an optional, open-label extension study that is part of an ongoing 
program to collect data on the benefit-risk profile of treatment with efmarodocokin alfa in 
patients with moderate to severe UC or CD.  This study is designed to assess the 
long-term safety and tolerability of efmarodocokin alfa 60 g/kg IV and to obtain 
long-term data on the effectiveness, immunogenicity, and exposure of efmarodocokin 
alfa.
While effective therapeutic options, including anti-integrin agents and TNF inhibitors, are 
available to reduce the acute symptomatic flares in disease activity in patients with 
moderate to severe IBD, no currently available therapy achieves sustained remission in 
more than 10%30% of patients with chronic IBD (Hanauer et al. 2002; Sandborn et al. 
2005; Feagan et al. 2013).  Furthermore, anti-integrin agents and TNF inhibitors are 
associated with severe adverse events, including hypersensitivity reactions and 
increased risk of infections (including serious infections such as tuberculosis).  
Consequently, patients and physicians must carefully weigh the benefitrisk ratio both 
before starting and while managing long-term treatment with anti-integrin agents or 
TNF inhibitors.
IL-22 stimulates mucin and anti-microbial peptide production in the intestine, which can 
modulate bacterial growth and protect the intestinal epithelium.  Changes in bacterial 
flora have been associated with a variety of immunologically mediated diseases and, 
along with altered epithelial barrier function, are thought to be key drivers in the 
inflammatory process of IBD (Sugimoto et al. 2008; Zheng et al. 2008; Eidenschenk et al. 
2014).  Efmarodocokin alfa, an IL-22 fusion protein, is a novel therapeutic agent being 
developed to promote mucosal healing and achieve sustained clinical remission while 
potentially allowing reduction or elimination of the immunosuppression associated with 
current therapies for IBD.
As efmarodocokin alfa is an investigational medicinal product (IMP), the full safety 
profile will be further characterized as clinical development progresses.  A safety plan is 
outlined in Section 5.1.
Refer to the Efmarodocokin Alfa Investigator's Brochure for details on clinical and 
nonclinical studies and additional safety information.
Because efmarodocokin alfa is an agonist, intermittent drug exposure (rather than 
continuous drug exposure) may be required for a therapeutic effect and a supportive 
benefit-risk profile. As such, Study GA40209 will enable the Sponsor to gather 
preliminary data on the benefit-risk profile, including immunogenicity of intermittent treat-
to-remission strategy. This study is designed to minimize potentially unnecessary 


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exposure during Phase III studies and to understand the benefit-risk profile in specific 
populations from the parent studies GA29469 and GA39925 (described below). 
This open-label extension study GA40209 will provide an additional management option 
for patients and will actively exclude patients only on the basis of potential or identified 
safety risks of treatment with efmarodocokin alfa. The study design and duration and 
the inclusion of specific responder and non-responder populations (as defined in 
Sections 3.1.4.1 and 3.1.4.2 and described below) will allow the Sponsor to assess the 
potential benefits and risks of the dosing strategy and inform Phase III study designs, 
dosing, and safety management plans.
Vedolizumab and Placebo Non-Responders
Allowing vedolizumab and placebo non-responders to enter Study GA40209 provides 
patients an additional disease-management option. In addition, the study enables the 
Sponsor to gather more data on the benefit-risk profile of treatment with efmarodocokin 
alfa in patients with active disease who have never been exposed to efmarodocokin alfa. 
It is known that patients treated with vedolizumab can take longer to achieve 
clinical response (up to 10 weeks per summary of product characteristics).  For 
patients randomly allocated to the vedolizumab arm (in parent study GA39925), 
Study GA40209 provides another option for patients treated with vedolizumab who have 
not subjectively improved or met protocol-defined response criteria at Week 8 and
cannot wait until 10 weeks to assess if vedolizumab is working for them or to receive an 
additional dose of vedolizumab at Week 14 per label. As Study GA40209 is optional, 
patients may wait to Week 10 to assess if vedolizumab is working prior to deciding on 
enrolling in this study or continuing vedolizumab outside of the study.
Efmarodocokin Alfa Non-Responders
Inclusion of efmarodocokin alfa non-responders will enable the Sponsor to gather more 
data on the benefit-risk profile of continuing efmarodocokin alfa treatment in patients 
with active disease. The 8-week induction timepoint in parent study GA39925 was 
chosen to balance seeing a biological effect of efmarodocokin alfa and minimizing time 
on placebo for patients randomly allocated to the placebo arm. At this time, the optimal 
induction time period is not known. In addition, patients may subjectively improve with
efmarodocokin alfa in parent study GA39925 but be classified per protocol as 
non-responders (e.g., decline in stool frequency from 20 to 10 times per day with no 
change in stool frequency subscore). Therefore, protocol-defined non-responders to 
efmarodocokin alfa are not actively excluded from Study GA40209. Inclusion of these 
patients from parent study GA39925 enables a preliminary assessment of the 
benefit-risk of longer duration of treatment, in particular, for more refractory populations 
(e.g., anti-TNF inadequate responders). In addition, for more refractory populations, 
combination therapy is often required to induce response and remission. 


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For all non-responders in parent study GA39925, Study GA40209 will provide a 
preliminary assessment of combination therapy strategies with concomitant medications 
prohibited or not used in parent study GA39925 (e.g., use of steroids for patients not on 
steroids or use of higher doses of steroids). Furthermore, this study will provide an 
additional option for patients for whom the benefit-risk of continuing in Study GA40209 
may be preferred over pursuing other clinical trials or treatment options (e.g., patients 
who are subjectively improving but do not meet protocol-defined response criteria).
Vedolizumab Responders
Vedolizumab responders from parent study GA39925 are not excluded should the
patient want to switch to efmarodocokin alfa. Those patients also have the option to 
continue vedolizumab outside of the study. For vedolizumab responders (in particular 
for those who have not achieved clinical remission), Study GA40209 is a preliminary 
assessment of the benefit-risk of switching to efmarodocokin alfa.
Placebo Responders
Placebo responders are not excluded should the patient choose to receive
efmarodocokin alfa, in particular those patients who have not achieved clinical 
remission. Inclusion of placebo responders will provide further data on the benefit-risk of 
treatment with efmarodocokin alfa.
Efmarodocokin Alfa Responders
For patients who responded to efmarodocokin alfa in the parent studies, Study GA40209
provides the option to continue efmarodocokin alfa treatment as they would be excluded 
from future controlled trials with efmarodocokin alfa.  Study GA40209 will provide 
preliminary data to understand the benefit-risk of further treatment for patients who 
respond to efmarodocokin alfa and the durability of remission off-treatment to help 
assess the benefit-risk including immunogenicity of a treat-to-remission strategy. 
Study GA40209 will provide preliminary information as to whether or not this dosing 
strategy should be studied further in Phase III.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the long-term safety and tolerability of efmarodocokin alfa in 
patients with moderate to severe UC or CD.  In addition, the study will obtain long-term 
data on the efficacy, immunogenicity, and exposure of efmarodocokin alfa.  Specific 
objectives and corresponding endpoints for the study are outlined below.  For endpoint 
determination, endoscopic scores will be based on interpretation by a central reader.
In this protocol, "study drug" refers to efmarodocokin alfa.  


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Table 1
Objectives and Corresponding Endpoints
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability 
of efmarodocokin alfa
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE scale
Change in targeted vital signs, physical findings, and 
clinical laboratory test results during and following 
efmarodocokin alfa administration
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
efmarodocokin alfa
Clinical response a at Weeks 28, 52, 80, and 104
Clinical remission b at Weeks 28, 52, 80, and 104
Durability of clinical remission, defined as time from 
achieving clinical remission b to loss of clinical 
remission b
Change from baseline (i.e., either the baseline score 
in the parent study or the last score prior to initiation 
of the most recent course c of efmarodocokin 
alfa during the extension study, whichever score is 
the most recent) in PRO2 in patients with Crohn's 
disease
Exploratory Pharmacokinetic
Objective
Corresponding Endpoints
To evaluate potential relationships 
between long-term drug exposure and 
the safety and efficacy of 
efmarodocokin alfa
Relationship between serum concentration or PK 
parameters for efmarodocokin alfa and exploratory 
efficacy endpoints
Relationship between serum concentration or PK 
parameters for efmarodocokin alfa and safety 
endpoints
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate the immune response to 
efmarodocokin alfa
Presence of ADAs to efmarodocokin alfa during the 
study relative to the presence of ADAs at baseline 
(Study Week 0)
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers that can 
increase the knowledge and 
understanding of disease biology
Relationship between biomarkers in stool and 
colonic tissue (listed in Section 4.5.6) and efficacy, 
safety, or immunogenicity endpoints
ADAanti-drug antibody; NCI CTCAE National Cancer Institute Common Terminology Criteria 
for Adverse Events; PKpharmacokinetic; PRO2Patient-Reported Outcome-2.
Note:  For endpoint determination, endoscopic scores will be based on interpretation by a central 
reader.
a Clinical response during the extension study, as defined in Section 3.1.4.2.
b Clinical remission during the extension study, as defined in Section 3.1.4.3.
c Efmarodocokin alfa 60 g/kg IV Q4W.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This open-label extension study (GA40209) will evaluate the long-term safety and 
tolerability of efmarodocokin alfa in patients with moderate to severe UC or CD.  In 
addition, the study will obtain long-term data on the efficacy, immunogenicity, and 
exposure of efmarodocokin alfa.  This study will enroll up to approximately 320 patients 
from Phase Ib Study GA29469 and Phase II Study GA39925 (parent studies).
Enrollment numbers may be less based on the actual number of patients who rollover 
into Study GA40209.  Criteria for enrollment in the extension study are outlined in 
Sections 4.1.1 and 4.1.2.
3.1.2
Efmarodocokin Alfa Administration
Patients enrolled in the extension study will receive efmarodocokin alfa treatment or 
undergo observation for up to approximately 2 years (through Week 104), as determined 
on the basis of the patient's disease status, as outlined in Table 2.  Upon entry into the 
extension study, patients will receive efmarodocokin alfa 60 g/kg IV Q4W or undergo 
observation, depending on their disease status at the time of their last endoscopy in the 
parent study.  The first dose of efmarodocokin alfa in the extension study may not be 
administered less than 2 weeks after last dose of study drug in parent study.  During the 
extension study, patients will receive efmarodocokin alfa 60 g/kg IV Q4W or undergo 
observation, depending on their disease status at a scheduled visit or a disease 
evaluation visit (details on disease evaluation visits are provided in Section 3.1.5).


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Table 2
Efmarodocokin Alfa Treatment Algorithm
Patient's Disease Status
Action to Be Taken
Meets criteria for clinical remission a

Discontinue efmarodocokin alfa (if 
applicable)

Undergo observation and assessments per 
schedule of activities (see Appendix 1)
Does not meet criteria for clinical remission a 

Receive efmarodocokin alfa 60 g/kg IV 
Q4W until clinical remission is achieved b

Undergo assessments per schedule of 
activities (see Appendix 1)
Meets criteria for disease flare c (off treatment) 
after entry into study

Consult with Medical Monitor to determine 
appropriate course of action prior to 
administration of efmarodocokin alfa (if 
applicable)
Experiences disease worsening as a result of 
efmarodocokin alfa treatment, in the 
investigator’s judgment, or disease flare while 
receiving efmarodocokin alfa c

Permanently discontinue efmarodocokin 
alfa

Initiate rescue therapy at discretion of 
investigator

Undergo safety follow-up assessments 
8 weeks after final dose of efmarodocokin 
alfa d
Q4W every 4 weeks.
a Clinical remission during the extension study, as defined in Section 3.1.4.3.
b First dose of efmarodocokin alfa in the extension study to be administered no less than 2 
weeks after last dose of study drug in parent study
c Disease flare during the extension study, as defined in Section 3.1.4.4. 
d See Section 3.1.6 and Appendix 1 for details regarding safety follow-up.
3.1.3
Study Participation during Year 2
The duration of the study has been extended from 1 year to 2 years with the 
implementation of Protocol Version 6.  Patients who completed the study through 
Week 52 (Year 1) prior to the implementation of Protocol Version 6 may still be eligible 
for an additional year of treatment and/or observation, provided that certain criteria are 
met, as outlined in Table 4.  Participation during Year 2 is not required for such patients, 
and those who do not participate will be considered to have completed the study per 
protocol, provided required safety follow-up assessments have been completed.


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Table 3
Algorithm for Continued Study Participation during Year 2
Patient Disposition Status at Time of 
Implementation of Protocol Version 6
Action to Be Taken
Has not yet reached Week 52

Patient will continue study treatment or 
observation through Week 104 per algorithm in 
Table 2.
Has completed Week 52 visit but has 
not yet completed required safety 
follow-up assessments

Patient may resume study treatment or 
observation through Week 104 per algorithm in 
Table 2.  If resuming study treatment, there must 
be a minimum of 2 weeks since the last dose of 
efmarodocokin alfa. a
Has completed Week 52 visit and 
required safety follow-up assessments b

Re-consent patient within 8 weeks of 
implementation of Protocol Version 6.

Conduct study re-entry screening assessments 
(including endoscopy) over a 3-week period to 
confirm study eligibility per criteria outlined in 
Section 4.1 and evaluate disease status.  Daily 
diary recording will be re-initiated to enable 
collection of patient-reported outcome data for 
MCS, CDAI, and PRO2 assessments (see 
Section 4.5.4).

If eligible for study re-entry, patient will resume
study treatment (within 1 week of establishing 
eligibility) or undergo observation through 
Week 104 per algorithm in Table 2. 
CDAICrohn's Disease Activity Index; MCSMayo Clinic Score; PRO2Patient-Reported
Outcome-2.
a If resuming study treatment, there will be no visit window deviation if there is a minimum of 
2 weeks since the last dose of efmarodocokin alfa.
b Also includes patients who have completed Week 52 visit but do not require safety follow-up 
assessments because they did not receive efmarodocokin alfa during the study.
3.1.4
Key Definitions for the Study
3.1.4.1
Definitions for Clinical Response during Study GA29469
For some patients from Study GA29469, entry into the extension study will be based on 
whether the patient met criteria for clinical response (see Section 4.1.1).  Definitions for 
clinical response during Study GA29469 are provided below for patients with UC and 
patients with CD.  In these definitions, "baseline" refers to the baseline score in the 
parent study.
For patients with UC, clinical response during the parent study is defined as meeting 
both of the following:

A 3-point decrease from baseline in modified Mayo Clinic Score (mMCS)
mMCS is a composite of three Mayo Clinic Score (MCS) assessments:  stool 
frequency, rectal bleeding, and centrally read endoscopy (see Appendix 2).


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
A 1-point decrease from baseline in Mayo rectal bleeding subscore or a Mayo 
rectal bleeding subscore of 0 or 1
For patients with CD, clinical response during the parent study is defined as meeting any 
one of the following:

A 100-point decrease from baseline in Crohn's Disease Activity Index (CDAI)
(see Appendix 6)

For patients with a baseline CDAI of250:  a CDAI of 150 combined with a 
70-point decrease from baseline in CDAI

A 50% decrease from baseline in Simple Endoscopic Score for Crohn's Disease 
(SES-CD) (see Appendix 7)
3.1.4.2
Definitions for Clinical Response during the Extension Study
Definitions for clinical response during the extension study are provided below for 
patients with UC and patients with CD.  In these definitions, "baseline" refers to either 
the baseline score in the parent study or the last score prior to initiation of the most 
recent course of efmarodocokin alfa 60 g/kg IV Q4W during the extension study, 
whichever score is the most recent.
For patients with UC, clinical response during the extension study is defined as meeting 
one of the following:

A 3-point decrease from baseline in mMCS and a 1-point decrease from baseline 
in Mayo rectal bleeding subscore or a Mayo rectal bleeding subscore of 0 or 1

Achievement of clinical remission as defined in Section 3.1.4.3
For patients with CD, clinical response during the extension study is defined as meeting 
any one of the following:

A 100-point decrease from baseline in CDAI

For patients with a baseline CDAI of 250:  a CDAI of 150 combined with a 
70-point decrease from baseline in CDAI

A 50% decrease from baseline in SES-CD

Achievement of clinical remission as defined in Section 3.1.4.3
3.1.4.3
Definitions for Clinical Remission during the Extension Study
Definitions for clinical remission during the extension study are provided below for 
patients with UC and patients with CD.
For patients with UC, clinical remission is defined as meeting both of the following:

mMCS of 2

Mayo rectal bleeding subscore of 0 and other Mayo subscores of 1


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For patients with CD, clinical remission is defined as meeting one of the following:

Patients with disease restricted to the ileum:  CDAI of 150 and SES-CD of 2

Patients with disease not restricted to the ileum:  CDAI of 150, SES-CD of 4, and 
no ulcerations
3.1.4.4
Definitions for Disease Flare during the Extension Study
Definitions for disease flare during the extension study are provided below for patients 
with UC and patients with CD.  In these definitions, "lowest pMCS" and "lowest CDAI" 
refer to the lowest score after completion of treatment in either Study GA29469 or 
Part A of Study GA39925, or completion of the most recent course of efmarodocokin 
alfa 60 g/kg IV Q4W during the extension study, whichever is the most recent.
For patients with UC, disease flare is defined as meeting any one of the following:

A 3-point increase in partial MCS (pMCS) relative to the lowest pMCS and an 
absolute pMCS of 5 and a locally read endoscopy subscore of 2 
pMCS is a composite of three MCS assessments:  stool frequency, rectal 
bleeding, and Physician's Global Assessment (PGA) (see Appendix 4).

An absolute pMCS score of 7 and a locally read endoscopy subscore of 2 
For patients with CD, disease flare is defined as meeting both the following:

A CDAI of 220 at two consecutive visits (may include unscheduled visits)

A 70-point increase in CDAI, at two consecutive visits (may include unscheduled 
visits), relative to the lowest CDAI
The schedule of activities is provided in Appendix 1.
3.1.5
Disease Evaluation Visits
Patients with worsening disease, as determined by the investigator, should return to the 
clinic as soon as possible for a disease evaluation visit.  The investigator may also 
schedule a disease evaluation visit to determine if a patient has achieved clinical 
remission.  Patients with UC will undergo a flexible sigmoidoscopy and MCS evaluation 
at the disease evaluation visit.  Patients with CD will undergo an ileocolonoscopy and 
CDAI evaluation, with one exception:  Patients who experience worsening disease while 
receiving efmarodocokin alfa will not undergo an ileocolonoscopy unless the visit 
corresponds to a time when an ileocolonoscopy is already scheduled to occur.
After determination of the patient's disease status, the investigator may initiate or 
discontinue treatment with efmarodocokin alfa as appropriate (see efmarodocokin alfa
treatment algorithm in Table 2).


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3.1.6
Safety Follow-Up Visit and Early Termination Visit
Patients will undergo safety follow-up or early termination assessments as outlined 
below: 

Patients who receive at least one dose of efmarodocokin alfa must undergo safety 
follow-up assessments 8 weeks after their final dose of study drug.
Patients who discontinue the study prematurely (prior to Week 104) and have 
received at least one dose of efmarodocokin alfa should return to the clinic for 
an early termination visit within 1 week.  Patients who discontinue prematurely 
without having undergone at least 8 weeks of follow-up (observation) after their 
final dose of efmarodocokin alfa should also return to the clinic for a safety 
follow-up visit 8 weeks after their final dose.
Patients who are unwilling to complete the safety follow-up visit should return to 
the clinic for an early termination visit no later than 30 days after their final dose.

Patients who discontinue the study prematurely (prior to Week 104) and have not 
received efmarodocokin alfa should return to the clinic for an early termination visit 
within 30 days.  Follow-up assessments are not required for patients who 
discontinue the study at Week 104 without having received efmarodocokin alfa.
For patients who complete Week 52 and safety follow-up assessments prior to the 
implementation of Protocol Version 6 and re-enter the study, safety follow-up is to be 
repeated for Year 2, as outlined above.  Details regarding assessments at the safety 
follow-up visit and the early termination visit are provided in Appendix 1.
Patients who permanently discontinue study drug can receive rescue therapy at the 
investigator's discretion.
3.1.7
Corticosteroids
For patients on concomitant oral corticosteroids, the corticosteroid dose should be 
tapered until discontinuation.  The corticosteroid tapering schedule may be at the 
discretion of the investigator.  For patients who receive a course of efmarodocokin alfa
60 g/kg IV Q4W, tapering should be initiated once the patient is stable, based on the 
investigator’s judgment.  Patients who cannot tolerate up to two corticosteroid taper 
attempts without experiencing recurrence of IBD symptoms or symptoms of 
corticosteroid withdrawal will be discontinued from the study as outlined in Section 4.6.1.  
Any patient requiring corticosteroids above the baseline dose (with baseline defined as 
either the baseline dose in the parent study or the last dose prior to initiation of the most 
recent course of efmarodocokin alfa 60 g/kg IV Q4W during the extension study, 
whichever dose is the most recent) should be discontinued from the study.


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3.1.8
Internal Monitoring Committee
An Internal Monitoring Committee (IMC) will monitor data on safety, efficacy, and study 
conduct on an ongoing basis. The IMC consists of Sponsor representatives from 
Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis, 
and may invite representatives from other functional areas (e.g., Clinical Pharmacology, 
Research) or external experts on an ad hoc basis.  Sponsor representatives will not be 
involved in the conduct of the study or have any contact with study investigators or site 
staff. 
The IMC will review cumulative unblinded data on a periodic basis as defined in the IMC 
Charter. The data will include, but will not be limited to, demographic data, adverse 
events data (including serious adverse events and adverse events of special interest), 
ECG data, and relevant laboratory data. In addition to reviews on a periodic basis, ad 
hoc reviews may be requested by the IMC or the Sponsor at any time to address 
potential safety concerns. An interim efficacy analysis for parent Study GA39925 will be 
performed by the IMC (see Protocol GA39925, Section 6.9). 
After reviewing the data, the IMC may make recommendations such as the following: 

The trial will continue as planned.

The trial will continue with a reduction in dose level.

The trial will stop for safety reasons.

Additional analyses will need to be performed.

Enrollment will be held pending further safety evaluation.
The IMC may also provide recommendations for amending the protocol after 
consideration of all available data, including making further dose and duration 
adjustments to optimize benefit-risk. Final decisions will rest with the Sponsor's study 
team. 
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards (IRBs)/Executive Committees (ECs). Biannual summaries of the conclusions 
and recommendations of the IMC will be sent to the IRBs/ECs. 
A detailed description of the procedures, data flow, and meeting schedule of the IMC will 
be provided in the IMC Charter.


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3.2
END OF STUDY AND LENGTH OF STUDY
Patients in this study will receive treatment or undergo observation for up to 
approximately 2 years. The end of the study is defined as the date when the last patient 
completes his or her final study visit.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Efmarodocokin Alfa Dose and Schedule
The dose regimen of efmarodocokin alfa 60 g/kg IV Q4W was selected on the basis of 
an integrated analysis of the clinical, PK, and PD data from the completed Phase Ia 
study (GA29468) and data from the Phase Ib study (GA29469).  The 60 g/kg IV Q4W 
regimen would provide a preliminary assessment of the benefit-risk of a treat-to-
remission strategy to help inform the Phase III studies.  The 60 g/kg Q4W regimen 
enables drug exposure within the tolerable exposure range to evaluate whether 
efmarodocokin alfa is safe and efficacious in patients with UC or CD.
The dose regimen tested in Study GA40209 is similar to the highest dose regimen 
tested in the Phase II parent study GA39925 (90 g/kg IV Q4W in the first 8 weeks of 
treatment and 60 g/kg IV Q8W during the 4month maintenance phase).  The 
benefit-risk profile of the 60 g/kg IV Q4W regimen is anticipated to be similar to this 
regimen with a 33% lower Cmax (60 g/kg IV Q4W vs. 90 g/kg IV Q8W, respectively) 
during the first 8 weeks, but 2 times higher exposure over the subsequent 4 months 
(60 g/kg IV Q4W vs. 60 g/kg IV Q8W, respectively).  The dose regimen in 
Study GA40209 may be adjusted on the basis of emerging data from the parent study 
GA39925 as described above.
3.3.2
Rationale for Pharmacokinetic Sample Collection
This study will employ a sparse PK sampling schedule to allow for assessment of 
potential relationships between long-term drug exposure and the safety and efficacy of 
the study drug. 
3.3.3
Rationale for Biomarker Assessments
Biomarkers will be assessed in stool and colonic tissue to demonstrate evidence of 
biologic activity of efmarodocokin alfa in patients with UC and CD. The relationship 
between stool and colonic tissue biomarkers and safety and immunogenicity endpoints 
may also be explored.  The assessment of biomarkers may include, but not be limited to, 
measurement of DMBT1 in colonic tissue biopsies.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Up to approximately 320 patients with moderate to severe UC or CD from 
Study GA29469 or Study GA39925 will be enrolled in this study.


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4.1.1
Inclusion Criteria
4.1.1.1
Inclusion Criteria for Study Entry
Patients must meet the following criteria for study entry:

Prior enrollment in Study GA29469 or Study GA39925, with one of the following
having occurred during that study:
Patients previously enrolled in Study GA29469

Unable to achieve clinical response (defined for patients with UC and CD in 
Section 3.1.4.1) during the study and completion of the study through at least
Day 85

Initiation of protocol-defined rescue therapy during the study and completion of 
the study through at least Day 85

Completion of the study through Day 134
Patients previously enrolled in Study GA39925

Unable to achieve protocol-defined clinical response by Week 8 

Initiation of protocol-defined rescue therapy during the study and completion of 
the study through at least Week 8

Protocol-defined disease flare after Week 8

Completion of the study through Week 30

Age 1880 years, inclusive, at time of signing Informed Consent Form
4.1.1.2
Inclusion Criteria for Study Entry and Study Re-Entry
Patients must meet the following criteria for study entry and study re-entry:

Signed Informed Consent Form (at time of initial entry and again at time of study 
re-entry)

Ability to comply with requirements of the study, in the investigator's judgment

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 8 weeks after the final dose of 
study drug or 18 weeks after final dose of study drug from Study GA39925 (due to 
the possibility of receiving vedolizumab), whichever is longer
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices (recommendations related to contraception and pregnancy testing in 
clinical trials, Clinical Trial Facilitation Group, final version, dated 2014-09-15, 
Section 4.1).


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
8 weeks after the final dose of study drug or 18 weeks after final dose of study 
drug from Study GA39925, whichever is longer, to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
4.1.2.1
Exclusion Criteria for Study Entry
Patients who meet any of the following criteria will be excluded from study entry:

Withdrawal of consent from parent study

Discontinuation of study drug as required by the parent study protocol

Discontinuation of study drug and withdrawal from Study GA29469 prior to Day 85 
or from Study GA39925 prior to Week 8

Non-compliance in the parent study, specifically defined as missing scheduled visits 
or non-adherence with background medications and concomitant medications
4.1.2.2
Exclusion Criteria for Study Entry and Study Re-Entry
Patients who meet any of the following criteria will be excluded from study entry and 
study re-entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 8 weeks after the final dose of study drug or 18 weeks after final dose of 
study drug from Study GA39925 (due to the possibility of receiving vedolizumab), 
whichever is longer

Any new malignancy since enrolling in the parent study

Any new significant uncontrolled comorbidity, such as cardiac, pulmonary, renal, 
hepatic, endocrine, or GI disorders, since enrolling in the parent study

Any new signs or symptoms of infection judged by the investigator to be clinically 
significant since enrolling in the parent study

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) since 
enrolling in the parent study

Prior treatment with etrolizumab, natalizumab, efalizumab, or any other anti-integrin 
agents (other than vedolizumab)


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
Use of IV corticosteroid or topical corticosteroid (i.e., enemas or suppositories) at 
the time of entry into this study

Abnormal laboratory value recorded at the last visit in the parent study, as defined
below:

Hemoglobin 90 g/L (9 g/dL)

Serum creatinine 1.5upper limit of normal (ULN)

ALT, AST, or ALP 2.5ULN, total bilirubin 1.5ULN, or presence of 
abnormalities in synthetic function tests judged to be clinically significant by the 
investigator
Patients with known Gilbert syndrome who have unconjugated 
hyperbilirubinemia will not be excluded.

Platelet count 100109/L (100,000/L)

ANC 1.5109/L (1500/L)

Absolute lymphocyte count 0.5109/L (500/L)
4.1.2.3
Exclusion Criterion for Study Re-Entry
Patients who meet the following criterion will be excluded from study re-entry:

Use of prohibited concomitant therapy, as outlined in Section 4.4.2.2, since enrolling 
in the extension study
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
All patients in this study will have the opportunity to receive treatment with 
efmarodocokin alfa at a dose of 60 g/kg IV Q4W until remission is achieved.  All 
patients, study site personnel, Sponsor agents, and Sponsor personnel will be unblinded 
to the treatment assignment of this study; however, the treatment assignment from the 
parent study will remain blinded until the parent study is unblinded.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The IMP for this study is efmarodocokin alfa.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Efmarodocokin Alfa
Efmarodocokin alfa will be supplied by the Sponsor as a sterile solution in single-use 
2-mL vials.  Diluent will also be supplied by the Sponsor.  For information on the 
formulation and handling of efmarodocokin alfa, see the pharmacy manual and the
Efmarodocokin Alfa Investigator's Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.2.  Study drug will be administered 
in a monitored setting where there is immediate access to trained personnel and 
adequate equipment and medicine to manage potentially serious reactions.


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Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.
4.3.2.1
Efmarodocokin Alfa
Efmarodocokin alfa will be administered by IV infusion, with the initial infusion in this 
study delivered over approximately 60 (10) minutes.  If the 60-minute infusion is 
tolerated without infusion-associated adverse events (e.g., fevers or chills), the second 
infusion may be delivered over 30 (10) minutes.  If the 30-minute infusion is tolerated, 
the next infusion may be delivered over 15 (5) minutes. If the 15-minute infusion is 
tolerated, all subsequent infusions may be delivered over 5 (1) minutes.  For patients 
who re-enter the study for the second year, the infusion time upon study re-entry can be 
reduced to 5 (1) minutes if the 15-minute infusion was tolerated during the first year of 
the study; otherwise, the infusion time will be equivalent to the last tolerated infusion 
time prior to study re-entry.
If a patient experiences an infusion-associated adverse event, refer to the pharmacy 
manual for management of infusion reactions.  All subsequent infusions should be 
delivered at the previously tolerated rate. 
Patients should be monitored for at least 30 minutes after each infusion.
Weight-based efmarodocokin alfa infusions, with a maximum dose given to be based on 
100 kg total body weight, will be prepared per the instructions outlined in the 
pharmacy manual.
4.3.3
Investigational Medicinal Product Accountability
The IMP required for completion of this study (efmarodocokin alfa) will be provided by 
the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMP supplied by the Sponsor, using the interactive voice or 
web-based response system (IxRS) to confirm the shipment condition and content.  
Any damaged shipments will be replaced. 
The IMP will either be disposed of at the study site according to the study site's 
institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation.  The site's method of destroying Sponsor-supplied IMPs 
must be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form.  The investigator or designee must confirm that 
appropriate temperature conditions have been maintained during transit, either by time 
monitoring (shipment arrival date and time) or temperature monitoring, for all IMP 


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received and that any discrepancies have been reported and resolved before use of the 
IMP.  The IMP must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized staff.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Efmarodocokin Alfa
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP (efmarodocokin alfa) or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing efmarodocokin alfa in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from entry 
into the extension study to the final visit of the extension study.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
At this time there is no evidence to suggest an interaction between efmarodocokin alfa 
and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines.  If a 
patient in the study elects to have a SARS-CoV-2 vaccine, it should not be given on 
the same day as study drug dosing to distinguish any possible infusion-related 
reactions/injection-related reactions from each agent should one occur. The 
SARS-CoV-2 vaccine should be recorded on the Concomitant Medication eCRF. 
If there is any doubt as to whether a medication is permitted during the trial, the study 
site staff should contact the Medical Monitor.  


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4.4.1
Rescue Therapy
The initiation of rescue therapy for patients with UC or CD will require permanent 
discontinuation of study treatment.  Rescue therapy is defined as follows:

Initiation of IV corticosteroid or rectal corticosteroid (i.e., enemas or suppositories)

Initiation of oral corticosteroid or increase in dose of oral corticosteroid compared 
with baseline, with baseline defined as either the baseline dose in the parent study 
or the last dose prior to initiation of the most recent course of efmarodocokin alfa
60 g/kg IV Q4W during the extension study, whichever dose is the most recent
For patients receiving ongoing concomitant oral corticosteroids upon entry into 
the study, the corticosteroid dose should be tapered until discontinuation as 
described in Section 3.1.7.

Initiation of immunosuppressants (i.e., AZA, 6-MP, MTX, or TNF inhibitors)

Initiation of natalizumab, etrolizumab, efalizumab, or other anti-integrin agents

Initiation of cyclosporine, tacrolimus, sirolimus, or MMF

Initiation of tofacitinib

Initiation of ustekinumab
4.4.2
Other Concomitant Therapy
4.4.2.1
Permitted Concomitant Therapy
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Patients will be permitted to use the 
following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Topical or oral 5-ASA
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).
Patients may continue on stable regimens of drugs they are receiving as treatment for 
coexistent stable diseases (e.g., anti-hypertensives, cholesterol-lowering drugs, or 
bronchodilators).
Over-the-counter preparations deemed acceptable by the Sponsor and the investigator 
at the beginning of the study will be allowed during the study.  Initiation of 


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over-the-counter medications during the study will need to be approved by the 
investigator and the Sponsor.
4.4.2.2
Prohibited Concomitant Therapy
Use of the following therapies is prohibited as specified below:

Initiation of oral probiotics or increase in dose of oral probiotics compared with 
baseline, with baseline defined as either the baseline dose in the parent study or the 
last dose prior to initiation of the most recent course of efmarodocokin alfa 60 g/kg 
IV Q4W during the extension study, whichever dose is the most recent

Use of rituximab

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab)

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs)
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, 
myalgias, or menstrual cramps) and aspirin up to 325 mg/day is permitted.

Use of anticoagulants (including, but not limited to, warfarin, heparin, enoxaparin, 
dabigatran, apixaban, rivaroxaban)
Use of antiplatelet agents, such as aspirin up to 325 mg/day or clopidogrel, is 
permitted.

Apheresis (e.g., Adacolumnapheresis)

Use of an investigational drug
4.4.3
Additional Restrictions
At study visits where fasting lipids are measured, no food or fluids other than water will 
be allowed for approximately 8 hours prior to the visit and until after study laboratory 
samples are obtained.  On study-drug dosing days, no food will be allowed from at 
least 2 hours before dosing until 30 minutes after the last infusion, when a light meal will 
be allowed.
To avoid potential contamination of blood supply with the investigational product, 
patients will be restricted from donating blood for 6 months after receiving the final dose 
of efmarodocokin alfa.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  
Data collected from the final visit of the parent study will serve as Study Week 0 (initial 
visit) data for the extension study.  Procedures and assessments that were performed at 
the final visit of the parent study do not need to be repeated at Study Week 0, with the 
exception of the ADA sample.  A baseline ADA sample should be collected at baseline 
(Study Week 0).


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline in the 
extension study (Study Week 0).  In addition, medication use (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) from the time the patient exited the parent study to the time the patient 
entered the extension study will be recorded.  Past resolved adverse events will be 
recorded in the medical history if clinically significant.  Refer to Section 5.3.5.4 for 
information on recording adverse events that had not resolved at the end of the parent 
study.  At the time of each follow-up physical examination, an interval medical history 
should be obtained and any changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
For patients who re-enter the study (see Section 3.1.3), adverse events that occur after 
completion of Week 52 and required safety follow-up assessments but prior to obtaining 
informed consent for study re-entry should be captured on the General Medical History 
and Baseline Conditions eCRF (rather than the Adverse Event eCRF), unless it is a 
serious adverse event related to prior study treatment.
4.5.3
Physical Examinations
A complete physical examination, performed at baseline in the extension study
(Study Week 0) and other specified visits, should include an evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, GI, genitourinary, and neurologic systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
Limited, symptom-directed physical examinations, including an abdominal examination, 
should be performed at specified postbaseline visits and as clinically indicated.  
Changes from baseline (Study Week 0) abnormalities should be recorded in patient 


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notes.  New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  These measurements will be taken while the 
patient is in a seated position after at least 10 minutes of rest.
4.5.5
Clinical Outcome Assessments
Clinical outcome for UC will be assessed through the MCS (see Section 4.5.5.1), 
which incorporates stool frequency and rectal bleeding as reported by the patient
(see Section 4.5.5.4), the PGA as reported by the clinician (see Section 4.5.5.5), and 
endoscopic evaluations (see Section 4.5.5.6). Clinical outcome for CD will be assessed 
through the CDAI (see Section 4.5.5.2), which incorporates loose-stool frequency, 
abdominal pain severity, and general well-being as reported by the patient 
(see Section 4.5.5.4) as well as other factors assessed by the clinician, and the SES-CD
(see Section 4.5.5.3).
4.5.5.1
Mayo Clinic Score, Modified Mayo Clinic Score, and Partial 
Mayo Clinic Score
The MCS (including mMCS and pMCS) will be assessed in patients with UC.
The MCS is a composite of four assessments, each having a scoring range of 03: 
stool frequency, rectal bleeding, endoscopy, and PGA. The MCS has a range of 0–12, 
with higher scores indicating more severe disease (see Appendix 2).
The mMCS is a composite of three assessments from the MCS, each having a scoring 
range of 03: stool frequency, rectal bleeding, and centrally read endoscopy. The 
mMCS has a range of 09, with higher scores indicating more severe disease
(see Appendix 3).
The pMCS is a composite of three assessments from the MCS, each having a scoring 
range of 03: stool frequency, rectal bleeding, and PGA. The pMCS has a range of 09, 
with higher scores indicating more severe disease (see Appendix 4).
UC patients are to report their stool frequency and rectal bleeding on a daily basis, as 
described in Section 4.5.5.4 (see Appendix 5). 
4.5.5.2
Crohn's Disease Activity Index and Patient-Reported 
Outcome-2 Score
The CDAI quantifies the signs and symptoms of patients with CD. The CDAI consists of 
eight factors; each factor is summed after adjustment with a weighting factor 
(Best et al. 1979). The components of the CDAI include number of liquid or soft stools
(loose-stool frequency), abdominal pain severity, general well-being, presence of 
complications, use of diphenoxylate/atropine (Lomotil) or other opiates for diarrhea, 


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presence of an abdominal mass, hematocrit, and percent deviation from standard weight
(see Appendix 6).  It is preferred, but not required, that the clinician who completes the 
CDAI not be the same clinician who assesses adverse events.
The Patient-Reported Outcome-2 (PRO2) evaluates two patient-reported factors:  
loose-stool frequency and abdominal pain severity (Khanna et al. 2015).  The score is 
calculated using the CDAI-weighted sum of the average loose-stool frequency and 
abdominal pain scores in a 7-day period.
CD patients are to report their loose-stool frequency, abdominal pain severity, and 
general well-being on a daily basis, as described in Section 4.5.5.4.
4.5.5.3
Simple Endoscopic Score for Crohn's Disease
The SES-CD will be assessed in patients with CD. SES-CD is assessed through 
endoscopy and is a composite of four factors, each having a scoring range of 03: ulcer 
size, percentage of ulcerated surface, percentage of surface affected by other lesions, 
and extent of stenosis.  These factors are scored in up to five ileocolonic segments 
(Daperno et al. 2004).  Higher scores indicate more severe disease (see Appendix 7).  
It is preferred, but not required, that the clinician who completes the SES-CD not be the 
same clinician who assesses adverse events.
4.5.5.4
Patient-Reported Outcomes
Patient-reported outcome (PRO) data will be collected through use of a diary and/or 
paper questionnaires.  Site staff will provide the diary and/or instructions for completing 
the questionnaires. Data captured between clinic visits should be reviewed with the 
patient at each clinic visit.  The data will be available for access by appropriate study 
personnel.
The PRO questionnaires, translated into the local language as appropriate, will be 
completed in their entirety at specified timepoints during the study. To ensure 
instrument validity and compliance with health authority requirements, questionnaires 
will be self-administered before the patient receives any information on disease status, 
before non-PRO assessments are performed, and before administration of study
treatment, unless otherwise specified. Study site staff will ensure that questionnaires 
are provided to the patients for completion per the schedule of assessments 
(see Appendix 1) and will confirm completion or document any reasons for 
non-completion before the visit concludes.
Stool Frequency and Rectal Bleeding
Stool frequency and rectal bleeding are components of the MCS, mMCS, and pMCS 
(see Section 4.5.5.1).  Patients with UC are to record stool frequency and rectal bleeding 
in the daily diary throughout the study (see Appendix 5).  Because the endoscopy and 
associated bowel preparation can interfere with the assessment of patient-reported 
outcomes, diary entries on days of bowel preparation, endoscopy, and the day after 


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endoscopy will not be used to calculate any stool frequency scores. Stool frequency and 
rectal bleeding scores from the three most recent diary entries (prior to bowel 
preparation), the endoscopy, and PGA will be used to calculate an MCS. 
Loose-Stool Frequency, Abdominal Pain Severity, and General Well-Being
Loose-stool frequency, abdominal pain severity, and general well-being are components 
of the CDAI, and abdominal pain severity and loose-stool frequency are components of 
the PRO2 (see Section 4.5.5.2).  Patients with CD are to record loose-stool frequency, 
abdominal pain severity, and general well-being in the daily diary throughout the study
(see Appendix 6).  The Bristol Stool Scale will be provided to patients as a reference for 
determining loose stools (Types 6 and 7 on the Bristol Stool Scale; see Appendix 8).  
Because the endoscopy and associated bowel preparation can interfere with the 
assessment of other clinical parameters, diary entries on days of bowel preparation, the 
day of endoscopy, and the day after endoscopy will not be used to calculate scores for 
loose-stool frequency, abdominal pain severity, and general well-being.
4.5.5.5
Physician's Global Assessment
PGA data will be collected through use of a paper questionnaire.  The PGA is a 
component of the MCS and pMCS (see Section 4.5.5.1).  The PGA should reflect the 
clinician's assessment of the patient's current overall status, taking into account stool 
frequency and rectal bleeding scores, clinician endoscopy findings, patient-reported 
symptoms, clinician observations, physical examination findings, and other pertinent 
findings.  It is preferred, but not required, that the clinician who completes the PGA not 
be the same clinician who assesses adverse events.
4.5.5.6
Endoscopy with Biopsies
All patients will undergo an endoscopy, consisting of a flexible sigmoidoscopy for 
patients with UC and an ileocolonoscopy for patients with CD, with collection of biopsies 
at specified timepoints during the study and at the disease evaluation/early termination 
visit.  Endoscopy at the early termination visit should be conducted if the investigator 
deems it necessary. All patients will undergo annual endoscopies for colon cancer 
surveillance.  The endoscopies should include the following:

Removal of any adenomatous polyps

Performance of multiple random mucosal biopsies to evaluate for dysplasia
Annual dysplasia surveillance should be performed according to local 
guidelines, taking into consideration endoscopic technique as well as the 
appropriateness of performing surveillance for dysplasia in the presence of 
active inflammation.  Surveillance may be delayed per local guidelines (i.e., if 
there is extensive active inflammation) to enable more accurate pathologic 
diagnosis.
Every effort should be made to schedule on-treatment endoscopies on the same day as 
the protocol-specified study visit.


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Bowel preparation prior to the endoscopy should be done per local practice.  
Medications used for bowel preparation should be reported on the Concomitant 
Medications eCRF.  Scheduled stool samples should be taken prior to bowel 
preparation.
For each patient, a video recording will be performed during the endoscopy through use 
of a medical DVD recorder in the high-quality mode per the endoscopy manual.  Video 
recordings should be taken of the entire endoscopic procedure, starting from insertion 
into the bowel.  Biopsies should be performed upon withdrawal of the endoscope from 
the bowel.  The endoscopist should ensure that the video recording of the procedure will 
allow for adequate assessment of disease activity, taking into consideration the 
possibility of minor bleeding associated with biopsies.  Technical instructions for video 
recording and biopsy collection are provided in the laboratory manual.
All video recordings will be submitted to a central reading facility to be centrally reviewed 
for mucosal lesions and endoscopic severity by an independent gastroenterologist 
experienced in UC who is blinded to the patient's clinical activity, study visit, and 
treatment allocation.  Endoscopic videos will be assessed to objectively document 
disease activity.  Mayo endoscopic subscore (for patients with UC) and the 
endoscopy-based components of the SES-CD (for patients with CD) will be calculated 
on the basis of centrally read patient videos, with one exception:  for the determination of 
disease flare in patients with UC, the Mayo endoscopic subscore should be locally read 
to inform treatment decisions.
The clinician who performs the endoscopy will take into account endoscopy findings 
when completing the PGA (see Section 4.5.5.5).
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis.  Samples may be analyzed at a central laboratory if local analysis is not 
available.

Urinalysis:  specific gravity, pH, blood, quantitative protein, ketones, glucose, 
bilirubin, nitrite, leukocyte esterase, color, and appearance
If urinalysis is abnormal, the same urine sample will be sent to the laboratory for 
microscopic analysis (sediment, WBCs, RBCs, casts, crystals, epithelial cells, 
and bacteria), culture, and sensitivity.

Urine pregnancy test
All women of childbearing potential will undergo urine pregnancy tests monthly 
during the study.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.


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Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Serum pregnancy test, to confirm positive urine pregnancy test

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, uric acid, LDH

Lipase and CRP

Coagulation:  INR, aPTT, PT, fibrinogen

Lipids (fasting):  cholesterol, LDL cholesterol, HDL cholesterol, triglycerides
No food or fluids other than water will be allowed for approximately 8 hours 
prior to the visit and until after sample collection.
The following samples will be sent to the Sponsor or a designee for analysis:

Serum samples for study drug PK analysis
Serum ADA may be measured using PK samples if ADA samples have not 
been collected at the same timepoint.

Serum samples for study drug immunogenicity (ADA) analysis 
Serum concentrations may be measured in ADA samples if PK samples have 
not been collected at the same timepoint.
Baseline (Study Week 0) samples will be analyzed for all patients.
Postbaseline ADA samples will be analyzed for all patients receiving study drug.

Stool samples for exploratory research on biomarkers that may include, but will not 
be limited to, bacterial DNA

Colonic tissue samples obtained by biopsy performed during screening and 
subsequent endoscopic procedures (flexible sigmoidoscopy, ileocolonoscopy, or 
colonoscopy) for exploratory research on tissue histology and on biomarkers that 
may involve extraction of DNA or RNA and bacterial DNA and may include, but will 
not be limited to, analysis of IL-22RA2, IL-22RA1 and DMBT1
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.8), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional assay characterization as well as assay development and validation.  
Therefore, these samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.

Stool and colonic tissue samples collected for biomarker research will be destroyed 
no later than 15 years after the final Clinical Study Report has been completed.  
However, the storage period will be in accordance with the IRB/EC-approved 
Informed Consent Form and applicable laws (e.g., health authority requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.7
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings must be performed using an electrocardiograph machine equipped 
with computer-based interval measurements.  Lead placement should be as consistent 
as possible.  ECG recordings must be performed after the patient has been resting in a 
supine position for at least 10 minutes.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal if possible.  Circumstances that 
may induce changes in heart rate, including environmental distractions (e.g., television, 
radio, conversation) should be avoided during the pre-ECG resting period and during 
ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following will be transmitted to a central ECG vendor:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected through use of Fridericia's formula (QTcF), based on the machine readings of 
the individual ECG tracings.  Clinically significant waveform changes or other ECG 
abnormalities (see Section 5.3.5.7) must be documented as adverse events on the
Adverse Event eCRF.


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If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the value at Study Week 0 (initial visit), another ECG must be recorded, 
ideally within the next 5 minutes, and ECG monitoring should continue until QTcF has 
stabilized on two successive ECGs.  The Medical Monitor should be notified.  
Standard-of-care treatment may be instituted per the discretion of the investigator.  If a 
PK sample is not scheduled for that timepoint, an unscheduled PK sample should be 
obtained.  A decision on study drug discontinuation should be made.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.5.8
Optional Samples for Research Biosample Repository
4.5.8.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.8.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.8) will not be applicable at that site.


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4.5.8.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to efmarodocokin alfa or 
disease biology:

Leftover serum, plasma, stool, and colonic biopsy tissue samples and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover tissue 
samples from medically indicated procedures (e.g., esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion during the course of the 
study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing, or other genomic analysis methods.  
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.8.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.


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Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.8.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.8.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR specimens 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her specimens, the investigator must inform the Medical Monitor in writing of the 
patient's wishes through use of the appropriate RBR Subject Withdrawal Form and, if the 
trial is ongoing, must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from Study GA40209 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study GA40209.


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4.5.8.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study drug if they experience any of the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study drug

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy

Drug-related anaphylaxis or other severe (Grade 3 or 4) drug-related 
hypersensitivity reaction

Unresectable colonic mucosal dysplasia

High-grade colonic mucosal dysplasia or colon cancer

Requirement for rescue therapy outside defined limits of the protocol 
(see Section 4.4.1)

Inability to tolerate corticosteroid taper (see Section 3.1.7)

Disease flare (as defined in Section 3.1.4.4) while receiving efmarodocokin alfa

Disease worsening as a result of efmarodocokin alfa treatment, in the investigator's 
judgment

Malignancy or cervical Pap test with cervical intraepithelial neoplasia (CIN) 
of Grade 1, adenocarcinoma in situ (AIS), or high-grade squamous intraepithelial 
lesions (HSILs)

De novo or reactivated serious viral infection, such as hepatitis B virus, hepatitis C 
virus, HIV, disseminated varicella zoster virus, or disseminated herpes simplex virus.  
For other serious or severe infections, see Section 5.1.2.3 and Table 4.

Severe liver injury as defined by Hy's Law (see Section 5.3.5.7)

Grade 4 thromboembolism or deep vein thrombosis
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who receive at least one dose of efmarodocokin alfa must 


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undergo safety follow-up assessments 8 weeks after their final dose of study drug 
(see Section 3.1.6 and Appendix 1 for more information).
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, specifically defined as missing scheduled visits or 
non-adherence with concomitant medications for UC or CD
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. Patients who withdraw from the study may be replaced.
Follow-up assessments for patients who discontinue from the study prematurely are 
described in Section 3.1.6 and Appendix 1.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  For details on cessation of 
enrollment or stopping of the study, refer to Section 3.1.8 (Internal Monitoring 
Committee).  Reasons for terminating the study may include, but are not limited to, the 
following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Efmarodocokin alfa is not approved, and clinical development is ongoing.  The safety 
plan for patients in this study is based on clinical experience with efmarodocokin alfa in 
completed and ongoing studies.  The anticipated important safety risks for 
efmarodocokin alfa are outlined below.  Please refer to the Efmarodocokin Alfa
Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for clinically 
significant adverse events.  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  
In addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Efmarodocokin Alfa
The general risks associated with biologic agents and the potential or hypothetical risks 
of efmarodocokin alfa are based on available clinical and nonclinical data.  Risks are 
summarized below and are described in detail in the Efmarodocokin Alfa Investigator's 
Brochure.
5.1.1.1
Dermatologic Reactions
Results from Study GA29468, a Phase Ia single-dose study in HVs, showed that IV 
efmarodocokin alfa induced reversible skin changes, including dry lips and skin, patchy 
erythema, scaling skin (primarily on the face and upper body), and skin discomfort.  
At doses of up to 90 g/kg, the maximum tolerated dose for HVs in Study GA29468, 
most dermatologic manifestations were mild (Grade 1) and sometimes moderate 
(Grade 2).  These cutaneous adverse events were manageable with topical emollients 
that provided symptomatic relief when needed and were fully reversible (i.e., resolving 
within approximately 2 weeks of onset).
In the Phase Ib multiple-dose study (GA29469) in HVs and patients with UC, skin 
changes, similar in nature and duration to those occurring in Study GA29468 have been 
observed at tolerated dose levels.  Dermatologic manifestations at tolerated dose levels 
(e.g., dry, erythematous, scaling skin and skin discomfort) have been reversible and 
managed with topical emollients.  In two HVs, a dose level of 90 g/kg Q2W induced 
protocol-defined dermatologic dose-limiting adverse events that occurred after the 
second dose of blinded efmarodocokin alfa or placebo.  The dermatologic manifestations 
included severe (Grade 3) skin discomfort and severe (Grade 3) dry skin; topical 
emollients and topical corticosteroids provided minimal relief.  The adverse events were 
fully reversible.  For additional details, refer to the Efmarodocokin Alfa Investigator's 
Brochure.


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Patients with a history of psoriasis and other inflammatory skin disorders requiring oral 
corticosteroids, immunosuppressants, or biologic therapy within the past year were
excluded from the parent studies.
Guidelines for management of patients who develop dermatologic reactions are provided 
in Section 5.1.2.3.
5.1.1.2
Infusion-Related Reactions
With the introduction of a foreign biological molecule such as efmarodocokin alfa, there 
is a potential risk of infusion-related reactions.  Infusion-related reactions may include 
both acute allergic/hypersensitivity (e.g., anaphylactic) reactions and acute 
pseudoallergic/hypersensitivity-like (e.g., anaphylactoid) reactions.  Anaphylactic and 
anaphylactoid reactions are the more severe forms of allergic and pseudoallergic 
reactions, respectively.  However, in the Phase Ia single-dose study (GA29468) and the 
Phase Ib multiple-dose study (GA29469), no anaphylactic or anaphylactoid reactions 
were observed. 
Patients with a history of moderate or severe allergic, anaphylactic, or anaphylactoid 
reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine 
proteins, or hypersensitivity to efmarodocokin alfa or any of the excipients (sucrose, 
methionine, sodium phosphate, or polysorbate 20) were excluded from Study GA39925.  
Patients with a history of anaphylaxis, hypersensitivity, or drug allergies to human or 
humanized antibodies or fusion proteins were excluded from Study GA29469.  
Anaphylaxis and hypersensitivity reactions will be closely monitored.
Guidelines for management of patients who develop infusion-related reactions are 
provided in Section 5.1.2.3.
5.1.1.3
Epithelial Tumor Promotion
IL-22 has been reported to promote epithelial tumor progression, including squamous 
cell and basal cell carcinoma (Nardinocchi et al. 2015) and colorectal cancer 
(Kirchberger et al. 2013; Kryczek et al. 2014).  There has been no evidence of epithelial 
tumor promotion in the Phase Ia study (GA29468), the Phase Ib study (GA29469), or 
nonclinical studies to date.  Nevertheless, given the a priori elevated risk of malignancy 
in this patient population, and the potential for epithelial tumor promotion with IL-22 in 
tumor cells that may express the IL-22 receptor (refer to the Efmarodocokin Alfa
Investigator's Brochure), the trial includes selection criteria and additional safety 
monitoring to minimize any hypothetical risk.
Patients with any history of cancer were excluded from Study GA29469.  Patients with a 
history of cancer within the past 5 years and patients with a history of non-melanoma 
skin cancer or GI and/or colon cancer, or a known family history of GI and/or colon 
cancer (defined as one first-degree relative or two second-degree relatives) were
excluded from Study GA39925.  In addition, patients with a history of CIN of Grade 1, 


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cervical smear indicating the presence of AIS or HSILs, and patients who had evidence 
of unresectable colonic mucosal dysplasia or high-grade colonic mucosal dysplasia were
excluded from Study GA39925.  Patients in both parent studies had to have 
documentation of colon cancer surveillance within 1 year prior to enrollment.  
Guidelines for management of patients who develop epithelial tumor promotion are 
provided in Section 5.1.2.3.
5.1.1.4
Neutralization of Endogenous IL-22 by Anti-Drug Antibodies
Though not seen in nonclinical and human studies to date, there is a possibility that 
efmarodocokin alfa may induce ADAs that neutralize endogenous IL-22 and thus be 
associated with an increased risk for opportunistic infections (including bacterial and 
fungal infections).  ADAs may also reduce the therapeutic effect of efmarodocokin alfa.  
In addition, because IL-22 is involved in stimulating epithelial barrier repair, ADAs that 
neutralize endogenous IL-22 could impair epithelial barrier repair in the GI epithelium.  
These potential effects could be long-lasting if neutralizing ADAs are persistent.  
Any patient who is found to test positive for ADAs to efmarodocokin alfa, including ADAs 
that may neutralize endogenous IL-22, should be followed, when possible, every 
2 months for up to 6 months after the last dose of study drug, or until ADA titers are 
below the assay cut-point level, whichever occurs first.
Guidelines for management of patients who develop infections are provided 
in Section 5.1.2.3.
5.1.1.5
Worsening of Clotting/Coagulation Dysfunction in High-Risk 
Populations due to Increased Fibrinogen
Fibrinogen increases along with CRP are consistent with acute phase protein response, 
and are considered on-target effects of IL-22 signaling. A meta-analysis of clinical 
studies reported associations between plasma fibrinogen levels and the risks of coronary 
heart disease, stroke, other vascular mortality, and nonvascular mortality.  However, 
whether the high fibrinogen levels are causal or are an effect of inflammation is not 
established (FSC 2005). In mice, infusion of fibrinogen was shown to induce a state of 
hyperfibrinogenemia, which was then associated with an increased risk of coagulation 
dysfunction and thrombosis (Machlus et al. 2011) but the translatability to humans 
remains uncertain (Ariens 2011; Klovaite et al. 2011).
Dose dependent increases in fibrinogen have been observed following efmarodocokin alfa 
treatment in the nonclinical studies with cynomolgus monkeys and in the Phase I 
studies (GA29468 and GA29469) which included HVs, patients with UC, and patients 
with CD. These increases in fibrinogen were considered on-target effects of IL-22
signaling, with peak mean cohort values within 2-fold of baseline.  The fibrinogen 
increases were not accompanied by changes in other clotting parameters measured 
(prothrombin time, activated partial thromboplastin time, and internal normalized 


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ratio), or by clinical signs or adverse events of clotting/coagulation abnormalities. As 
of the data cutoff of 05 February 2021 in the ongoing blinded Phase II Study GA39925, 
there has been 1 serious adverse event of deep venous thrombosis in 1 patient (out of 
161 patients enrolled) that was considered unrelated to the study drug/placebo by the 
investigator. In a preliminary data analysis from the Phase II Study GA42969 in 
patients with severe COVID-19 pneumonia, the number of thrombotic or embolic 
adverse events were comparable between efmarodocokin alfa, comparator, and placebo 
arms.
Relative to the healthy population, a higher incidence of coagulation dysfunction and 
thromboembolic phenomena is reported in patients with IBD (Danese et al. 2007; 
Grainge et al. 2010). It is unclear but possible that a fibrinogen increase observed 
with efmarodocokin alfa treatment may contribute to worsening the risk of 
clotting/coagulation dysfunction in high-risk populations. To minimize the risk of 
clotting/coagulation dysfunction, investigators are advised to closely monitor patients 
for signs and symptoms suggestive of thromboembolism or deep vein thrombosis. If any 
Grade 2 or 3 thromboembolism or deep vein thrombosis occurs, efmarodocokin alfa 
should be withheld until the event resolves to Grade 1 or lower. Efmarodocokin alfa 
should be permanently discontinued in any patient who develops a Grade 4 
thromboembolism or deep vein thrombosis. Grade 2 or higher thromboembolism or deep 
vein thrombosis should be reported to the Sponsor in an expedited manner as an adverse 
event of special interest (see Section 5.2.3). Based on current data and literature, it is 
not believed that excluding patients with other risk factors, such as use of oral 
contraceptives, is justified. The association between fibrinogen and 
coagulation/clotting dysfunction is correlative, and it is important to assess if these 
risk factors, which are common in the general population, pose an enhanced risk in a 
controlled clinical trial setting.
Guidelines for management of patients who develop Grade ≥2 thromboembolism or deep 
vein thrombosis are provided in Section 5.1.2.3.
5.1.2
Management of Patients Who Experience Adverse Events
At this stage of development, the efmarodocokin alfa safety profile is not completely 
characterized.  For any treatmentemergent adverse event that the investigator believes 
may be related to efmarodocokin alfa, the investigator should consider whether the 
benefit-risk favors continued dosing for that individual patient (i.e., if the adverse event is 
improving and if a clear alternate cause can be identified). 
Guidelines for the monitoring and management of patients who experience specific 
adverse events are provided in Table 4.
5.1.2.1
Dose Modifications
The dose of efmarodocokin alfa should not be modified when managing individual 
patients who experience adverse events.


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5.1.2.2
Treatment Interruption
Study treatment may be temporarily suspended in patients who experience a 
treatment-emergent adverse event considered to be related to study drug.  If the event 
resolves to Grade 2 or better, treatment will resume at the next scheduled dose.  If more 
than one scheduled dose will be missed because of an on-going adverse event, the 
patient should be permanently discontinued from treatment, unless resumption of 
treatment is determined following investigator discussion with the Medical Monitor.  
Study treatment may be suspended for reasons other than a treatment-emergent 
adverse event (e.g., surgical procedures) after discussion with the Medical Monitor.  
The investigator and the Medical Monitor will determine the acceptable length of 
treatment interruption.
5.1.2.3
Management Guidelines
Dermatologic Reactions 
Investigators should remain vigilant for dermatologic signs or symptoms at scheduled 
study visits.  Symptomatic relief of dermatologic manifestations can include topical 
emollients for mild to moderate skin effects and topical corticosteroids and/or oral 
antihistamines for more severe skin effects.  Inability to achieve symptomatic relief may 
require local dermatologic assessment for further evaluation, including recommended 
biopsy and management.
Guidelines for the management of patients who develop dermatologic reactions are 
provided in Table 4.
Infusion-Related Reactions 
All infusions will be administered in the clinic to enable monitoring for possible 
infusion-related reactions.  Patients must be monitored for approximately 30 minutes 
after each study drug infusion.  Medicinal products for the treatment of severe reactions 
(e.g., epinephrine, antihistamines, and glucocorticoids) must be available for immediate 
use in the clinic.  Resuscitation equipment should also be available. 
Infusion-related reactions may include both acute allergic/hypersensitivity 
(e.g., anaphylactic) reactions and acute pseudoallergic/hypersensitivity-like 
(e.g., anaphylactoid) reactions.  These may have similar clinical manifestations, but they 
have different mechanisms (e.g., only allergic reactions are IgE-mediated) and risks of 
re-challenge.  Differentiating allergic reactions from pseudoallergic reactions is important 
because it may impact the understanding of the risk profile of the drug.  In instances 
where the reaction occurs with the first infusion of the study drug without any suspicion 
of prior sensitization, it is less likely to be an allergic reaction.  When a new reaction is 
seen with the second or subsequent infusions, or if there is an atypical presentation 
(e.g., rapid onset within 15 minutes or increase in severity when compared with previous 
reactions), there is a higher likelihood that the reaction is allergic.  Investigators should 
report infusion-related reactions using the most appropriate term, based on their medical 
judgment.  The investigator should also discuss with the Medical Monitor the possibility 


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of obtaining additional supportive data, if available, to inform the diagnosis of allergic 
versus pseudoallergic reaction (e.g., serum histamine, serial tryptase measurements).
Patients should be instructed to recognize the symptoms of a severe allergic 
(e.g., anaphylactic) or pseudoallergic (e.g., anaphylactoid) reaction and to contact a 
healthcare provider or seek immediate care in case of any such symptoms.  Patients are 
to be provided with alert cards to remind them and a caregiver or partner of these 
instructions.
Guidelines for the management of patients who develop infusion-related reactions are 
provided in Table 4.
Epithelial Tumors 
Investigators should remain vigilant for signs or symptoms of cancer in scheduled study 
visits.  Any signs or symptoms that could be suggestive of malignancy should be 
promptly and aggressively evaluated and reported to the Sponsor.  If a patient develops 
epithelial tumors (as defined in Table 4) during the study, study drug must be 
discontinued permanently. In cases of newly diagnosed malignancy or epithelial high 
grade dysplasia, unstained slides and/or representative tissue blocks may be requested 
by the Sponsor for further evaluation and characterization.
Guidelines for the management of patients who develop epithelial tumors are provided 
in Table 4.
Serious Infections 
To assess for the potential development of an immune response, including neutralizing 
ADAs against endogenous IL-22, antibody samples will be obtained at baseline
(Study Week 0), at regular intervals during treatment, and during the safety follow-up 
period and stored appropriately for further evaluation as needed.
Guidelines for the management of patients who develop infections are provided 
in Table 4.
Hepatic Events
If treatment-emergent ALT or AST elevations are observed, ALT, AST, alkaline 
phosphatase, and total bilirubin tests (i.e. liver function tests [LFTs]) should be repeated 
within 4872 hours to confirm the abnormality and to determine whether transaminases 
are increasing or decreasing.
For re-testing done locally or at a central laboratory facility, normal laboratory ranges 
should be recorded, results should be made available to trial investigators immediately, 
and the data should be included in the eCRF.
If treatment-emergent ALT or AST elevations are confirmed, other laboratory tests 
should be performed to rule out acute viral hepatitis (i.e., hepatitis A, B, C, D, or E), 


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autoimmune hepatitis (i.e., anti-nuclear antibody, anti-smooth muscle antibody, 
anti-mitochondrial antibody, or antiLKM-1 antibody), or functional hepatic impairment 
(i.e., INR or fractionated bilirubin).  Further LFT monitoring to ensure patient safety 
should be performed on the basis of clinical judgment and local practice.  Imaging tests 
and hepatology consultation should be considered.  In addition, a more detailed history 
of the event should be obtained, including the following: symptoms, prior or current 
diseases, concomitant drug use (including nonprescription medications and herbal and 
dietary supplements), alcohol use, recreational drug use, and special diets.
Regarding re-initiation of study drug, the benefit-risk assessment takes alternate causes 
(e.g., acute viral hepatitis, newly initiated concomitant medication, treated gallstone 
disease) and reversibility into consideration, but the recommendations for a specific 
patient are complex and require medical judgment (i.e., consultation between the 
investigator, medical monitor, and the IMC).  In general, re-initiation of study drug can be 
considered if there is clear evidence that the liver injury is not related to study drug or 
clearly attributable to other causes (as determined by the IMC), is showing signs of 
reversibility, and that the benefit-risk of continuing to receive study drug remains 
favorable.  Because establishing a diagnosis of drug-induced liver injury is frequently 
challenging, the IMC may involve outside hepatology experts or consultants as 
necessary.  If the study drug is re-initiated, there remains a potential risk of recurrence of 
liver injury due to the possibility of an erroneous causality assessment.  Hence, patients 
will need to be monitored carefully after re-initiation of study drug.  If LFTs worsen 
significantly after re-initiation, study drug should be permanently discontinued.
Guidelines for the management of patients who develop treatment-emergent ALT or 
AST elevations are provided in Table 4.  For patients with suspected or confirmed 
severe liver injury as defined by Hy’s Law, refer to Section 5.3.5.7.
Thromboembolism or Deep Vein Thrombosis
Investigators should remain vigilant for signs and symptoms suggestive of 
thromboembolism or deep vein thrombosis in scheduled study visits. Any signs or 
symptoms that could be suggestive of thromboembolism or deep vein thrombosis should 
be promptly and aggressively evaluated and reported in an expedited manner to the 
Sponsor (see Section 5.2.3). Guidelines for the management of patients who develop 
Grade ≥2 thromboembolism or deep vein thrombosis are provided in Table 4.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Dermatologic adverse event
Grade 1 or 2
Continue study drug.
Treat with topical emollients.
Grade 3 
Withhold study drug.
Treat with topical emollients and with topical corticosteroids 
and/or oral antihistamines.
If no symptomatic relief, refer patient to dermatologist for 
further assessment and treatment.
If treatment with oral immunosuppressants is required, 
discontinue study drug.
If event resolves to Grade 2 or better with topical treatment, 
resume study drug at the next scheduled dose.  If more than 
one scheduled dose will be missed because of an on-going 
adverse event, permanently discontinue study drug. 
Grade 4
Permanently discontinue study drug.
Refer patient to dermatologist for assessment and treatment.
Infusion-related reactions 
Grade 1 or 2
Reduce infusion rate to50% of original infusion rate. 
Interrupt infusion if symptoms persist. 
Provide supportive treatment if indicated. 
If infusion was interrupted, resume infusion at 50% of original 
infusion rate upon symptom resolution.
If infusion reaction reoccurs, discuss with Medical Monitor 
before premedicating with acetaminophen or 
diphenhydramine at subsequent infusions.
Grade 3 and 4 
Stop infusion immediately and administer supportive 
treatment as per local or institutional standard operating 
procedures (see Appendix 9 for guidance on anaphylaxis).
Permanently discontinue study drug.
Discuss with Medical Monitor the possibility of obtaining 
additional supportive data, if available, to inform the 
diagnosis of allergic versus pseudoallergic reaction 
(e.g., serum histamine, serial tryptase measurements).
ADAanti-drug antibody; AESIadverse event of special interest; LFT liver function test; 
PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Infection
Grade 1 or 2
Continue study drug.
Grade 3
Withhold study drug.
Collect PK and ADA sample if not collected at study visit, 
and treat according to local standards.
If the infection is clearly not study-drug related (i.e., there is a 
clear alternative explanation for the infection), the infection 
and symptoms are fully resolved at least 1 week prior to the 
next scheduled dose, and any treatment for the infection has 
been completed at least 1 week prior to the next scheduled 
dose, consult the Medical Monitor to determine if study drug 
can be resumed.  If these conditions are not met or the 
Medical Monitor indicates that study drug should not be 
resumed, permanently discontinue study drug.
Grade 4
Permanently discontinue study drug.
Collect PK and ADA sample if not collected at study visit, 
and treat according to local standards.
Suspected or confirmed COVID-19 infection
Grades 13
Withhold study drug
If the infection and symptoms are fully resolved at least 1 
week prior to the next scheduled dose, and any treatment for 
the infection has been completed at least 1 week prior to the 
next scheduled dose, consult the Medical Monitor to 
determine if study drug can be resumed. If these conditions 
are not met or the Medical Monitor indicates that study drug 
should not be resumed, permanently discontinue study drug.
Grade 4
Permanently discontinue study drug.
Epithelial tumor 
New malignancy, unresectable 
colonic mucosal dysplasia, or any 
high-grade colonic mucosal 
dysplasia
Permanently discontinue study drug.
New cervical intraepithelial 
neoplasia of Grade 1, cervical 
smear indicating the presence of 
adenocarcinoma in situ, or 
high-grade squamous 
intraepithelial lesion
Permanently discontinue study drug.
ADAanti-drug antibody; AESIadverse event of special interest; LFT liver function test; 
PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Hepatic event
ALT or AST 3ULN
to 5 ULN 
Continue study drug. 
Repeat LFTs within 48-72 hours. 
If LFT results confirmed, test for alternative cause(s) as 
described in Section 5.1.2.3.
ALT or AST 5ULN
to 8 ULN
Withhold study drug.
Repeat LFTs within 48-72 hours. 
If LFTs confirmed, test for alternative cause(s) as described 
in Section 5.1.2.3.
Monitor LFTs weekly until AST and ALT 5ULN.  
If event resolves to AST or ALT 5ULN within 2 weeks 
after event onset, resume study drug.  If not, monitor as 
described in the next category.
Any one of the following:

ALT or AST elevation
8ULN

ALT or AST 5ULN for 
more than 2 weeks

ALT or AST 3ULN
and (total bilirubin 
2 ULN or INR 1.5)

ALT or AST 3ULN with 
the appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, 
and/or eosinophilia (> 5%), 
or jaundice
Withhold study drug.
Repeat LFTs within 4872 hours. 
If LFTs confirmed, test for alternative cause(s) as described 
in Section 5.1.2.3. 
Monitor LFTs two to three times per week until decreasing or 
stabilized, then monitor LFTs weekly until AST and ALT are
5ULN and total bilirubin is 2 ULN.
Discontinuation of study drug should be considered.  
However, if event resolves to AST and ALT 5ULN with 
total bilirubin 2 ULN, study drug may be resumed after 
consultation with the Medical Monitor.  In general, 
re-initiation of study drug can be considered if there is clear 
evidence that the liver injury is not related to study drug or 
clearly attributable to other causes (as determined by the 
IMC), is showing signs of reversibility, and that the 
benefit-risk of continuing to receive study drug remains 
favorable (see Section 5.1.2.3).  If a decision is made to 
permanently discontinue study drug, offer medical 
management per local standard of care and follow for safety.
ADAanti-drug antibody; AESIadverse event of special interest; LFT liver function test; 
PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Thromboembolism or deep vein thrombosis
Grade 1
Continue study drug and monitor closely for worsening of 
symptoms.
Grade 2 or 3
Treat as per local standard of care. Withhold study drug 
until the event resolves to a Grade 1 or lower.
Report event to Sponsor in an expedited manner as an AESI
(see Section 5.2.3).
Grade 4
Permanently discontinue study drug.
Notify Medical Monitor and offer medical management per 
local standard of care, and follow for safety.
Report event to Sponsor in an expedited manner as an AESI
(see Section 5.2.3).
Efmarodocokin alfa-related adverse events not described above
Grade 1 or 2
Continue study drug.
Grade 3
Withhold study drug.
If event resolves to Grade 2 or better, resume study drug at 
the next scheduled dose.  If more than one scheduled dose 
will be missed because of an on-going adverse event, 
permanently discontinue study drug. 
Grade 4
Permanently discontinue study drug, offer medical 
management per local standard of care, and follow for safety.
ADAanti-drug antibody; AESIadverse event of special interest; LFT liver function test; 
PKpharmacokinetic; ULNupper limit of normal.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined 
in Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10
and 5.3.5.11 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline (Study Week 0)

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Any adverse event leading to discontinuation of study drug 

New or worsening neurologic signs and symptoms that are consistent with a 
diagnosis of progressive multifocal leukoencephalopathy

Suspected or confirmed COVID-19 infection

Grade ≥2 thromboembolism or deep vein thrombosis
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.  It is 
preferred, but not required, that the clinician who assesses adverse events not be the 


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same clinician who assesses UC or CD efficacy outcomes (e.g., PROs and 
endoscopic evaluation).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent for study entry has been obtained but prior to initiation of study 
drug, only serious adverse events caused by a protocol-mandated intervention 
(e.g., invasive procedures such as biopsies, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events).
After informed consent for study re-entry has been obtained (see Section 3.1.3) but prior 
to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) 
or prior study treatment should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events).
After initiation of study drug following study entry or study re-entry, all adverse events 
will be reported until 8 weeks after the final dose of study drug.
Any adverse event that occurs after completion of Week 52 and required safety 
follow-up assessments but prior to obtaining informed consent for study re-entry should 
be captured on the General Medical History and Baseline Conditions eCRF rather than 
the Adverse Event eCRF, unless it is a serious adverse event related to prior study 
treatment.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 
an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration
(see also Table 6):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "'infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF.


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5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
Persistent Adverse Events First Reported in Study GA40209 or in Parent 
Study
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  


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The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
Persistent Adverse Events First Reported in the Parent Study
An adverse event that is ongoing at the end of a parent study will be marked as not 
resolved in the eCRF for that study and will be reopened in Study GA40209 with the 
same start date, adverse event term, and severity recorded in the parent study.  The 
severity (NCI CTCAE grade) should be evaluated by the investigator at the start of 
Study GA40209 and updated in the Adverse Event Intensity or Grade Changes eCRF 
if applicable.
Recurrent Adverse Events
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal ECG Findings
Not every ECG abnormality qualifies as an adverse event.  An ECG finding must be 
reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all ECG findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated ECG abnormality should 
be classified as an adverse event.
If a clinically significant ECG abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis should be recorded on the Adverse Event eCRF.


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Observations of the same clinically significant ECG abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on 
recording persistent adverse events).
5.3.5.8
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of UC or CD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of UC, "ulcerative colitis progression" should be 
recorded on the Adverse Event eCRF.  If the death is attributed to progression of CD, 
"Crohn's disease progression" should be recorded on the Adverse Event eCRF.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.10
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening (Study Week 0)
visit for this study.  Such conditions should be recorded on the General Medical History 
and Baseline Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.11
Lack of Efficacy or Worsening of Ulcerative Colitis or Crohn's 
Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the MCS for patients with UC and the SES-CD for patients 
with CD, which includes endoscopic disease evaluation.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol (e.g., for study drug administration, 
insertion of access device for study drug administration, or procedure required by 
the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed through use of PRO data.  Sites are not expected to 
review the PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)   

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to the
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Pharmaceutical Product Development (PPD) Medical Monitor contact information:
Telephone Number 
(24-Hour Safety Hotline)
Fax Number
North America
+1 888 483 7729
+1 888 529 3580
North America (Alternate)
+1 800 201 8725
+1 888 488 9697
Europe, Middle East, Africa, 
or Asia Pacific
+44 1223 374 240
+44 1223 374 102
Alternate Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
Mobile Telephone No.:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent for study entry has been obtained but prior to initiation of study 
drug, only serious adverse events caused by a protocol-mandated intervention should 
be reported.  After informed consent for study re-entry has been obtained (see 
Section 3.1.3) but prior to initiation of study drug, only serious adverse events caused by 
a protocol-mandated intervention or prior study treatment should be reported.  The paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the event), by faxing 
the form using the fax number provided below:
Region
Fax Number
North America
+1 888 529 3580
Europe, Middle East, Africa, 
or Asia Pacific
+44 1223 374 102
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug following study entry or study re-entry, serious adverse 
events and adverse events of special interest will be reported until 8 weeks after the final 
dose of study drug.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Safety Risk Management by the EDC system.


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In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), by faxing the form using the fax number 
provided in Section 5.4.2.1.  Once the EDC system is available, all information will need 
to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur 8 weeks after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 8 weeks after the final dose of study drug or 18 weeks after final dose of study 
drug from Study GA39925, whichever is longer.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), by faxing the 
form using the fax number provided in Section 5.4.1.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study drug and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the investigator 
will submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
8 weeks after the final dose of study drug or 18 weeks after final dose of study drug from 
Study GA39925, whichever is longer.  The investigator should report the pregnancy on 
the paper Clinical Trial Pregnancy Reporting Form and submit the form to the Sponsor 
or its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
by faxing the form using the fax number provided in Section 5.4.1.  Attempts should be 
made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug.  When permitted by the site, the 
pregnant partner would need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  If the 
authorization has been signed, the investigator should submit a Clinical Trial Pregnancy 
Reporting Form with additional information on the pregnant partner and the course and 
outcome of the pregnancy as it becomes available.  An investigator who is contacted by 
the male patient or his pregnant partner may provide information on the risks of the 


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pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2).
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For efmarodocokin alfa, adverse events associated with 
special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with efmarodocokin alfa, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
two entries on the Adverse Event eCRF, one entry to report the accidental overdose and 
one entry to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked for both entries.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 


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serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
8 weeks after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, by faxing the paper Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through the use of the reference safety 
information in the document listed below:
Drug
Document
Efmarodocokin alfa
Efmarodocokin Alfa Investigator's Brochure


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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Currently there are no expected serious adverse drug reactions for efmarodocokin alfa
described in the Efmarodocokin Alfa Investigator’s Brochure.  Thus, any 
treatment-emergent serious adverse event deemed related to efmarodocokin alfa will be 
reported as a suspected unexpected serious adverse reaction (SUSAR).  Reporting of 
individual SUSARs to investigators, IRBs, ECs, and applicable health authorities will be 
done in accordance with applicable legislation.  
For the purpose of SUSAR reporting, the version of the Efmarodocokin Alfa
Investigator’s Brochure valid at the time the SUSAR occurs will apply.  SUSARs will be 
kept blinded unless required for medical safety reasons and/or country regulatory 
reasons. Unblinding to study personnel and Genentech study team members will be 
documented.
Six-month SUSAR reports related to efmarodocokin alfa will be provided as per local 
regulatory requirements.  If a significant safety issue arises altering the benefit-risk 
profile of efmarodocokin alfa, the investigators, IRBs, ECs, and applicable health 
authorities will be informed prior to the next update of the Efmarodocokin Alfa
Investigator's Brochure, in accordance with applicable legislation.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Data collected from the final visit of the parent study will serve as baseline 
(Study Week 0) data for the extension study.
Participation during Year 2 is not required for patients who completed the study through 
Week 52 (Year 1) prior to the implementation of Protocol Version 6, and those who do 
not participate will be considered to have completed the study per protocol, provided 
required safety follow-up assessments have been completed.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 48 patients will be enrolled in parent study GA29469, and approximately 
270 patients will be enrolled in parent study GA39925.  These patients will be potentially 
eligible for this extension study.
The purpose of this study is to evaluate the long-term safety and tolerability of 
efmarodocokin alfa; no formal hypothesis testing will be performed.  Assumptions for 
sample size determination are based on a 52-week study period, in line with the study 
duration prior to the implementation of Protocol Version 6.  Assuming approximately 50% 


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of patients from parent study GA39925 will enter this open-label extension study as 
non-responders (approximately 135 patients) and 20% of those patients will have 
sustained clinical remission at the end of the 52-week study period, a total of 
135 evaluable patients will provide a 95% confidence interval of 13.3% to 26.7% for 
the point estimate of 20%. In two different 52-week maintenance Phase III studies in 
patients with moderate to severely active ulcerative colitis, the percentage of patients 
randomly assigned to the placebo arm and who had at least one serious adverse event
was 6.6% (13/198) and 13.5% (37/275) respectively (Sandborn et al.; 2017; Feagan 
et al., 2013).  Assuming a 52-week serious adverse event rate of 6.6% or 13.5% for 
efmarodocokin alfa in Study GA40209, 135 evaluable patients will provide a 95% 
confidence interval of 3% to 12% or a 95% confidence interval of 8% to 20%, 
respectively.
6.2
SUMMARIES OF CONDUCT OF STUDY
The numbers of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Eligibility and other major protocol deviations will be listed and evaluated for their 
potential effects on the interpretation of study results.
Patients who withdraw from the study, irrespective of final outcome, will be considered 
as non-responders at analysis. All patients who received efmarodocokin alfa in this 
study will be pooled for analysis. Further subgroup analysis by dose change during the 
study or baseline characteristics may be performed if the sample size per subgroup is 
sufficient.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, and self-reported 
race/ethnicity) will be summarized through use of means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.
6.4
SAFETY ANALYSES
The safety analysis population will consist of all patients who received at least one dose 
of study drug. 
The safety analysis will contribute to the evaluation of the dosing strategy in the enrolled 
population over the study period, the impact of total cumulative dose received in 
consecutive months, the impact of intermittent dosing, the impact of total amount of drug 
received (including dose adjustments) or total number of infusions during the study.  
Safety will be analyzed through descriptive summaries of adverse events, laboratory test 
results, and clinical data on the basis of, but not limited to, the following:

All patients who receive at least one dose of study drug


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
Total dose received overall

Total number of infusions overall

Total number of consecutive monthly doses

Maximum total cumulative dose received in consecutive months
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v4.0.
6.5
EXPLORATORY EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all patients.
The exploratory efficacy endpoints will be summarized by descriptive statistics based on 
the following calculations, with clinical response and clinical remission as defined in 
Sections 3.1.4.2 and 3.1.4.3.  

Proportion of patients with a clinical response

Proportion of patients with a clinical remission

Time from clinical remission to loss of clinical remission

Change from baseline (i.e., either the baseline score in the parent study or the last 
score prior to initiation of the most recent course of efmarodocokin alfa 60 g/kg IV 
Q4W during the extension study, whichever score is the most recent) in PRO2 for 
patients with CD
6.6
EXPLORATORY PHARMACOKINETIC ANALYSES
Serum study drug concentrations at selected timepoints will be summarized by
descriptive statistics.  Some of the covariate effects (e.g. patient demographics or 
disease status at the time of entry) on exposure will also be evaluated. The relationship 
between serum concentration and some efficacy or safety endpoints will be explored.
6.7
EXPLORATORY IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one 
postbaseline ADA assessment. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (Study Week 0) (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 


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postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status, safety, PK, and biomarker endpoints will be 
analyzed and reported via descriptive statistics.
6.8
EXPLORATORY BIOMARKER ANALYSES
The biomarker data may be summarized descriptively.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and all other 
electronic data, including endoscopy and ECG data, will be sent directly to the Sponsor, 
using the Sponsor's standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PRO and clinician-reported outcome (ClinRO) data will be collected through the use of 
paper questionnaires.  The data from the questionnaires will be entered into the EDC 
system by site staff. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered on the eCRFs must not be obliterated or destroyed and must be retained per the 
policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO and ClinRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC), 
the General Data Protection Regulation (2016/679), and applicable local, regional, and 
national laws.


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8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  A 
separate, specific signature will be required to document a patient's agreement to 
participate in optional procedures.  Patients who decline to participate will not provide a 
separate signature.
After discussion of the study with the investigator, patients must be given ample time to 
review what has been discussed and have their questions answered prior to signing 
Consent Forms. Patients must be told that they are free to refuse to participate and may 
withdraw their consent at any time for any reason without penalty or loss of benefits to 
which they are otherwise entitled.  The Consent Forms must be signed and dated by the 
patient before his or her participation in the study.  The case history or clinical records 
for each patient shall document the informed consent process and that written informed 
consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient. All signed and 
dated Consent Forms must remain in each patient's study file or in the site file and must 
be available for verification by study monitors at any time.


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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient,
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
8.6
PATIENT RECRUITMENT
Recruitment procedures will follow the ICH E6 guideline for Good Clinical Practice and 
are customized in accordance with local requirements and regulations. Recruitment 
strategies for this study may include, but are not limited to, recruitment from the 
investigator's local practice or referrals from other physicians. All patient recruitment 
materials must be reviewed and approved by the IRB/EC prior to study use (see 
Section 8.3). To ensure that patients are adequately informed and free from coercion, 
patient recruitment procedures must adhere to the following guidelines: 

After discussion of the study with the investigator, patients must be given ample 
time to review what has been discussed and have their questions answered prior to 
signing Consent Forms (see Section 8.2).

Patients must be told that they are free to refuse to participate and may withdraw 
their consent at any time for any reason without penalty or loss of benefits to which 
they are otherwise entitled (see Section 8.2).

Patients must be provided with IRB/EC-approved study educational material and a 
copy of each signed Informed Consent Form (see Section 8.2).

Patients with the potential of exposure to any coercion will be excluded from the 
parent study (see Study GA39925, Section 4.1.2); therefore, they will not be eligible 
for Study GA40209.


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by Genentech.  A contract research organization will be 
contracted to manage the study and perform monitoring activities.  Centralized facilities 
(vendors) will perform endoscopy reading and interpretation; however, the investigator or 
a designee will also read the endoscopy as part of the MCS, mMCS, and SES-CD
evaluation.  In addition, a central vendor will collect ECG data.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests), as specified in Section 4.5.6.  Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.  
A selected group of assessments will be performed on site or by a local laboratory and 
urine pregnancy tests will be conducted by the patient at home if appropriate.
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study treatment inventory management.


Efmarodocokin Alfa—Genentech, Inc.
93/ Protocol GA40209, Version 7
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


Efmarodocokin Alfa—Genentech, Inc.
94/ Protocol GA40209, Version 7
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Efmarodocokin Alfa—Genentech, Inc.
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10.
REFERENCES
Ariens RAS. Elevated fibrinogen causes thrombosis. Blood 2011;117:468788.
Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the 
Crohn’s Disease Activity Index (CDAI). Gastroenterology 1979;77:8436.
Danese S, Papa A, Saibeni S, et al. Inflammation and coagulation in inflammatory 
bowel disease: the clot thickens. Am J Gastroenterol 2007;102:17486.
Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, 
simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest 
Endosc 2004;60:50512.
Eidenschenk C, Rutz S, Liesenfeld O, et al. Role of IL-22 in microbial host defense. In: 
Fillatreau S, O'Garra Anne, editors. Interleukin-10 in Health and Disease. Berlin 
Heidelberg: Springer-Verlag, 2014;21336.
Feagan BG, Rutgeerts P, Sands B, et al. Vedolizumab as induction and maintenance 
therapy for ulcerative colitis. N Engl J Med 2013;369:699710.
[FSC] Fibrinogen Studies Collaboration; Danesh J, Lewington S, Thompson SG, et al. 
Plasma fibrinogen level and the risk of major cardiovascular diseases and 
nonvascular mortality: an individual participant meta-analysis. JAMA 
2005;294:1799809.
Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and 
remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:65763.
Gurney AL. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral 
tissues. Int Immunopharmacol 2004;4:66977.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for 
Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:154149.
Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient 
reported outcome measures for the assessment of Crohn's disease activity. 
Aliment Pharmacol Ther 2015 Jan;41:7786.
Kirchberger S, Royston DJ, Boulard O, et al. Innate lymphoid cells sustain colon cancer 
through production of interleukin-22 in a mouse model. J Exp Med 
2013;210:91731.
Klovaite J, Benn M, Yazdanyar S, et al. High platelet volume and increased risk of 
myocardial infarction: 39,531 participants from the general population. J Thromb 
Haemost 2011;9:4956.
Kryczek I, Nagarsheth N, Peng D, et al. IL-22(+)CD4(+) T cells promote colorectal
cancer stemness via STAT3 transcription factor activation and induction of the 
methyltransferase DOT1L. Immunity 2014;40:77284.


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96/ Protocol GA40209, Version 7
Machlus KR, Cardenas JC, Church FC, et al. Causal relationship between 
hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice. Blood 
2011;117: 495363.
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the 
inflammatory bowel diseases with time, based on systematic review. 
Gastroenterology 2012;142:4654.
Nardinocchi L, Sonego G, Passarelli F, et al. Interleukin-17 and interleukin-22 promote 
tumor progression in human nonmelanoma skin cancer. Eur J Immunol 
2015;45:92231.
Neufert C, Pickert G, Zheng Y, et al. Activation of epithelial STAT3 regulates intestinal 
homeostasis. Cell Cycle 2010;9:6525. 
Ouyang W, Rutz S, Crellin NK, et al. Regulation and functions of the IL-10 family of 
cytokines in inflammation and disease. Annu Rev Immunol 2011;29:71109.
Pickert G, Neufert C, Leppkes M, et al. STAT3 links IL-22 signaling in intestinal epithelial 
cells to mucosal wound healing. J Exp Med 2009;206:146572.
Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance 
therapy for Crohn's disease. N Engl J Med 2005;353:191225.
Sandborn WJ, Su C, Sands BC, et al. Tofacitinib as induction and maintenance therapy 
for ulcerative colitis. N Engl J Med 2017;376:172336.
Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a 
mouse model of ulcerative colitis. J Clin Invest 2008;118:53444.
Wolk K, Kunz S, Witte E, et al. IL-22 increases the innate immunity of tissues. Immunity 
2004;21:24154.
Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense 
against attaching and effacing bacterial pathogens. Nat Med 2008;14:2829.


Efmarodocokin Alfa—Genentech, Inc.
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Appendix 1
Schedule of Activities
Activity
Baseline Efmarodocokin Alfa-Specific Activities b, c
(5 days)
Q8W, 
When Not 
Undergoing 
Efmarodocokin 
Alfa-Specific 
Activities e
(1 week)
Ongoing Activities f
DE/ET 
Visit g
UV
Visit h
Re-entry 
Screening
(3 weeks) i
Safety 
FU j
(5 
days)
Study 
Week
Treatment 
Initiation d
Q4W 
When Not 
in Clinical 
Remission
4 and 8 Weeks 
after Achieving 
Clinical 
Remission
Study Week 
(2 weeks)
0 a
28
52
80
104
Informed consent
x
x k
Review eligibility 
criteria
x
x
Medical history and 
baseline conditions
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events l
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs m
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
Complete physical 
examination n
x
x
Limited physical 
examination o
x
x
x
x
x
x
ECG p
x
x
x p
x
x
x
x
x
x
x
Hematology q and 
chemistry r
x
x
x
x
x
x
x
Lipase, coagulation,
and lipids s (fasting)
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
98/ Protocol GA40209, Version 7
Activity
Baseline Efmarodocokin Alfa-Specific Activities b, c
(5 days)
Q8W, 
When Not 
Undergoing 
Efmarodocokin 
Alfa-Specific 
Activities e
(1 week)
Ongoing Activities f
DE/ET 
Visit g
UV
Visit h
Re-entry 
Screening
(3 weeks) i
Safety 
FU j
(5 
days)
Study 
Week
Treatment 
Initiation d
Q4W 
When Not 
in Clinical 
Remission
4 and 8 Weeks 
after Achieving 
Clinical 
Remission
Study Week 
(2 weeks)
0 a
28
52
80
104
Pregnancy test t
x
x
x
Q4W
x
x
x
Urinalysis u
x
x
x
x
x
PK sample v
x
x
x
x
x
x
x
ADA sample w
x a
Q12W w
x
x
x
x
x
Stool sample x
x
x
x
x
x
x
x
x
Diary
x i, y
Efmarodocokin 
alfa c, z
x d
x
Annual colon 
surveillance 
colonoscopy with 
biopsy aa
x bb
UC-Specific Activities
Flexible 
sigmoidoscopy 
with biopsy aa
x
x
x
x
x
x
x
MCS (pMCS plus 
endoscopy) cc
x
x
x
x
x
x
x
pMCS dd
x
x
x
x ee
x


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
99/ Protocol GA40209, Version 7
Activity
Baseline Efmarodocokin Alfa-Specific Activities b, c
(5 days)
Q8W, 
When Not 
Undergoing 
Efmarodocokin 
Alfa-Specific 
Activities e
(1 week)
Ongoing Activities f
DE/ET 
Visit g
UV
Visit h
Re-entry 
Screening
(3 weeks) i
Safety 
FU j
(5 
days)
Study 
Week
Treatment 
Initiation d
Q4W 
When Not 
in Clinical 
Remission
4 and 8 Weeks 
after Achieving 
Clinical 
Remission
Study Week 
(2 weeks)
0 a
28
52
80
104
CD-Specific Activities
Ileocolonoscopy 
with biopsy aa
x
x
x
x
x
x
x
CDAI (including 
PRO2)
x
x
x
x
x
x
x
x
x
x
x
x
x
SES-CD
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; CDCrohn's disease; CDAI Crohn's Disease Activity Index; CRPC-reactive protein; DEdisease evaluation; 
eCRFelectronic Case Report Form; ETearly termination; FUfollow-up; MCS Mayo Clinic Score; PGAPhysician’s Global Assessment; 
PKpharmacokinetic; pMCSpartial Mayo Clinic Score; PRO2Patient-Reported Outcome-2; Q4W every 4 weeks; Q8W every 8 weeks; 
Q12W every 12 weeks; QTcFQT interval corrected through use of Fridericia's formula; SES-CDSimple Endoscopic Score for Crohn's Disease; 
UCulcerative colitis;  UVunscheduled visit.
Notes:  All activities should be performed prior to study drug administration, unless otherwise stated.
The duration of the study has been extended from 1 year to 2 years with the implementation of Protocol Version 6.  Patients who completed the study 
through Week 52 (Year 1) prior to the implementation of Protocol Version 6 may still be eligible for an additional year of treatment and/or 
observation, provided that certain criteria are met, as outlined in Table 3.  Participation during Year 2 is not required for such patients, and those who 
do not participate will be considered to have completed the study per protocol, provided required safety follow-up assessments have been 
completed.
a Day 1 of Study Week 0.  Data collected from the final visit of the parent study will serve as baseline Study Week 0 (initial visit) data for the 
extension study.  Activities that were performed at the final visit of the parent study do not need to be repeated at Study Week 0, with the exception 
of the ADA sample.  A baseline ADA sample should be collected at Study Week 0.
b Efmarodocokin alfa-specific activities to be performed while patients are receiving efmarodocokin alfa 60 g/kg IV Q4W or undergoing follow-up 4 
and 8 weeks after achieving clinical remission.
c Efmarodocokin alfa 60 g/kg IV Q4W will be administered in patients who do not meet criteria for clinical remission, with the first dose occurring 
after loss of clinical remission is confirmed.  For patients who were not in clinical remission at the time of their final endoscopy in the parent study, 
the first dose of efmarodocokin alfa in the extension study will occur at Study Week 0 (initial visit).


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
100/ Protocol GA40209, Version 7
d Treatment initiation (i.e., first visit of period in which patient receives efmarodocokin alfa) may coincide with the Study Week 0 (baseline) visit or a 
subsequent scheduled visit that confirms the patient is not in clinical remission.  The first dose of efmarodocokin alfa in the extension study is to be 
administered no less than 2 weeks after the last dose of study drug in parent study.  For patients who complete the Week 52 visit but have not yet 
completed required safety assessments prior to the implementation of Protocol Version 6 (see Section 3.1.3):  If treatment is resumed (follow 
“Q4W When Not in Clinical Remission” column), there must be a minimum of 2 weeks since the last dose of efmarodocokin alfa.  For patients 
who complete the Week 52 visit and (if required) safety follow-up assessments prior to the implementation of Protocol Version 6:  If the patient 
qualifies for study re-entry and is not in clinical remission, efmarodocokin alfa must be given within 1 week of establishing eligibility (follow “Q4W 
When Not in Clinical Remission” column).
e For patients who achieve clinical remission while receiving efmarodocokin alfa, Q8W visits begin 16 weeks after achieving clinical remission.
f
Additional activities to be performed in all patients.
g Patients with worsening disease, as determined by the investigator, should return to the clinic as soon as possible for a disease evaluation visit.  
The investigator may also schedule a disease evaluation visit to determine if a patient has achieved clinical remission.  Patients who discontinue 
study drug prematurely (prior to Week 104) for the reasons listed in Section 4.6.1 and have received at least one dose of efmarodocokin alfa
should return to the clinic for an early termination visit within 1 week of the event and will then enter the safety follow-up period.  Patients who are 
unwilling to complete the safety follow-up period should return to the clinic for an early termination visit no later than 30 days after their final dose.  
Patients who discontinue the study prematurely (prior to Week 104) and have not received efmarodocokin alfa should return to the clinic for an 
early termination visit within 30 days.  Endoscopy at the early termination visit should be conducted if the investigator deems it necessary. 
h An unscheduled visit represents a visit that is not specified by the protocol but is determined to be necessary by the investigator or Sponsor 
(e.g., for evaluation of an adverse event).  The indicated assessments are required for an unscheduled visit.  Other assessments are optional for 
an unscheduled visit, per investigator discretion.
i
Patients who complete Week 52 and (if required) safety follow-up assessments prior to the implementation of Protocol Version 6 and agree to 
participate during Year 2 will undergo re-entry screening over a 3-week period to confirm study eligibility per criteria outlined in Section 4.1 and 
evaluate disease status.  Daily diary recording will be re-initiated during re-entry screening to enable collection of patient-reported outcome data for 
MCS, CDAI, and PRO2 assessments (see Section 4.5.5).
j
Patients who receive at least one dose of efmarodocokin alfa must undergo safety follow-up assessments 8 weeks after their final dose.  Patients 
who discontinue prematurely without having undergone at least 8 weeks of follow-up (observation) after their final dose of efmarodocokin alfa
should return to the clinic for a safety follow-up visit 8 weeks after their final dose.  Patients who are unwilling to return the clinic for the safety 
follow-up visit should undergo assessments indicated for an early termination visit no later than 30 days after their final dose.  For patients who 
complete Week 52 and safety follow-up assessments prior to the implementation of Protocol Version 6 and re-enter the study, safety follow-up is 
to be repeated for Year 2.
k Patients who complete Week 52 and (if required) safety follow-up assessments prior to the implementation of Protocol Version 6 and agree to 
participate during Year 2 must be re-consented within 8 weeks of implementation of Protocol Version 6.


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
101/ Protocol GA40209, Version 7
l
After informed consent for study entry has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-
mandated intervention should be reported.  After informed consent for study re-entry has been obtained (see Section 3.1.3) but prior to initiation of 
study drug, only serious adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, discontinuation 
of medications) or prior study treatment should be reported.  After initiation of study drug following study entry or study re-entry, all adverse events 
will be reported until 8 weeks after the final dose of study drug.  After this period, the Sponsor should be notified if the investigator becomes aware 
of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  Any adverse event that occurs after 
completion of Week 52 and required safety follow-up assessments but prior to obtaining informed consent for study re-entry should be captured on 
the General Medical History and Baseline Conditions eCRF rather than the Adverse Event eCRF, unless it is a serious adverse event related to 
prior study treatment.
m Vital signs include measurements of respiratory rate, pulse rate, systolic blood pressure, diastolic blood pressure, and temperature.  Patient should 
be in a seated position after at least 10 minutes of rest prior to measuring vital signs.
n A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline (Study Week 0) 
on the General Medical History and Baseline Conditions eCRF. 
o Perform a limited, symptom-directed examination, including an abdominal examination, at specified timepoints or as clinically indicated.  Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF.
p Patient must be resting in a supine position for at least 10 minutes prior to ECG assessment.  ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after any meal if possible.  
ECGs should be performed at each dosing visit until after the shortest tolerated infusion delivery time is reached (i.e., infusion is tolerated without 
infusion-associated adverse event).
q Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).
r
Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, and LDH.
s Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.  Patients must be fasting (no food or fluids other than water 
will be allowed for approximately 8 hours prior to the visit and until after sample collection).
t
For women of childbearing potential undergoing efmarodocokin alfa treatment, urine pregnancy tests will be performed monthly, at specified 
subsequent visits.  For women of childbearing potential not undergoing efmarodocokin alfa treatment, urine pregnancy tests will be performed 
Q4W.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
u Urinalysis includes specific gravity, pH, blood, qualitative protein, ketones, glucose, bilirubin, nitrite, leukocyte esterase, color, and appearance. If 
urinalysis is abnormal, the same urine sample will be sent to the laboratory for microscopic analysis (sediment, WBCs, RBCs, casts, crystals, 
epithelial cells, and bacteria), culture, and sensitivity.
v PK samples should be collected in patients with signs and symptoms of serious opportunistic infections or if the mean QTcF is 500 ms and/or 
60 ms longer than the baseline (Study Week 0) value, if not already scheduled to be collected at that timepoint.


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
102/ Protocol GA40209, Version 7
w ADA samples may be used to assess PK if needed.  ADA samples should be collected in patients with signs and symptoms of serious 
opportunistic infections or infusion-related reactions, if not already scheduled to be collected at that timepoint.  For patients receiving 
efmarodocokin alfa Q4W, ADA samples should be collected at treatment initiation (prior to dosing) and every 12 weeks thereafter.
x Stool samples should be obtained prior to bowel preparation.
y Patients with UC are to record stool frequency and rectal bleeding in the daily diary throughout the study (see Section 4.5.5.4).  Patients with CD 
are to record loose-stool frequency, abdominal pain severity, and general well-being in the daily diary throughout the study (see Section 4.5.5.4).
z Patients who do not meet criteria for clinical remission will receive efmarodocokin alfa 60 g/kg IV Q4W until clinical remission is achieved.
aa Video recordings should be taken of the entire endoscopic procedure, starting from insertion into the bowel.  Biopsies should be performed upon 
withdrawal of the endoscope from the bowel.  Technical instructions for video recording and biopsy collection are provided in the laboratory 
manual.
bb Patients will undergo annual colonoscopies for colon cancer surveillance.  The colonoscopies should include removal of any adenomatous polyps 
and performance of multiple random mucosal tissue samples (see Section 4.5.5.6).  This colonoscopy can substitute for the flexible sigmoidoscopy 
(for patients with UC) or be part of the ileocolonoscopy (for patients with CD) if the procedures are scheduled to occur during the same time period.
cc MCS is a composite of four assessments, each having a scoring range of 03:  stool frequency, rectal bleeding, endoscopy, and PGA.
dd pMCS is a composite of three assessments from the MCS, each having a scoring range of 03:  stool frequency, rectal bleeding, and PGA.
ee pMCS may be performed at an unscheduled visit as determined by the investigator or Sponsor.


Efmarodocokin Alfa—Genentech, Inc.
103/Protocol GA40209, Version 7
Appendix 2
Mayo Clinic Score
Please respond to the following questions after reviewing the patient's Signs and 
Symptoms of Ulcerative Colitis Daily Diary at each visit as per the schedule of activities.
1. Stool frequency 
0Normal
112 stools/day more than normal
234 stools/day more than normal
34 stools/day more than normal
2. Rectal bleeding
0None
1Visible blood with stool less than half the time
2Visible blood with stool half of the time or more
3Passing blood alone
3. Mucosal appearance at endoscopy
0Normal or inactive disease
1Mild disease (erythema, decreased vascular pattern)
2Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3Severe disease (spontaneous bleeding, ulceration)
4. Physician's Global Assessment
0Normal
1Mild
2Moderate
3Severe


Efmarodocokin Alfa—Genentech, Inc.
104/Protocol GA40209, Version 7
Appendix 3
Modified Mayo Clinic Score
Please respond to the following questions after reviewing the patient's Signs and 
Symptoms of Ulcerative Colitis Daily Diary at each visit as per the schedule of activities.
1. Stool frequency 
0Normal
112 stools/day more than normal
234 stools/day more than normal
34 stools/day more than normal
2. Rectal bleeding
0None
1Visible blood with stool less than half the time
2Visible blood with stool half of the time or more
3Passing blood alone
3. Mucosal appearance at endoscopy
0Normal or inactive disease
1Mild disease (erythema, decreased vascular pattern)
2Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3Severe disease (spontaneous bleeding, ulceration)


Efmarodocokin Alfa—Genentech, Inc.
105/Protocol GA40209, Version 7
Appendix 4
Partial Mayo Clinic Score
Please respond to the following questions after reviewing the patient's Signs and 
Symptoms of Ulcerative Colitis Daily Diary at each visit as per the schedule of activities.
1. Stool frequency
0Normal
112 stools/day more than normal
234 stools/day more than normal
34 stools/day more than normal
2. Rectal bleeding
0None
1Visible blood with stool less than half the time
2Visible blood with stool half of the time or more
3Passing blood alone
3. Physician's Global Assessment
0Normal
1Mild
2Moderate
3Severe


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106/Protocol GA40209, Version 7
Appendix 5
Signs and Symptoms in Ulcerative Colitis Daily Diary:  
Stool Frequency and Rectal Bleeding
Please respond to the following questions before you go to bed each evening.    
1. How many stools/bowel movements did you have today, compared to your 
normal number?
0Normal
112 stools/day more than normal
234 stools/day more than normal
34 stools/day more than normal
2. How much rectal bleeding did you experience today?
0None
1Visible blood with stool less than half the time
2Visible blood with stool half of the time or more
3Passing blood alone


Efmarodocokin Alfa—Genentech, Inc.
107/Protocol GA40209, Version 7
Appendix 6
Crohn's Disease Activity Index 
(Includes Patient-Reported Outcome-2 Score)
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or 
very soft stools
7-day total number of liquid or very soft 
stools (reported on the 7 days 
immediately prior to the study visit)
2
Abdominal pain
7-day total of daily abdominal pain scores 
on a 3-point scale: 0none, 1mild, 
2moderate, 3severe (reported on the 
7 days immediately prior to the study visit)
5
General well-being
7-day total of daily general well-being 
scores on a 4-point scale: 0 generally 
well, 1slightly under par, 2poor, 
3very poor, 4terrible (reported on the 
7 days immediately prior to the study visit)
7
Extra-intestinal 
manifestations of 
Crohn's disease
Total number of checked boxes (check all
that apply):
☐Arthritis/arthralgia
☐Iritis/uveitis
☐Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
☐Anal fissure, fistula, or abscess
☐Other fistula
☐Fever over 37.8°C during past week
20
Lomotil/Imodium/ 
opiates for diarrhea
Yes 1
No0
30
Abdominal mass
None0
Questionable2
Definite5
10
Hematocrit (%)a
Males: subtract value from 47
Females: subtract value from 42
6
Body weight b
[1(Body weight/Standard weight)] 100
1
Final score
Add totals:
a If hematocrit subtotal0, enter 0.
b If body weight subtotal10, enter 10.
Adapted from:  Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease 
activity index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70:43944.


Efmarodocokin Alfa—Genentech, Inc.
108/Protocol GA40209, Version 7
Appendix 7
Simple Endoscopic Score for Crohn's Disease
Table 1
Definitions of Simple Endoscopic Score for Crohn's Disease
Simple Endoscopic Score for Crohn's Disease Values
Variable
0
1
2
3
Size of ulcers
None
Aphthous ulcers
(Ø 0.1 to 0.5 cm)
Large ulcers 
(Ø 0.5 to 2 cm)
Very large ulcers 
(Ø2 cm)
Ulcerated 
surface
None
10%
10%30%
30%
Affected surface
Unaffected 
segment
50%
50%75%
75%
Presence of 
narrowings
None
Single, can be 
passed
Multiple, can be 
passed
Cannot be 
passed
Ødiameter.
Table 2
Example of SES-CD Scoring Form
Ileum
Right 
colon
Transverse 
colon
Left 
colon
Rectum
Total
Presence and size of ulcers (03)
Extent of ulcerated surface (03)
Extent of affected surface (03)
Presence and type of narrowings (03)
SES-CD =
Adapted from:  Daperno M, D’Haens G, Van Assche G, et al. Development and 
validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. 
Gastrointest Endosc 2004;60:50512.


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109/Protocol GA40209, Version 7
Appendix 8
Bristol Stool Form Scale


Efmarodocokin Alfa—Genentech, Inc.
110/Protocol GA40209, Version 7
Appendix 9
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the 
following procedures should be performed:
1.
Stop the study drug infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.