A Phase 1b, Randomized, Adaptive, Double-Blind, Placebo-Controlled, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of PT101 in Subjects With Active Ulcerative Colitis
Phase: PHASE1
Conditions: Ulcerative Colitis
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04924114 
Document Date: 
13-May-2022
A Phase 1b, Randomized, Adaptive, Double-Blind, Placebo-
Controlled, Multicenter Study to Investigate the Safety,
Tolerability, Pharmacokinetics, and Pharmacodynamics of
Multiple Doses of PT101 in Subjects with Active Ulcerative
Colitis

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 2 of 157
PROTOCOL SYNOPSIS
Protocol Number
PT101-201
Version
Amendment 8; 13-May-2022
Phase
Phase 1b
Product Name
PT101
Sponsor
Pandion Therapeutics, Inc., a wholly-owned 
subsidiary of Merck & Co., Inc., Rahway, NJ, USA 
(known as MSD outside the United States and 
Canada)
134 Coolidge Ave
Watertown, MA 02472
USA
Protocol Title
A Phase 1b, Randomized, Adaptive, Double-Blind, Placebo-Controlled, Multicenter Study to 
Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of PT101 in Subjects with Active Ulcerative Colitis
Study Objectives
Primary
●To evaluate the safety and tolerability of PT101 in subjects with active ulcerative colitis 
(UC) following multiple subcutaneous (SC) doses
Secondary
●To assess the pharmacokinetics (PK) of PT101 in subjects with UC following multiple SC 
doses
●To assess the pharmacodynamics (PD) of PT101 in subjects with UC following multiple 
SC doses
●To assess the immunogenicity of PT101 in subjects with UC following multiple SC doses
●To assess the PK/PD relationship of PT101 in subjects with UC following multiple SC 
doses
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 3 of 157
Exploratory
●To assess improvement in disease activity in subjects with UC following multiple SC doses 
of PT101
●To evaluate changes in PT101- and UC-associated biomarkers following multiple SC doses
of PT101
Study Endpoints
Primary
●Safety and tolerability as assessed by incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events (TESAEs), and changes in laboratory 
values, electrocardiograms (ECGs), physical exam findings, and vital signs through Week 
12
Secondary
●PK parameters of PT101 through Week 12
●PD parameters of PT101 through Week 12
●Anti-drug antibodies (ADA) to PT101 through Week 12
●The relationship between the PT101 PK and PD response
Exploratory
●Mean change from baseline in modified Mayo Score at Week 12
●Mean change from baseline in total Mayo Score at Week 12
●Mean change from baseline in partial Mayo Score at Weeks 2, 4, 6, 8, 10, and 12
●Mean change from baseline in Robarts Histopathology Index (RHI) score at Week 12
●Mean change from baseline in UC-100 score at Week 12
●Mean change from baseline in fecal calprotectin (FC) at Weeks 4 and 12
●Mean change from baseline in high sensitivity C-reactive protein (hs-CRP) levels at Weeks 
2, 4, 8, and 12 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 4 of 157
●Mean change from baseline in patient-reported outcome (PRO) measures at Week 12:
o
Inflammatory Bowel Disease Questionnaire (IBDQ)
o
Short Form-36 (SF-36)
●Proportion of subjects achieving clinical remission at Week 12
●Proportion of subjects achieving endoscopic improvement at Week 12
●Proportion of subjects achieving clinical response at Week 12
●Proportion of subjects achieving symptomatic remission at Weeks 2, 4, 6, 8, 10, and 12
●Proportion of subjects achieving symptomatic response at Weeks 2, 4, 6, 8, 10, and 12
●Proportion of subjects achieving endoscopic remission at Week 12
●Proportion of subjects achieving histologic remission at Week 12
●Proportion of subjects achieving histologic response at Week 12
●Proportion of subjects achieving mucosal healing at Week 12
●Change from baseline in partial Mayo Score beyond Week 12
●Incidence and characterization of TEAEs and laboratory abnormalities beyond Week 12
●Changes in PT101- and UC-associated biomarkers
Study Population
Inclusion Criteria
1. Male or female, 18 to 80 years of age, inclusive.
2. Diagnosis of UC at least 3 months prior to screening; diagnosis must be confirmed by 
endoscopy during the screening period. Source documentation of biopsy results (e.g., 
histopathology report) and endoscopic evidence consistent with the diagnosis of UC in the 
assessment of the Investigator is required.
3. Active UC as follows: subjects with mildly to severely active UC (i.e., 3-component 
modified Mayo Score of 4 to 9, with a rectal bleeding (RB) subscore of ≥ 1, stool frequency 
(SF) subscore of ≥ 1, and endoscopic subscore ≥1 excluding physician global assessment 
[PGA] subscore); and PGA score ≥ 1.
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 5 of 157
Note: The SF and RB Mayo subscores must be calculated based on the subject’s Mayo 
Score diary data recorded over the 3 consecutive days prior to the endoscopy (excluding 
the bowel preparation day; see Section 7.2.1 and Appendix 3).
4. Inadequate response, loss of response, or intolerance to at least 1 prior conventional 
therapy, and no more than 2 prior advanced therapies. 
●
Conventional Therapies
o
Oral 5-aminosalicylates
o
Rectal corticosteroids
o
Oral and/or intravenous (IV) corticosteroids
o
Oral thiopurines 
●
Advanced therapies:
o
Biologic therapy (e.g., anti-tumor necrosis factor-alpha (TNF-α), anti-integrin, anti-
interleukin therapies)
o
Janus kinase (JAK) inhibitors
o
Sphingosine-1-phosphate receptor 1 (S1P1) inhibitors 
5. Subjects at risk for colorectal cancer must have a colonoscopy prior to or at screening as 
follows: 
●
Subjects > 50 years of age must have documentation of a colonoscopy within 3 years 
of the screening visit to exclude adenomatous polyps. Subjects whose adenomas have 
been completely excised at screening are eligible.
●
Subjects with extensive colitis for ≥ 8 years, or disease limited to the left side of the 
colon for ≥10 years, must either have had a full colonoscopy to assess for the presence 
of dysplasia within 1 year before first administration of study drug or a full 
colonoscopy to assess for the presence of malignancy at the screening visit.
6. Meets the following tuberculosis (TB) screening criteria:
●
No evidence of active TB, latent TB, or inadequately treated TB as evidenced by 1 of 
the following:
o
Negative QuantiFERON test or equivalent assay reported by the central lab at 
screening or within 90 days prior to randomization date OR
o
History of fully treated active or latent TB according to local standard of care. 
Investigator must verify adequate previous anti-TB treatment and provide 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 6 of 157
documentation; these subjects do not require QuantiFERON testing and eligibility 
must be approved by the Sponsor or Medical Monitor prior to enrollment in the 
study.
7. Women of childbearing potential (WOCBP) and males with female partners of 
childbearing potential must utilize highly effective contraceptive methods beginning 4 
weeks prior to first dose of study drug and continue for 30 days after the last dose of study 
drug. 
8. Body mass index (BMI) 18 to 35 kg/m2 inclusive and weight ≥50 kg.
9. Willing and able to comply with this protocol and be available for the entire duration of 
the study.
Exclusion Criteria
1. Prior treatment with recombinant IL-2 or modified IL-2 therapy, including PT101.
2. Known sensitivity to PT101 or its excipients.
3. Known history of hypersensitivity to IL-2.
4. Disease limited to the rectum (i.e., within 15 cm of the anal verge).
5. Diagnosis of toxic megacolon.
6. Suspected or known colon stricture or stenosis.
7. Diagnosis of Crohn's disease, or indeterminant colitis.
8. Has severe colitis as evidenced by: 
●
Current hospitalization for the treatment of UC
●
Likely to require a colectomy within 12 weeks of Day 1 visit, according to the 
Investigator
●
Symptom complex at screening or Day 1 visit that includes at least 4 of the following:
o
Diarrhea with ≥ 6 bowel movements/day with macroscopic blood in stool
o
Focal severe or rebound abdominal tenderness
o
Persistent fever (≥ 37.5°C) for at least 3 consecutive days within 28 days prior to 
Day 1 dosing
o
Tachycardia (> 90 beats/minute)
08NYPB

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CCI
1<3%

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CCI
CCI
CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 14 of 157
Study drug interruption must occur in the following circumstances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree.

A nonserious infection (e.g., acute upper respiratory tract infection, simple urinary tract 
infection)

Positive urine pregnancy test (pending confirmation of pregnancy)

Subject is scheduled for elective or emergency surgery (excluding minor skin 
procedures under local or no anesthesia)
Study drug administration may be resumed only after resolution of the condition causing 
interruption and requires consultation with and approval by the medical monitor.
During the time of study drug interruption for any of the above, the subject may continue to 
have study visits and to take part in procedures and assessments if deemed medically 
appropriate by the investigator. Subjects with SARS-CoV 2 infection (or suspected infection) 
must follow local site-specific regulations and the PT101-201 COVID-19 Risk Management 
Plan regarding study visits and procedures.
Individual Stopping Rules
Dosing of study drug will be permanently discontinued in a subject if any of the following 
occurs:

Subject withdraws consent 

Severe worsening of UC disease activity defined as:
o
Requirement for hospitalization due to UC worsening; or
o
Partial Mayo Score increase of ≥ 3 points from baseline value to at least 5 points 
on 2 consecutive visits; or
o
An increase in partial Mayo Score to 9 points on 2 consecutive visits if the baseline
partial Mayo Score is > 6 
Disease worsening visits may include unscheduled visits.

Elevated absolute eosinophil count (AEC):
o
Severe eosinophilia defined as AEC > 5.0 giga/L confirmed on repeat measurement 
after at least 24 hours 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 15 of 157
o
Persistent moderate eosinophilia defined as AEC > 1.5 to < 5.0 giga/L confirmed 
on repeat measurement after at least 24 hours; recurring after 2 consecutive 
administrations of study drug
o
Any new elevation of AEC > upper limit of normal (ULN) confirmed on repeat 
measurement after at least 24 hours and associated with new onset of suspected 
eosinophil-related end organ injury (see below)
Eosinophil-Related Organ Injury
Manifestations of eosinophil-related organ injury may include but are not limited to the 
following:
o
Gastrointestinal: new onset eosinophilic esophagitis/gastritis
o
Hepatic: significant elevation in liver aminotransferases, liver fibrosis, hepatic 
impairment
o
Pulmonary: eosinophilic pneumonia or new onset or worsening of asthma
o
Cardiac: heart failure, dysrhythmia, intraluminal thrombus
o
Neurologic: peripheral neuropathy or cranial neuropathy
o
Cutaneous: cutaneous fibrosis
o
Renal: interstitial nephritis, eosinophiluria, impaired renal function

Potential drug-induced liver injury (DILI) defined by new onset of an elevated aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) laboratory value that is ≥ 
3X the ULN and an elevated total bilirubin laboratory value that is ≥ 2X the ULN and, 
at the same time, an alkaline phosphatase laboratory value < 2X the ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing
o
Subjects with potential DILI should stop further study drug administration and the 
Investigator should follow directions provided in the DILI Guidance Document 
(Appendix 7). 

Subjects with a marked prolongation of the QTc interval identified on ECG during the 
study (e.g., increase in QTc to > 500 ms, or > 60 ms over baseline, Appendix 8)

New onset of clinically significant cardiovascular disease such as myocardial 
infarction, unstable ischemic heart disease, stroke, heart failure, or clinically significant 
changes in ECG
08NYPB

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CCI
CCI
CCI
1<3%

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CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 19 of 157
TABLE OF CONTENTS
PROTOCOL SYNOPSIS.............................................................................................................2
TABLE OF CONTENTS ...........................................................................................................19
LIST OF TABLES .....................................................................................................................23
LIST OF FIGURES....................................................................................................................23
LIST OF APPENDICES ............................................................................................................24
ABBREVIATIONS....................................................................................................................25
1
INTRODUCTION ........................................................................................................28
1.1
Ulcerative Colitis ..........................................................................................................28
1.2
Current Treatment Options for Patients with Ulcerative Colitis...................................28
1.3
PT101............................................................................................................................29
1.4
Rationale for Current Study ..........................................................................................30
2
OBJECTIVES AND ENDPOINTS ..............................................................................30
2.1
Objectives......................................................................................................................31
2.1.1
Primary Objective............................................................................................31
2.1.2
Secondary Objectives ......................................................................................31
2.1.3
Exploratory Objectives....................................................................................31
2.2
Endpoints ......................................................................................................................31
2.2.1
Primary Endpoint.............................................................................................31
2.2.2
Secondary Endpoints.......................................................................................31
2.2.3
Exploratory Endpoints.....................................................................................32
3
INVESTIGATIONAL PLAN.......................................................................................33
3.1
Summary of Study Design ............................................................................................33
3.1.1
Initial Blinded Treatment Phase ......................................................................34
3.1.1.1
Planned Cohorts (Cohorts 1–3) ................................................................34
3.1.1.2
Optional Cohorts (Cohorts 4–6) ...............................................................35
3.1.1.3
Dose-Limiting Toxicity............................................................................35
3.1.1.4
Cohort Progression Criteria......................................................................35
3.1.1.5
In-Cohort Stopping Rules.........................................................................35
3.1.2
Continued Blinded Treatment and Open-Label Phases...................................36
3.1.3
Study Periods...................................................................................................36
3.1.4
Early Termination or Unscheduled Visit.........................................................37
3.1.5
Dose Modification and Dose Schedule Deviation...........................................37
3.1.6
Study Drug Interruption Considerations..........................................................37
3.1.7
Individual Stopping Rules ...............................................................................38
3.2
Discussion and Rationale for Study Design..................................................................40
3.2.1
Method of Assigning Patients to Treatment Groups .......................................40
3.2.2
Rationale for Selection of Doses .....................................................................40
3.2.3
Randomization and Blinding...........................................................................42
3.2.4
Risk-Benefit Profile.........................................................................................43
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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 20 of 157
4
STUDY POPULATION ...............................................................................................43
4.1
Inclusion Criteria...........................................................................................................43
4.2
Exclusion Criteria .........................................................................................................45
4.3
Lifestyle Considerations................................................................................................48
4.3.1
Activity Restrictions........................................................................................48
4.4
Childbearing Potential...................................................................................................48
4.5
Removal of Patients from Therapy or Assessment.......................................................48
4.5.1
Discontinuation of Study Treatment................................................................48
4.5.2
Subject Withdrawal From Study .....................................................................49
4.6
Subject Replacement Strategy.......................................................................................49
5
TREATMENTS ............................................................................................................49
5.1
Investigational Study Drug ...........................................................................................49
5.1.1
Description ......................................................................................................49
5.1.2
Dose and Administration.................................................................................50
5.1.3
Storage and Handling ......................................................................................50
5.1.4
Packaging and Labeling...................................................................................50
5.1.5
Preparation.......................................................................................................50
5.2
Concomitant Therapy....................................................................................................51
5.2.1
Vaccine Guidelines..........................................................................................51
5.2.2
Prohibited Concomitant Therapy.....................................................................51
5.2.3
Allowed Concomitant Therapy .......................................................................53
5.2.3.1
Corticosteroid Tapering............................................................................53
5.3
Rescue Medications and Supportive Care.....................................................................53
5.4
Treatment Compliance..................................................................................................53
6
STUDY ACTIVITIES ..................................................................................................54
6.1
Schedule of Events........................................................................................................54
6.2
Screening Visit..............................................................................................................54
6.2.1
Screen Failure..................................................................................................54
6.2.2
Rescreening of Subjects...................................................................................54
6.3
Initial Blinded Treatment Phase....................................................................................55
6.3.1
Treatment Administration Visits .....................................................................55
6.3.2
Post-Dose Assessment Visits...........................................................................55
6.3.3
Early Termination Visit...................................................................................55
6.3.4
End of Study Visit ...........................................................................................55
6.4
Continued Blinded Treatment and Open Label Phases.................................................56
6.4.1
Continued Blinded Treatment Phase...............................................................56
6.4.2
Open-Label Phase............................................................................................56
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol Parameters
................................................................................................................................56
7
STUDY ASSESSMENTS.............................................................................................57
7.1
Screening/Baseline Assessments ..................................................................................57
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Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
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7.2
Response/Efficacy Assessments ...................................................................................57
7.2.1
Mayo Score......................................................................................................57
7.2.1.1
eDiary Instructions and Review ...............................................................58
7.2.1.2
Endoscopy ................................................................................................58
7.2.2
Modified Mayo Score and Partial Mayo Score ...............................................59
7.2.3
Geboes Score and Robarts Histopathology Index ...........................................60
7.2.3.1
Geboes Score............................................................................................60
7.2.3.2
Robarts Histopathology Index..................................................................60
7.3
Patient-Reported Outcomes and Quality of Life Measures...........................................61
7.3.1
Inflammatory Bowel Disease Questionnaire...................................................61
7.3.2
Short Form-36 .................................................................................................62
7.4
Pharmacokinetic and Immunogenicity Assessments ....................................................62
7.5
Pharmacodynamics and Biomarker Assessments .........................................................62
7.5.1
Pharmacodynamic Assessments......................................................................62
7.5.2
Biomarker Assessments...................................................................................62
7.5.2.1
Future Research........................................................................................63
7.5.2.2
Genetic Analysis.......................................................................................63
7.6
Safety Assessments.......................................................................................................63
7.6.1
Adverse Events................................................................................................63
7.6.1.1
Definitions................................................................................................63
7.6.1.2
Procedures for Eliciting and Recording Adverse Events .........................67
7.6.1.3
Reporting Periods for Adverse Events and Serious Adverse Events........69
7.6.1.4
Serious Adverse Events Require Immediate Reporting ...........................69
7.6.1.5
Sponsor Safety Reporting to Regulatory Authorities...............................70
7.6.1.6
Events of Clinical  Interest .......................................................................70
7.6.1.7
Definition and Treatment of Overdose.....................................................71
7.6.2
Clinical Laboratory Tests ................................................................................71
7.6.3
Stool Sample for Enteric Pathogens Detection................................................72
7.6.4
HBV, HCV, HIV and TB Testing ...................................................................72
7.6.5
12-lead Electrocardiogram ..............................................................................72
7.6.6
Vital Signs .......................................................................................................73
7.6.7
Physical Examination......................................................................................74
7.6.8
Pregnancy Testing ...........................................................................................74
7.7
Appropriateness of Measurements................................................................................74
8
DATA QUALITY CONTROL AND QUALITY ASSURANCE................................75
8.1
Site Training and Monitoring Procedures.....................................................................75
8.2
Data Management Procedures.......................................................................................76
8.3
Access to Source Data...................................................................................................76
8.4
Accuracy and Reliability of Data..................................................................................76
8.5
Quality Assurance Procedures ......................................................................................76
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 22 of 157
8.6
Data Handling and Record Keeping .............................................................................77
8.6.1
Data Handling..................................................................................................77
8.6.2
Investigator Record Retention.........................................................................77
9
DATA ANALYSIS METHODS...................................................................................77
9.1
Determination of Sample Size ......................................................................................77
9.2
Study Endpoint Definitions...........................................................................................78
9.3
Statistical and Analytical Plans.....................................................................................78
9.3.1
General Considerations....................................................................................78
9.3.1.1
Subject Disposition...................................................................................78
9.3.1.2
Subject Characteristics .............................................................................78
9.3.1.3
Protocol Deviations ..................................................................................78
9.3.1.4
Prior and Concomitant Therapy ...............................................................78
9.3.1.5
Randomization and Blinding....................................................................79
9.3.1.6
Adjustments for Covariates ......................................................................79
9.3.1.7
Handling of Dropouts and Missing Data..................................................79
9.3.1.8
Multiple Comparisons and Multiplicity ...................................................79
9.3.1.9
Data Transformations and Derivations.....................................................79
9.3.2
Analysis Sets ...................................................................................................79
9.3.2.1
Intent-to-Treat Analysis Set......................................................................79
9.3.2.2
Full Analysis Set.......................................................................................79
9.3.2.3
Per Protocol Analysis Set.........................................................................80
9.3.2.4
Safety Analysis Set...................................................................................80
9.3.3
Examination of Subgroups ..............................................................................80
9.3.4
Safety and Efficacy Analyses..........................................................................80
9.3.5
Exploratory Efficacy Analyses........................................................................82
9.3.6
Pharmacokinetic and Immunogenicity Analyses.............................................82
9.3.6.1
Pharmacokinetic Analyses........................................................................82
9.3.6.2
Biomarker Analyses .................................................................................82
9.3.7
Safety Analyses ...............................................................................................82
9.3.7.1
Extent of Exposure ...................................................................................82
9.3.7.2
Adverse Events.........................................................................................82
9.3.7.3
Deaths and Serious Adverse Events.........................................................83
9.3.7.4
Clinical Laboratory Results......................................................................83
9.3.7.5
Other Safety Analyses..............................................................................83
10
INFORMED 
CONSENT, 
ETHICAL 
REVIEW, 
AND 
REGULATORY 
CONSIDERATIONS..............................................................................................83
10.1
Informed Consent..........................................................................................................83
10.2
Ethical Review..............................................................................................................84
10.3
Regulatory Considerations............................................................................................84
10.3.1
Investigator Information..................................................................................85
10.3.2
Protocol Amendments and Study Termination................................................85
08NYPB

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CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 24 of 157
LIST OF APPENDICES
Appendix 1:
Schedule of Events ..........................................................................................89
Appendix 2:
Guidance on Contraception ...........................................................................100
Appendix 3:
Mayo Scoring System....................................................................................101
Appendix 4:
Original Geboes Scoring System...................................................................103
Appendix 5:
Robarts Histopathology Index.......................................................................105
Appendix 6:
Composite UC-100........................................................................................106
Appendix 7:
Drug-Induced Liver Injury Guidance Document ..........................................107
Appendix 8: 
12-Lead Electrocardiogram Abnormality Criteria.........................................116
Appendix 9: 
Sponsor Signature Page.................................................................................119
Appendix 10:
Investigator Signature Page...........................................................................120
Appendix 11:
Document History .........................................................................................121
Appendix 12: 
SUMMARY OF CHANGES.........................................................................122
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 25 of 157
ABBREVIATIONS
Abbreviation
Definition
6-MP
6-mercaptopurine
ADA
anti-drug antibody
ADL
activities of daily living
AE
adverse event
AEC
absolute eosinophil count
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-inf
area under the curve from time 0 to infinity
AUC0-t
area under the curve from time 0 to time t
AZA
azathioprine
BCG
bacille Calmette-Guerin
β-hCG
beta human chorionic gonadotropin 
BLRM
Bayesian Logistic Regression Model
BMI
body mass index
BP
blood pressure
Cmax
maximum concentration
Cmin
minimum concentration (trough)
CBC
complete blood count
CBT
continued blinded treatment
CL/F
apparent clearance
CMH
Cochran–Mantel–Haenszel test
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DRC
data review committee
ECI
events of clinical interest
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOS
end of study
ET
early termination
EWOC
Escalation With Overdose Control
FAS
full analysis set
Fc
fragment crystallizable
FC
fecal calprotectin
GDPR
General Data Protection Regulation
GLP
Good Laboratory Practice
HBV
hepatitis B virus
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 26 of 157
Abbreviation
Definition
HBVcAb
HBV core antibody
HBVsAg
HBV surface antigen
HCV
hepatitis C virus
HCP
health care professional
HIV
human immunodeficiency virus
hs-CRP
high sensitivity C-reactive protein
HR
heart rate
HV
Healthy volunteer 
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBT
initial blinded treatment
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Council for Harmonisation 
IEC
independent ethics committee
IgG1
immunoglobulin G1
IL-2
interleukin-2
IL-2M
interleukin-2 mutein
IL-2R
interleukin-2 receptor
IL-2Rα
interleukin-2 receptor alpha (also known as CD25)
IL-2Rβ
interleukin-2 receptor beta (also known as CD122)
IL-2Rγ
interleukin-2 receptor gamma (also known as CD132)
IND
investigational new drug
INR
International Normalized Ratio
IPT
immunophenotyping
IRB
institutional review board
ITT
intent-to-treat
IWRS
interactive web response system
JAK
Janus kinase
LAIV
live attenuated influenza vaccine
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMR
measles, mumps, and rubella
MMRM
mixed-model-repeated measure
MMRV
measles, mumps, and rubella plus varicella
MTD
maximum tolerated dose 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no observed adverse effect level 
OL
open-label
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamics
PGA
physician global assessment
PK
pharmacokinetics
08NYPB

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 28 of 157
1
INTRODUCTION
1.1
Ulcerative Colitis
Ulcerative colitis (UC) is a chronic inflammatory disease of the rectal and colonic mucosa that 
is characterized by periods of remission and relapse. UC often first appears during young 
adulthood, and typically presents with blood in the stool and diarrhea. Additional symptoms 
vary depending on the severity of inflammation and extent of disease and can include
incontinence, increased frequency of bowel movements, mucus discharge, and abdominal 
discomfort. Up to 15% of patients initially present with severe disease, which is often
associated with systemic symptoms, including fever, weight loss, and malaise. Furthermore, 
UC is associated with an increased risk of colorectal cancer (Ungaro, 2017). With poorly 
controlled disease, the risk of developing colorectal cancer increases with time (Jess, 2012).
The pathogenesis of UC is multifactorial, involving genetic predisposition, epithelial barrier 
defects, dysregulated immune responses, and environmental factors (Chang, 2020). Although 
the precise cause of UC is unknown, genetically susceptible individuals appear to have a 
dysregulated mucosal immune response to commensal gut flora and studies show that the 
homeostatic balance between regulatory T cells (Tregs) and effector T cells is disturbed in the 
colonic mucosa of patients with UC (Ordás, 2012; Ungaro, 2017). 
The incidence and prevalence of UC have been increasing worldwide. In a systematic review 
of population-based studies, the highest reported prevalence values were reported in Europe 
and North America. In Europe, the incidence and prevalence ranged from approximately 
1-58 per 100,000 person years and 2.4–505 per 100,000 person years, respectively and in North 
America, the incidence and prevalence ranged from 8.8–23.1 per 100,000 person years and 
139.8–286.3 per 100,000 person years, respectively. Since the end of the 20th century, the 
incidence of both Crohn’s disease and UC have also been increasing in newly industrialized 
countries in Africa, Asia, and South America (Ng, 2018). 
1.2
Current Treatment Options for Patients with Ulcerative Colitis
While several treatment options are available and in development for the treatment of UC, 
there are currently no curative therapies. Goals of treatment include improved quality of life, 
reduction in long-term corticosteroid use, and minimization of cancer risk. Treatment of UC is 
dependent on the severity and the location of disease. Mild to moderate UC treatment may be 
treated with oral aminosalicylates, topical mesalamine, or topical steroids. For moderately 
active disease, oral corticosteroids and immunomodulators such as azathioprine (AZA) and 
6-mercaptopurine (6-MP) may be utilized (Danese and Fiocchi, 2011). For more severe 
disease, tumor necrosis factor-alpha (TNF-α) antagonists such as infliximab (Remicade®), 
adalimumab (Humira®), and golimumab (Simponi®), or an α4β7 integrin antagonist such as 
vedolizumab (Entyvio®) are often employed. Tofacitinib (Xeljanz®), an oral Janus kinase 
(JAK) inhibitor is also approved for the treatment of adult patients with moderately to severely 
active disease (Harbord, 2017). Although these agents may be effective in inducing disease 
remission, many are associated with toxicities. The use of 6-MP and AZA can result in 
neutropenia, pancytopenia, pancreatitis, nephrotoxicity, hepatotoxicity, and in rare cases, 
hepatosplenic T-cell lymphoma (Bousvaros, 2010; Carter, 2004; Chaparro, 2009; Turner and 
08NYPB

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 31 of 157
2.1
Objectives
2.1.1
Primary Objective
●
To evaluate the safety and tolerability of PT101 in subjects with active UC following 
multiple SC doses
2.1.2
Secondary Objectives
●
To assess the PK of PT101 in subjects with UC following multiple SC doses 
●
To assess the PD of PT101 in subjects with UC following multiple SC doses 
●
To assess the immunogenicity of PT101 in subjects with UC following multiple SC 
doses 
●
To assess the PK/PD relationship of PT101 in subjects with UC following multiple SC 
doses
2.1.3
Exploratory Objectives
●
To assess improvement in disease activity in subjects with UC following multiple SC 
doses of PT101
●
To evaluate changes in PT101- and UC-associated biomarkers following multiple SC 
doses of PT101
2.2
Endpoints
2.2.1
Primary Endpoint
●
Safety and tolerability as assessed by incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events (TESAEs), and changes in 
laboratory values, electrocardiograms (ECGs), physical exam findings, and vital signs
through Week 12
2.2.2
Secondary Endpoints
●
PK parameters of PT101 through Week 12
●
PD parameters of PT101 through Week 12
●
Anti-drug antibodies (ADA) to PT101 through Week 12
●
The relationship between the PT101 PK and PD response 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 32 of 157
2.2.3
Exploratory Endpoints
●
Mean change from baseline in modified Mayo Score at Week 12
●
Mean change from baseline in total Mayo Score at Week 12
●
Mean change from baseline in partial Mayo Score at Weeks 2, 4, 6, 8, 10, and 12
●
Mean change from baseline in Robarts Histopathology Index (RHI) score at Week 12
●
Mean change from baseline in UC-100 score at Week 12
●
Mean change from baseline in fecal calprotectin (FC) at Weeks 4 and 12
●
Mean change from baseline in high sensitivity C-reactive protein (hs-CRP) levels at 
Weeks 2, 4, 8, and 12 
●
Mean change from baseline in patient-reported outcome (PRO) measures at Week 12
o
Inflammatory Bowel Disease Questionnaire (IBDQ)
o
Short Form-36 (SF-36)
●
Proportion of subjects achieving clinical remission at Week 12 
●
Proportion of subjects achieving endoscopic improvement at Week 12 
●
Proportion of subjects achieving clinical response at Week 12
●
Proportion of subjects achieving symptomatic remission at Weeks 2, 4, 6, 8, 10, and 12
●
Proportion of subjects achieving symptomatic response at Weeks 2, 4, 6, 8, 10, and 12
●
Proportion of subjects achieving endoscopic remission at Week 12 
●
Proportion of subjects achieving histologic remission at Week 12 
●
Proportion of subjects achieving histologic response at Week 12
●
Proportion of subjects achieving mucosal healing at Week 12
●
Change from baseline in partial Mayo Score beyond Week 12
●
Incidence and characterization of TEAEs and laboratory abnormalities beyond 
Week 12
●
Changes in PT101- and UC-associated biomarkers 
08NYPB

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 36 of 157
termination of dosing within the cohort; DRC may also recommend de-escalation to lower 
doses/reduced frequency dosing regimen. If dosing within a cohort is terminated, the next-
lower dose may be declared the maximum tolerated dose (MTD). Alternatively, an additional 
cohort at an intermediate dose may be added to better define the MTD.
The study may be stopped at the discretion of the Sponsor based on recommendations of the 
DRC. In all cases, necessary measures will be taken to ensure appropriate safety follow-up for 
all subjects in the trial.
3.1.2
Continued Blinded Treatment and Open-Label Phases
Subjects who have achieved clinical response (based on the modified Mayo Score using the 
endoscopic score derived by the Investigator) at Week 12 will be eligible to enter the continued 
blinded treatment (CBT) phase of the study. Subjects in the CBT phase will receive the same 
treatment allocation (PT101 or placebo) as received during the IBT phase; subjects who
received PT101 will continue receiving PT101 at the same dose/regimen. Corticosteroid 
tapering will be initiated at Week 12 of the IBT phase for subjects entering the CBT phase.
Subjects who do not achieve clinical response at Week 12 will have the option to enter an
open-label (OL) phase of the study. Subjects in the OL phase will receive PT101 at the same 
dose/regimen as received by subjects in their cohort during the IBT phase. Subjects 
participating in the OL phase who achieve a clinical response using the partial Mayo Score at 
Week 24 of the OL phase will also undergo corticosteroid tapering. Subjects who do not 
achieve a clinical response using the partial Mayo Score at Week 24 of the OL phase may 
continue on open-label treatment if it is considered in the best interest of the subject at the 
discretion of the Investigator.
Subjects with insufficient data to assess clinical response at Week 12 of IBT will not be eligible 
to enter the CBT or OL phases and will be discontinued from the study.
For subjects not entering the CBT or OL phases, the site will conduct a follow-up phone call 
approximately 48 hours after the Day 85 visit to confirm no adverse events related to study 
procedures had occurred.
Participation in the CBT and OL is for a maximum of 9 months. 
The clinic will perform a follow-up call approximately 90 days after the last dose of study drug 
for all subjects in the trial (those who complete IBT only or enter the CBT or OL phase) to 
assess any changes in UC disease status.
3.1.3
Study Periods
The study will be conducted as follows:

Screening Period: will begin when the informed consent form (ICF) is signed. During 
this period, a subject will undergo baseline assessments to determine eligibility for 
study participation. Endoscopy (flexible sigmoidoscopy or colonoscopy as indicated) 
08NYPB

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 38 of 157

Subject is scheduled for elective or emergency surgery (excluding minor skin 
procedures under local or no anesthesia)
Study drug administration may be resumed only after resolution of the condition causing 
interruption, and requires consultation with and approval by the medical monitor.
During the time of study drug interruption for any of the above, the subject may continue to 
have study visits and to take part in procedures and assessments if deemed medically 
appropriate by the investigator. Subjects with SARS-CoV 2 infection (or suspected infection) 
must follow local site specific regulations and the PT101-201 COVID-19 Risk Management 
Plan regarding study visits and procedures.
3.1.7
Individual Stopping Rules
Dosing of study drug will be permanently discontinued in a subject if any of the following 
occurs:

Subject withdraws consent 

Severe worsening of UC disease activity defined as:
o
Requirement for hospitalization due to UC worsening; or
o
Partial Mayo Score increase of ≥ 3 points from baseline value to at least 5 points 
on 2 consecutive visits; or
o
An increase in partial Mayo Score to 9 points on 2 consecutive visits if the baseline
partial Mayo Score is > 6 
Disease worsening visits may include unscheduled visits.

Elevated absolute eosinophil count (AEC):
o
Severe eosinophilia defined as AEC > 5.0 giga/L confirmed on repeat measurement 
after at least 24 hours 
o
Persistent moderate eosinophilia defined as AEC > 1.5 to < 5.0 giga/L confirmed 
on repeat measurement after at least 24 hours; recurring after 2 consecutive 
administrations of study drug
o
Any new elevation of AEC > upper limit of normal (ULN) confirmed on repeat 
measurement after at least 24 hours and associated with new onset of suspected 
eosinophil-related end organ injury (see below) 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 39 of 157
Eosinophil-Related Organ Injury
Manifestations of eosinophil-related organ injury may include but are not limited to the 
following:
o
Gastrointestinal: new onset eosinophilic esophagitis/gastritis
o
Hepatic: significant elevation in liver aminotransferases, liver fibrosis, hepatic 
impairment
o
Pulmonary: eosinophilic pneumonia or new onset or worsening of asthma
o
Cardiac: heart failure, dysrhythmia, intraluminal thrombus
o
Neurologic: peripheral neuropathy or cranial neuropathy
o
Cutaneous: cutaneous fibrosis
o
Renal: interstitial nephritis, eosinophiluria, impaired renal function

Potential drug-induced liver injury (DILI) defined by new onset of an elevated aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) laboratory value that is ≥ 
3X the ULN and an elevated total bilirubin laboratory value that is ≥ 2X the ULN and, 
at the same time, an alkaline phosphatase laboratory value < 2X the ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing
o
Subjects with potential DILI should stop further study drug administration and the 
Investigator should follow directions provided in the DILI Guidance Document 
(Appendix 7). 

New onset of clinically significant cardiovascular disease such as myocardial 
infarction, unstable ischemic heart disease, stroke, heart failure, or clinically significant 
changes in ECG

Subjects with a marked prolongation of the QTc interval identified on ECG during the 
study (e.g., increase in QTc to > 500 ms, or > 60 ms over baseline, Appendix 8)

New onset of pulmonary edema, interstitial lung disease, or clinically significant 
dyspnea

New onset of clinically significant peripheral edema or reduced blood pressure (semi 
recumbent [supine or seated also acceptable, per site standard procedures]) SBP < 90 
mmHg associated with symptoms such as lightheadedness, sustained over at least the 
next 90 minutes):
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 40 of 157
o
SBP (supine or seated also acceptable) will be obtained as triplicate 
measurements every 30 minutes over the following 90 minutes (i.e. at 30, 60-
and 90 minutes). If a subject’s SBP remains < 90 mmHg for the median of all 
3 measurements over the 90 minute period, this is defined as a sustained finding, 
and dosing will end for that particular subject.

Reduction of estimated glomerular filtration rate (eGFR) < 60 mL/min confirmed on 
repeat measurement after at least 24 hours

Serious infection requiring hospitalization or intravenous antibiotics

Investigator or Sponsor determines that the subject will not benefit from further study 
drug

Adverse event or laboratory or physical examination finding that in the opinion of the 
Investigator or Sponsor presents excessive risk to the subject

Adverse event of Grade 3 or higher in severity that is attributable to study drug, or any 
unexplained ≥Grade 3 AE that is not reasonably related to the underlying disease 
process

Subject becomes pregnant or plans a pregnancy within the study conduct

Subject is unable to comply with the protocol requirements

Sponsor or Regulatory Agency terminates the study
3.2
Discussion and Rationale for Study Design
This study is a double-blind, randomized, placebo-controlled trial. 
The efficacy endpoints utilize subject-reported and physician-reported components of the 
Mayo Score; therefore, the use of a double-blind, randomized design will minimize bias that 
could be introduced by subject or Investigator knowledge of the treatment assignment. As UC 
has a relapsing and remitting course, the use of a placebo comparator will ensure that a true 
treatment effect is being assessed.
3.2.1
Method of Assigning Patients to Treatment Groups
Centralized registration and treatment assignment for eligible subjects will be completed using 
an interactive web response system (IWRS).
3.2.2
Rationale for Selection of Doses
Study PT101-201 will represent the initial multiple-dose regimen of PT101 in patients with 
UC to determine an improved benefit-risk profile for the proposed study duration of 12 weeks
08NYPB

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MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 43 of 157
to facilitate planning for subsequent dosing cohorts. All unblinded personnel will be fire-
walled from the operational study team at the Sponsor and CRO to prevent inadvertent 
unblinding of treatment assignment and to minimize the risk of introducing bias into the study 
results. Designation of unblinded study personnel will be authorized by the Sponsor’s Chief 
Medical Officer and the lead study biostatistician. A roster of unblinded personnel will be 
maintained in the TMF. All unblinded personnel will be trained in steps necessary to maintain 
an adequate firewall. 
3.2.4
Risk-Benefit Profile
Although a number of therapeutic options are available for patients with UC, existing agents 
are limited by low efficacy and/or toxicities. Moderately to severely active UC remains a 
serious, life-threatening disease for which new therapies are needed. PT101 is an IL-2M that 
selectively activates Tregs over other cell types and may therefore represent a unique 
opportunity to rebalance the immune system in patients with UC.
Adverse events associated with PT101 in cynomolgus monkey studies and the Phase 1a SAD 
study are detailed in the Investigator Brochure. Overall, on the basis of the available 
nonclinical and clinical data the risk-benefit profile of PT101 is judged acceptable for the 
proposed clinical study. The information obtained in this study will be used for the further 
clinical development of PT101.
Sites will adhere to COVID-19 rules and regulations as mandated by local authorities. Trial 
subject safety and data validity will be prioritized. In case of conflict, safety will be given 
priority. Further information can be found in the PT101-201 COVID-19 Risk Management 
Plan.
4
STUDY POPULATION
Subjects must meet all of the inclusion and none of the exclusion criteria to be eligible for this 
study. Eligibility criteria may not be waived by the investigator.
4.1
Inclusion Criteria
1. Male or female, 18 to 80 years of age, inclusive.
2. Diagnosis of UC at least 3 months prior to screening; diagnosis must be confirmed by 
endoscopy during the screening period. Source documentation of biopsy results (e.g., 
histopathology report) and endoscopic evidence consistent with the diagnosis of UC in the 
assessment of the Investigator is required.
3. Active UC as follows: subjects with mildly to severely active UC (i.e., 3-component 
modified Mayo Score of 4 to 9, with a rectal bleeding subscore of ≥ 1, stool frequency 
subscore of ≥ 1, and endoscopic subscore ≥ 1 excluding physician global assessment [PGA]
subscore) and PGA score ≥ 1.
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 44 of 157
Note: The stool frequency (SF) and rectal bleeding (RB) Mayo subscores must be 
calculated based on the subject’s Mayo Score diary data recorded over the 3 consecutive 
days prior to the endoscopy (excluding the bowel preparation day; see Section 7.2.1 and 
Appendix 3).
4. Inadequate response, loss of response, or intolerance to at least 1 prior conventional 
therapy, and no more than 2 prior advanced therapies.
●Conventional Therapies
o
Oral 5-aminosalicylates
o
Rectal corticosteroids
o
Oral and/or intravenous (IV) corticosteroids
o
Oral thiopurines
●Advanced therapies:
o
Biologic therapy (e.g., anti- tumor necrosis factor-alpha (TNF-α), anti-integrin, 
anti-interleukin therapies)
o
Janus kinase (JAK) inhibitors
o
Sphingosine-1-phosphate receptor 1 (S1P1) inhibitors 
5. Subjects at risk for colorectal cancer must have a colonoscopy prior to or at screening as 
follows: 
●Subjects > 50 years of age must have documentation of a colonoscopy within 3 years 
of the screening visit to exclude adenomatous polyps. Subjects whose adenomas have 
been completely excised at screening are eligible.
●Subjects with extensive colitis for ≥ 8 years, or disease limited to the left side of the 
colon for ≥10 years, must either have had a full colonoscopy to assess for the presence 
of dysplasia within 1 year before first administration of study drug or a full 
colonoscopy to assess for the presence of malignancy at the screening visit. 
6. Meets the following tuberculosis (TB) screening criteria:
●No evidence of active TB, latent TB, or inadequately treated TB as evidenced by 1 of 
the following:
o
Negative QuantiFERON test or equivalent assay reported by the central lab at 
screening or within 90 days prior to randomization date, OR
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 45 of 157
o
History of fully treated active or latent TB according to local standard of care. 
Investigator must verify adequate previous anti-TB treatment and provide 
documentation; these subjects do not require QuantiFERON testing, and 
eligibility must be approved by the Sponsor or Medical Monitor prior to 
enrollment in the study.
7. Women of childbearing potential (WOCBP) and males with female partners of 
childbearing potential must utilize highly effective contraceptive methods beginning 
4 weeks prior to first dose of study drug and continue for 30 days after the last dose of 
study drug (see Appendix 2 for details). 
8. Body mass index (BMI) 18 to 35 kg/m2 inclusive and weight ≥50 kg.
9. Willing and able to comply with this protocol and be available for the entire duration of 
the study.
4.2
Exclusion Criteria
1. Prior treatment with recombinant IL-2 or modified IL-2 therapy, including PT101.
2. Known sensitivity to PT101 or its excipients.
3. Known history of hypersensitivity to IL-2.
4. Disease limited to the rectum (i.e., within 15 cm of the anal verge).
5. Diagnosis of toxic megacolon.
6. Suspected or known colon stricture or stenosis.
7. Diagnosis of Crohn’s disease, or indeterminant colitis.
8. Has severe colitis as evidenced by: 
●Current hospitalization for the treatment of UC
●Likely to require a colectomy within 12 weeks of Day 1 visit, in the opinion of the 
Investigator
●Symptom complex at screening or Day 1 visit that includes at least 4 of the following:
o
Diarrhea with ≥ 6 bowel movements/day with macroscopic blood in stool
o
Focal severe or rebound abdominal tenderness
o
Persistent fever (≥ 37.5°C) for at least 3 consecutive days within 28 days prior 
to Day 1 dosing
08NYPB

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!!' D$G/N
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($($$$9')'%"(B#"("$()
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#)"GBG/'
:6-
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:6-6+
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$("$($)#( ",
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4 / ) 
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CCI
1<3%

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/)$',4,$$*TC$*T0)$
CCI
CCI
1<3%

	
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>6+6-
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CCI
CCI
CCI
CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 51 of 157
5.2
Concomitant Therapy
All concomitant medications administered will be recorded from randomization through the 
safety reporting period. Any concomitant medication given for AEs that are the result of a 
study protocol-specified intervention should be recorded from the time of informed consent.
5.2.1
Vaccine Guidelines
Prior to study participation, it is recommended that the subject’s vaccinations be brought up to 
date according to local vaccination standards.
Inactivated vaccines (such as inactivated influenza vaccines) should be administered according 
to local vaccination standards whenever medically appropriate; however, there are no available 
data on the concurrent use of PT101 and its impact on immune responses following 
vaccination.
Live or attenuated vaccines (including, but not limited to varicella, measles, mumps, and 
rubella [MMR], MMR plus varicella [MMRV], live attenuated influenza vaccine [LAIV], 
yellow fever, Ty21a oral typhoid, bacille Calmette-Guerin [BCG], smallpox, and rotavirus) are 
prohibited within 4 weeks of screening, throughout the study, and for 12 weeks after the last 
dose of study drug.
Regarding precautions related to the vaccination of household or close contacts, subjects 
participating in this study are recommended to follow country-specific guidelines or those of 
the 
US 
Centers 
for 
Disease 
Control 
regarding 
contacts 
as 
appropriate 
(https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html).
In 
general, household contacts and other close contacts of subjects in this trial may receive all 
age- and exposure-appropriate vaccines.
5.2.2
Prohibited Concomitant Therapy
Some medications and treatments may have an impact on the safety of the subjects and/or 
efficacy assessments of this study. Prohibited concomitant medications that may impact 
efficacy assessments or impact subject safety are presented in Table 1. Subjects who initiate 
any of these concomitant medications at any time during the IBT phase of the study must be
discontinued from study drug and will not be eligible for the OL or CBT phase of the study. 
Subjects who initiate any of these concomitant medications at any time during the OL or CBT 
phase of the study must be discontinued from study drug.
Medications or vaccinations specifically prohibited in the exclusion criteria and in Table 1 are 
not allowed during the ongoing study. If there is a clinical indication for any medications or 
vaccinations specifically prohibited (i.e., as supportive care or to treat AEs as deemed 
necessary by the investigator or the subject’s physician), discontinuation from study drug may 
be required. The investigator should discuss any questions regarding this with the Medical 
Monitor. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject’s primary physician. However, the decision to continue the subject on study 
drug requires the mutual agreement of the investigator, the Sponsor, and the subject.
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 52 of 157
Table 1:
Prohibited Concomitant Medications that May Impact Efficacy 
Assessments or Impact Subject Safety
Drug Class
Agents Disallowed
Prohibited Period
TNFα antagonist
Infliximab (t½: 9.5 days) 
Adalimumab (t½: 10-20 days)
Golimumab (t½: 12-14 days)
Certolizumab (t½: 14 days)
5 half-lives prior to Day 1* through the end 
of treatment
Integrin antagonist
Vedolizumab (t½: 25 days)
Natalizumab (t½: 11 days)
5 half-lives prior to Day 1* through the end 
of treatment
Interleukin antagonist
Ustekinumab (t½: 19 days)
5 half-lives prior to Day 1* through the end 
of treatment
JAK inhibitor
Baricitinib (t½: 12 hours)
Tofacitinib (t½: 3 hours)
Tofacitinib XR (t½: 6-8 hours)
Upadacitinib (t½: 8-14 hours)
5 half-lives prior to Day 1* through the end 
of treatment
S1P1 inhibitor
Fingolimod (t½: 6-9 days)
Ozanimod (t½: 11 days)
Siponimod (t½: 30 hours)
5 half-lives prior to Day 1* through the end 
of treatment
Rectal compounds
Rectal 
mesalamine, 
rectal 
corticosteroids
2 weeks prior to screening endoscopy
through the end of treatment
Antidiarrheal agents**
Loperamide, 
diphenoxylate/atropine
2 weeks prior to screening endoscopy
through the end of treatment
Other (non-biologic)
Cyclosporine (oral), thalidomide, 
tacrolimus, leflunomide, and any
investigational agent
2 weeks prior to Day 1 through the end of 
treatment
Investigational biologics
Any investigational biologic agent
30 days prior to Day 1 (or at least 5 half-
lives) through the end of treatment 
*If subject has taken the concomitant medication within 5 half-lives prior to Day 1, but has an undetectable serum level on a 
commercially available assay assessed at screening, this is also acceptable for inclusion.
** Subjects who mistakenly use an antidiarrheal for a limited period of time (1 – 2 days) may be allowed to continue 
participation in the study following discussion and approval by the Medical Monitor and the Investigator.
If other prohibited concomitant medications, as shown in Table 2 are taken by a subject prior 
to study participation or during the study, the Investigator must contact the Medical Monitor.
Table 2:
Other Prohibited Concomitant Medications
Drug Class
Agents Disallowed
Prohibited Period
Other biologics
Fecal 
Microbiota 
Transplant 
(FMT), antibody based or other 
systemic 
biologics, 
eg, 
denosumab, trastuzumab
Requires 
Medical 
Monitor 
consultation
08NYPB

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$$,$$$$#)"$) $(
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4"#$$ "$$/"$)
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 ) $ 4 , #( , H(  $) $ $(( 
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CCI
CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 54 of 157
6
STUDY ACTIVITIES
6.1
Schedule of Events
Adverse events and concomitant medications will be recorded from randomization through the 
safety reporting period (see Section 7.6.1.3). Adverse events that are the result of study 
protocol-specified intervention (defined in Section 7.6.1.1) as well as any concomitant 
medications given for treatment of these adverse events, should be recorded from the time of 
informed consent. Schedules of events (SOEs) are provided in Appendix 1. Descriptions of all 
study assessments are presented in Section 7.
On applicable visits, all PRO and quality of life-related assessments must be completed prior
to other study procedures. 
6.2
Screening Visit
Documented, signed, and dated informed consent must be obtained by the Investigator or 
his/her designee prior to the performance of any study related procedures, including washout 
of prohibited medications. In regions where the legal age of consent is older than 18 years, 
informed consent must be obtained from and signed by both the subject and his or her legally 
acceptable representative, as applicable. A copy of the signed ICF must be given to the subject 
for their records.
After informed consent has been obtained, the subject has approximately 4 weeks (± 1 week)
to complete all screening procedures. The subject’s eligibility for the study will be evaluated 
during this period based on medical history, physical examination, laboratory values, Mayo 
Score diary data (SF and RB), and additional assessments, including screening endoscopy. 
Subjects who meet all of the inclusion and none of the exclusion criteria can be enrolled in the 
treatment period. For subjects eligible for this study, the ramdomization number is the same as 
the screening number. 
Refer to Appendix 1 for all the procedures to be performed during the Screening Period. 
6.2.1
Screen Failure
A screen failure is defined as a subject who has provided informed consent and fails to meet 
the inclusion and/or exclusion criteria. Subjects who fail screening will not be randomized into 
the study nor receive study drug. 
6.2.2
Rescreening of Subjects
Subjects may be rescreened once after consultation with the Medical Monitor. In these cases,
a new screening number must be assigned for each subject rescreened. Rescreening should 
include all screening procedures listed in the SOEs (see Table 3 and Table 4) unless noted 
otherwise and a new ICF must be signed to confirm ongoing consent for the study.
08NYPB

	
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1<3%

	


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=6:6+
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$$($)'"4$/(4###C	$("
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CCI
CCI
CCI
CCI
CCI
CCI
1<3%

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 57 of 157

Modification of the PK/PD sample processing and shipping details based on newly 
available data
7
STUDY ASSESSMENTS
7.1
Screening/Baseline Assessments
Only subjects who meet all eligibility criteria specified in Section 4 will be enrolled in this 
study.
Subject medical history includes a thorough review of significant past medical history, current 
conditions, review of body systems, response to prior UC treatment, and any concomitant 
medications.
7.2
Response/Efficacy Assessments
7.2.1
Mayo Score
The Mayo Score is an instrument designed to measure disease activity in patients with UC. 
The Mayo Score ranges from 0 to 12 points and consists of the following 4 subscores, each 
graded from 0 to 3, with higher scores indicating more severe disease (see Appendix 3).

Stool frequency (SF)

Rectal bleeding (RB)

Findings of flexible sigmoidoscopy

Physician global assessment (PGA)
Calculation of the SF and RB subscores requires an assessment of the subject’s bowel 
movement frequency and quantification of the amount of blood in the stool. The SF and RB
Mayo subscores will be calculated based on the subject’s Mayo Score diary data recorded in 
the week prior to the endoscopy (for modified Mayo Score) or prior to the visit (for partial 
Mayo Score) (see Section 7.2.1.1 for eDiary instructions and review).
The mucosal appearance during the sigmoidoscopic/colonoscopic portion of the endoscopic 
examination will be assessed for calculation of the Mayo endoscopic subscore based on the 
scoring system provided in Appendix 3. The endoscopic appearance will be read by both the 
Investigator and a central reader. Additional details are provided in the Central Imaging 
Management Solutions manual. Centrally read endoscopic subscores will be used for both IBT 
eligibility and the efficacy analyses. The Investigator-read endoscopic subscores will be used 
to assess eligibility for the OL and CBT phases.
The PGA subscore is assessed by the Investigator and is recorded at all study visits. The 
endoscopic subscore and the PGA must be performed by a physician qualified to perform 
08NYPB

MK-6194-002-08
Study PT101-201 Clinical Protocol
Amendment 8; 13-May-2022
PT101
Pandion Therapeutics, Inc. - Confidential
Page 58 of 157
endoscopy. It is recommended that the same physician performs all such assessments for a 
particular subject throughout the study.
7.2.1.1
eDiary Instructions and Review
The SF and RB subscores are recorded daily in an eDiary. Subjects should be provided access 
to the eDiary and instructions for daily documentation of SF and RB. Additionally, all subjects 
will be provided with paper diary forms for cases where the subject doesn’t have access to a 
suitable device for eDiary capture or as backup to the eDiary in case there is an issue with the 
subject’s electronic device. Subjects should begin filling out the diary on the day of their initial 
screening visit and continue to fill it out on a daily basis throughout the remainder of the study. 
Subjects should be counseled about what is meant by normal SF: the average daily SF the 
subject experienced the last time the subject was in remission. If the subject has never been in 
remission, the normal SF is defined as the average daily SF before the initial onset of signs and 
symptoms of UC.
For the daily SF question, subjects should be counseled that a stool is defined as a visit to the 
toilet when they have either a bowel movement, pass blood only, pass mucus only, or pass 
blood and mucus. For the RB question, subjects should be counseled to select the category that
describes their most severe RB over the last 24 hours. Subjects should be counseled to select 
“No Blood Seen” if they do not have a stool during a given day.
The modified Mayo Score will be used for the purposes of determining eligibility at screening 
and efficacy assessments at Week 12, the subscores for SF and RB will be calculated based on 
the data recorded in the diary for 3 consecutive days (excluding the bowel preparation day)
during the week prior to the endoscopy. Thus, sites need to ensure subjects are entering eDiary
(preferred) or paper diary forms data daily, especially prior to an endoscopy. Subjects must be 
instructed to document SF and RB on a daily basis and site personnel should be monitoring 
subject’s compliance. For all subjects, the site will ensure that the SF and RB data are being
entered in the ediary or paper diary forms by the subject by conducting a follow up phone call 
within 3 days before the endoscopy bowel preparation day at Screening and Week 12. 
The partial Mayo Score will be assessed throughout the study and be used at Week 24 for the 
subjects in the OL phase to determine if the subject can start steroid tapering (if applicable). 
The subscore for SF and RB will be calculated based on the data recorded in the diary on 3 
days (no need to be consecutive days) during the week prior to the corresponding visit where 
the partial Mayo Score is assessed.
7.2.1.2
Endoscopy
A colonoscopy or flexible sigmoidoscopy will be performed and recorded for central reader 
review at Screening and Week 12 (or upon ET as applicable).
Screening endoscopies will occur as follows:
●
Only in subjects with a RB subscore ≥ 1, a SF subscore ≥1 and PGA ≥1 may proceed 
with screening endoscopy.
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
Clinical response (based on the partial Mayo Score): decrease in partial Mayo Score of 
≥ 2.  
Note: the clinical response based on the partial Mayo Score will be used in the decision 
to taper steroid (as applicable) at Week 24 for subjects in the OL phase.

Endoscopic improvement: Mayo endoscopic subscore of less than or equal to 1

Endoscopic remission: Mayo endoscopic subscore of 0

Mucosal healing: Geboes index score < 2 and endoscopic remission (Mayo endoscopic
subscore of 0)

Symptomatic remission: SF subscore 0 or 1 with a decrease of ≥1 point from baseline, 
and RB subscore of 0

Symptomatic response: ≥30% decrease from baseline in composite sum of SF and RB
subscores

UC-100: Composite UC-100 score (1 + 16 × Mayo SF subscore [0 to 3] + 6 × Mayo 
endoscopic subscore [0 to 3] + 1 × RHI score [0 to 33]) ranges from 1 (no disease 
activity) to 100 (severe disease activity)
7.2.3
Geboes Score and Robarts Histopathology Index 
7.2.3.1
Geboes Score
The original Geboes score (GS) is the most commonly used colon mucosal histological score 
in the UC field. It is divided into 6 grades: architectural changes (Grade 0), chronic 
inflammatory infiltrate (Grade 1), lamina propria neutrophils and eosinophils (Grade 2), 
neutrophils in epithelium (Grade 3), crypt destruction (Grade 4) and erosions or ulcerations 
(Grade 5), and each grade of the score is divided in 4 subcategories (see Appendix 4). The 
Geboes score ranges from 0 to 5.4, with higher scores indicating more severe inflammation; 
typically, UC is defined as active histological inflammation with a Geboes score of ≥2B.1 
(Ma, 2021).
7.2.3.2
Robarts Histopathology Index
The RHI is a recently validated instrument that measures histological disease activity in 
patients with UC (see Appendix 5). The RHI is divided into 4 categories: chronic inflammatory 
infiltrate, lamina propria neutrophils, neutrophils in epithelium, and erosion or ulceration (each 
ranging from 0–4). The RHI is comparable to, and often correlates with the Geboes score.
Endpoints based on the GS and RHI are defined below:

Histologic remission: Geboes index score < 2B.1 or RHI score ≤ 3, with subscores of 
0 for lamina propria neutrophils and 0 for neutrophils in epithelium
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
Histologic response: change from baseline RHI ≥ 7 points

Mucosal healing: Histologic remission (as defined by the Geboes or RHI score) and 
endoscopic remission (Mayo endoscopic subscore of 0)

UC-100: Composite UC-100 score (1 + 16 × Mayo SF subscore [0 to 3] + 6 × Mayo 
endoscopic subscore [0 to 3] + 1 × RHI score [0 to 33]) ranges from 1 (no disease 
activity) to 100 (severe disease activity) (see Appendix 6)
7.3
Patient-Reported Outcomes and Quality of Life Measures
Paper questionnaires will be used to record the following patient-reported outcomes (PRO) 
and quality of life assessments during the study:

IBDQ

SF-36
PRO and quality of life measurements are collected and evaluated in a different manner than 
AEs; therefore, no attempt will be made to resolve any apparent discrepancies between AE and 
PRO data. 
7.3.1
Inflammatory Bowel Disease Questionnaire
IBDQ is a psychometrically validated PRO instrument for measuring the disease-specific 
quality of life in patients with inflammatory bowel disease, including UC. The IBDQ 
comprises 32 items that are grouped into 4 dimensions: bowel function (loose stools, 
abdominal pain), emotional status (anger, depression, irritability), systemic symptoms (fatigue, 
altered sleep pattern) and social function (work attendance, need to cancel social events).
The 4 domains are scored as follows:

Bowel symptoms: 10 to 70

Systemic symptoms: 5 to 35

Emotional function: 12 to 84

Social function: 5 to 35
The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher 
score indicates better quality of life. A score of at least 170 corresponds to clinical remission 
and an increase of at least 16 points indicates a clinically meaningful improvement.
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7.3.2
Short Form-36 
The SF-36 is a widely used general health status questionnaire that assesses 8 domains of
functional health and well-being: Physical Functioning, Role Limitations due to Physical 
Health Problems, Bodily Pain, Social Functioning, Mental Health, Role Limitations due to 
Emotional Problems, Vitality, and General Health Perceptions. Scales are scored from 0 to 
100, with higher scores indicating a better health-related quality of life. A Physical Health 
component summary score and Mental Health component summary score are calculated from 
the 8 domain scores. The SF-36 is a psychometrically valid and reliable instrument. The 
concepts measured by the SF-36 are not specific to any age, disease, or treatment group, 
allowing comparison of relative burden of different diseases and the relative benefit of different 
treatments.
7.4
Pharmacokinetic and Immunogenicity Assessments
Blood samples for PK and ADA analyses will be collected at baseline and at the timepoints 
specified in the SOE tables in Appendix 1.
PK parameters that will be assessed include Cmax, Tmax, AUC0-t, Cmin, AUC0-inf, t½, CL/F, and 
Vd/F. ADA to PT101 will be assessed using a standard 3-tier approach to measure binding 
antibody with a screening assay, ADA titer using a confirmatory assay, and neutralizing 
antibody to PT101 in subjects with confirmed positive titers.
7.5
Pharmacodynamics and Biomarker Assessments
Blood samples for PD and biomarker analyses will be collected at baseline and at the 
timepoints specified in the SOE tables in Appendix 1.
7.5.1
Pharmacodynamic Assessments 
Whole blood will be collected for immunophenotyping (IPT) and receptor occupancy (RO)
and analyzed by flow cytometry to enumerate immune cell subsets and assess CD25 (IL-2Rα) 
RO on Tregs.
7.5.2
Biomarker Assessments
Changes in additional PT101- and UC-associated exploratory biomarkers (e.g., proteomics) 
will be assessed in serum, blood, RNA, PBMCs, stool, and colonic tissue biopsy samples.
CRP will be assayed using a validated, high-sensitivity CRP assay. FC will be evaluated in 
stool samples using a validated method. Additional tests may also be performed on the stool 
samples for additional markers related to intestinal inflammation and treatment response.
Details on collecting, aliquoting, storing and shipping samples will be detailed in the Lab 
Manual.
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7.5.2.1
Future Research
The Sponsor will also conduct future research on specimens for which consent was provided 
during this study. The objective of collecting/retaining specimens for future research is to 
explore and identify biomarkers that inform the scientific understanding of diseases (including 
UC) and/or their therapeutic treatments (including PT101).
If the subject provides documented informed consent for future research, the following 
specimens will be obtained as part of future research:

Additional blood samples (for serum)

Backup serum samples 

Backup blood samples 

Backup stool samples 

Leftover tissue samples
7.5.2.2
Genetic Analysis
Genetic analysis will be conducted on specimens for which consent was provided during the 
study. Genetic variation may impact a subject’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Samples 
collected may also be used to develop tests/assays including diagnostic tests related to the 
disease under study, related diseases, and study drug(s).
7.6
Safety Assessments
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, Events of Clinical Interest (ECIs), recording of concomitant 
medication, ECG, vital signs, physical examinations and laboratory tests.
Safety will be monitored over the course of the study by a DRC as described in Section 3.
7.6.1
Adverse Events
7.6.1.1
Definitions
Adverse Event
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an AE is 
any untoward medical occurrence in a patient or clinical investigational subject administered 
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a medicinal product and which does not necessarily have a causal relationship with this 
treatment.
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions eCRF:
●
From the time of informed consent through the day prior to randomization, 
only those AEs that are the result of a study protocol-specified intervention
must be recorded. A protocol-specified intervention AE is defined as an 
untoward medical event occurring as a result of a protocol mandated 
procedure.
●
All medical conditions present or ongoing before randomization should be 
recorded as part of the subject’s medical history.
●
All AEs (regardless of relationship to study drug) should be recorded from 
randomization
through the end of the safety reporting period 
(see Section 7.6.1.3). Complications that occur in association with any 
procedure should be recorded as AEs whether or not the procedure was 
protocol mandated.
●
Changes in pre-existing medical conditions and AEs, including changes in 
severity, frequency, or character, during the safety reporting period should 
be recorded.
●
In general, an abnormal laboratory value should not be recorded as an AE 
unless it is associated with clinical signs or symptoms, requires an 
intervention, results in a SAE, or results in study termination or 
interruption/discontinuation of study treatment. When recording an AE 
resulting from a laboratory abnormality, the resulting medical condition 
rather than the abnormality itself should be recorded (e.g., record “anemia” 
rather than “low hemoglobin”).
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Serious Adverse Events
An AE should be classified as an SAE if it meets one of the following criteria:
Fatal:
AE resulted in death
Life threatening:
The AEs placed the patient at immediate risk of death. This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe.
Hospitalization:
The AE resulted in hospitalization or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed 
consent in the study or routine check-ups are not SAEs by this 
criterion. 
Disabling/ 
incapacitating:
An AE that resulted in a persistent or significant incapacity or 
substantial disruption of the patient’s ability to conduct normal life 
functions.
Congenital anomaly 
or birth defect:
An adverse outcome in a child or fetus of a patient exposed to the 
molecule or study treatment regimen before conception or during 
pregnancy.
Medically 
significant:
The AE did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious 
agent.
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Adverse Event Severity
AE severity should be graded using the NCI CTCAE, Version 5.0 (27 November 2017). The 
general categories for each grade are:
Grade 
Severity 
Alternate Description 
1 
Mild (apply event-specific NCI CTCAE 
grading criteria) 
Asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate (apply event-specific NCI 
CTCAE grading criteria) 
Minimal; local or noninvasive 
intervention indicated; limiting age 
appropriate instrumental ADL 
3 
Severe (apply event-specific NCI 
CTCAE grading criteria) 
Severe or medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; disabling; 
limiting self-care ADL 
4 
Very severe, life-threatening, or 
disabling (apply event-specific NCI 
CTCAE grading criteria) 
Life-threatening consequences; urgent 
intervention indicated 
5 
Death related to AE 
Death related to AE 
Abbreviations: AE=adverse event; ADL=activities of daily living; NCI CTCAE=National Cancer Institute 
Common Terminology Criteria for Adverse Events. 
Note: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above).
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Relationship of the Adverse Event to Study Treatment
The relationship of each AE to study treatment should be evaluated by the Investigator using 
the criteria below. If the Investigator’s opinion of not related to study drug for an SAE is given, 
an alternative cause of the event such as underlying disease(s), concomitant therapy, and other 
risk factors must be provided.
Related:
There is evidence to suggest a causal relationship between the drug 
and the AE, such as:
●A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
●One or more occurrences of an event that is not commonly 
associated with drug exposure, but is otherwise uncommon in the 
population exposed to the drug 
Relationship of the Adverse Event to Study Procedure
The relationship of each AE to study procedure should be evaluated by the Investigator using 
the following criteria:
Related:
There is evidence to suggest there is a reasonable possibility of a 
causal relationship between the study procedure and the AE
Unrelated:
There is no reasonable possibility of a causal relationship between the 
study procedure and the AE
7.6.1.2
Procedures for Eliciting and Recording Adverse Events
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means by 
recording them on the eCRF, as appropriate.
Eliciting Adverse Events
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs.
Recording Adverse Events
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions eCRF:
●
Description including onset and resolution dates
●
Whether it met SAE criteria
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●
Severity
●
Relationship to study treatment or other causality
●
Outcome
Diagnosis vs. Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms.
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate adverse event.
Recording Serious Adverse Events
For SAEs, record the event(s) on the eCRF with the seriousness criteria assessment.
The following should be considered when recording SAEs:
●
Death is an outcome of an event. The event that resulted in the death should 
be recorded and reported on both an SAE form and eCRF.
●
For hospitalizations, surgical, or diagnostic procedures, the illness leading 
to the surgical or diagnostic procedure should be recorded as the SAE, not 
the procedure itself. The procedure should be captured in the narrative as 
part of the action taken in response to the illness.
Pregnancy and Exposure During Breastfeeding
Female subjects who become pregnant must discontinue study drug. A determination regarding 
study drug discontinuation will be made by the Investigator and/or Sponsor for male subjects
with a partner pregnancy after evaluating the risks and benefits of continuing with the study.
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 30 days after the last dose of study drug(s) including any pregnancies that 
occur in the partner of a male study subject. Only report pregnancies that occur in a male 
patient’s partner if the estimated date of conception is after the male subject’s first study drug 
dose. A completed Pregnancy Report Form by the Investigator (or designee) should be 
submitted to Alimentiv Safety within 24 hours after learning of the pregnancy. Suspicion that 
study drug may have interfered with the effectiveness of a contraceptive medication must also 
be recorded as an AE.
All pregnancies will be monitored for the full duration; all perinatal and neonatal outcomes 
should be reported. Infants should be followed for a minimum of 8 weeks.
Although infant exposure during breastfeeding is not considered an AE, any infant exposure 
during breastfeeding by a subject (spontaneously reported to the investigator or their designee) 
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occurring during the study is reportable. The Sponsor should be notified within 24 hours of 
learning of the event.
Collection of data on the eCRF: All pregnancies and infant exposure during breastfeeding (as 
described above) that occur within 30 days of the last dose of study drug(s) will also be 
recorded on the Adverse Events eCRF.
Non-elective abortion, whether accidental, therapeutic, or spontaneous, should be reported as 
an SAE. Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.6.1.1) should be reported as SAEs.
7.6.1.3
Reporting Periods for Adverse Events and Serious Adverse Events
The safety reporting period for all AEs and SAEs is from time of study drug randomization
through the end of treatment visit or 28 days after the last study treatment, whichever is later.
However, all AEs that are the result of a study protocol-specified intervention are to be 
recorded from the time of informed consent.
All SAEs that occur after the safety reporting period and are considered study treatment-related 
in the opinion of the Investigator should also be reported to the sponsor.
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent. All non-serious AEs will be followed through the safety 
reporting period. Certain non-serious AEs of interest may be followed until resolution, return 
to baseline, or study closure.
7.6.1.4
Serious Adverse Events Require Immediate Reporting
The Investigator (or designee) is required to complete the SAE page in the eCRF enabling 
transmission to Alimentiv Safety using the electronic data capture (EDC) system. In the event 
EDC transmission is not possible, (e.g., there are access or system problems), then the 
Investigator (or designee) must report the SAE to Alimentiv Clinical Safety by emailing or 
faxing a completed paper SAE form:
All SAEs must be reported to Alimentiv Clinical Safety group within 24 hours after the 
Investigator recognizes/classifies the event as a SAE. 
The initial SAE report should include at a minimum: subject number, a narrative description 
of the event, and an assessment by the Investigator of the intensity of the event and relationship 
of the event to study drug. The initial SAE report received from the site should be as complete 
as possible. A complete follow-up SAE report must be submitted when information not 
available at the time of the initial report becomes available. The Sponsor (or designee) may 
request SAE follow-up information. Copies of any relevant data from the hospital notes (e.g., 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
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There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, as causality assessment is one of the 
criteria used when determining regulatory reporting requirements, it is particularly important 
that the Investigator always assess causality for every event before the initial transmission of 
the SAE data. The Investigator may change his/her opinion of causality considering follow-up 
information and send an SAE follow-up report with the updated causality assessment.
The Investigator (or designee) is responsible for continuing to report to the Sponsor Clinical 
Safety any new or relevant follow-up information that he/she learns about the SAE.
The Investigator (or designee) is responsible for notifying their institutional review 
board/independent ethics committee (IRB/IEC) of SAEs that occur according to local 
regulations and guidelines.
Reports of pregnancy, exposure during breastfeeding, cancer, and ECIs (per Section 7.6.1.6), 
will be reported in the same timeframe as SAEs.
7.6.1.5
Sponsor Safety Reporting to Regulatory Authorities
Investigators are required to report all SAEs to the sponsor (see Section 7.6.1.4).
The sponsor or Alimentiv will report all SAEs to regulatory authorities as required per local 
regulatory reporting requirements. 
7.6.1.6
Events of Clinical  Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
ECIs for this study include:
1.
An overdose of Sponsor's product, as defined in Section 7.6.1.7
2.
An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 
2X the ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The study-site guidance for assessment and follow up 
of these criteria can be found in Appendix 7 and in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
08NYPB

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phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor. However, abnormalities of liver blood tests that do not meet the criteria noted 
above are not ECIs for this study.
3.
Skin rash or pruritis being rated by the Investigator as Grade 3 in intensity
4.
Dyspnea, all intensities
5.
Significant eosinophilia defined as AEC > 5.0 giga/L confirmed on repeat measurement 
after at least 24 hours or eosinophil-associated organ injury.
7.6.1.7
Definition and Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
The Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the Sponsor 
based on the clinical evaluation of the subject.
7.6.2
Clinical Laboratory Tests
The following laboratory assessments will be performed by the central lab to evaluate safety 
at scheduled timepoints during the course of the study:
●
The chemistry panel is to include the following tests: albumin, alkaline 
phosphatase, ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, 
CRP, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total 
bilirubin, amylase, lipase, and uric acid.
●
Hematology panel (complete blood count [CBC] with differential). 
Differential includes neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils.
●
Coagulation parameters include prothrombin time/partial thromboplastin 
time/international normalized ratio (PT/PTT/INR)
●
Creatinine clearance – the same method of assessment should be used at 
each timepoint
●
Urinalysis
○
Standard urinalysis
○
Urine protein and creatinine for urine protein/creatinine ratio
08NYPB

	
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PT101
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machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and QTc 
intervals. The correction formula to be used for QTc is Fridericia.
Triplicate ECG measurements will be obtained at the screening visit and on Day 1. On Day 1 
only, triplicate ECGs will be performed ~12 hours after study drug administration. The median 
of these measurements will be used to calculate change from baseline for safety evaluations 
(and for rechecks, if needed). Single measurements will be performed on Day 85 and ET visits.
At each time point when triplicate ECGs are required, 3 individual ECG tracings should be 
obtained at least 1 minute apart. The full set of triplicates should be completed in no more than 
6 minutes.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Subjects may need to be shaved to ensure proper lead 
placement. Female subjects may need to remove interfering garments.
During an ECG, subjects should be in a quiet setting without distractions. Subjects should rest 
in a supine position for at least 5 minutes before ECG recording and should refrain from talking 
or moving their arms or legs. 
Screening ECG read results will be used as baseline ECG to evaluate subject eligibility and 
should be maintained in the subjects source documentation for this study. Any clinically 
significant changes from the baseline ECG should be recorded as AEs and evaluated further, 
as clinically warranted. Refer to Appendix 8 for evaluation and potentially significant findings.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be held 
until the QTc is within 60 msec of baseline and the QTc is < 500 msec.
If blood sample collection and/or measurement of vital signs is scheduled at the same timepoint 
as ECG recording, the procedures should be performed in the following order: ECG, vital 
signs, blood sample collection.
7.6.6
Vital Signs
Vital signs measures include HR, BP, respiratory rate, and temperature. Weight will also be 
measured.
Vital Sign Measurements (Heart Rate, Blood Pressure, Respiratory Rate, Temperature)
Subjects should be resting in a quiet setting without distractions in a semirecumbent position 
for at least 5 minutes before having vital sign measurements obtained. Supine or seated 
positions are also acceptable (per site standard procedures) as long as the position used is 
consistent across subjects at a given site. Vital signs will include HR, systolic and diastolic BP, 
respiratory rate, and body temperature at timepoints indicated in the SOEs. The correct size of 
the BP cuff and the correct positioning on the subject’s arm is essential to increase the accuracy 
of BP measurements.
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All HR and BP will be taken as a single measurement. 
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual subject and should be the same for all subjects enrolled at a site.
7.6.7
Physical Examination
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head (eyes, ears, nose, and throat), heart, lungs, neck, neurological, and 
skin.
An abbreviated or targeted interim physical examination may be done to assess areas with 
previously noted abnormalities and/or that are associated with any new complaints from the 
subject.
7.6.8
Pregnancy Testing 
For WOCBP, a serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test
will be performed at screening and before dosing. A negative pregnancy result is required 
before the subject may receive study drug. Additional pregnancy testing will be performed as 
specified in the SOEs in Appendix 1.
7.7
Appropriateness of Measurements
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. Immunogenicity is commonly 
assessed for biologics; therefore, standard tests will be performed to detect the possible 
presence of specific antibodies to PT101. Pharmacokinetic assessments are also frequently 
employed in clinical studies to help characterize dose-exposure-response relationships.
Standardized and internationally accepted criteria for the evaluation of UC will be used to 
assess disease activity in this study, including the Mayo Score, the Geboes score, the RHI, and 
UC-100 (Jairath, 2019; Jauregui-Amezaga, 2017; Magro, 2020; Mosli, 2017; Pai, 2019). The 
PRO and quality of life instruments used in this study are standardized questionnaires that have 
been widely used in clinical trials in multiple countries (Irvine, 1994; Ware and 
Sherbourne, 1992; Yalcin and Bump, 2003). 
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8
DATA QUALITY CONTROL AND QUALITY ASSURANCE
8.1
Site Training and Monitoring Procedures
A study manual with instructions for study compliance and eCRF completion will be provided.
Prior to the enrollment of subjects at the site, the Sponsor or its designated clinical and medical 
personnel will review the following items with the Investigator and clinic staff:
●
The protocol, study objectives, eligibility requirements, study procedures, 
registration and withdrawal processes
●
Current Investigator’s Brochure/ package insert
●
Recording and reporting AEs and SAEs
●
Enrollment goals and study timelines
●
The eCRF completion process and source documentation requirements
●
Monitoring requirements
●
IRB/IEC review and approval process
●
Informed consent process
●
Good clinical practice guidelines and related regulatory documentation 
requirements
●
Key study team roles and responsibilities
●
Investigational product storage, accountability, labeling, dispensing and 
record keeping
●
Subject coding and randomization (if applicable)
●
Study samples/specimen collection, handling and shipping
●
Protocol compliance
●
Clinical study record keeping, document retention, and administrative 
requirements
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Sponsor representative will review 
regulatory documentation, eCRFs, source documentation, and investigational product storage, 
preparation, and accountability. The eCRFs will be reviewed for completeness, adherence to 
the provided guidelines, and accuracy compared to the source documents. The investigators 
must ensure that the monitor is allowed to inspect all source documents pertinent to study 
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subjects, and must cooperate with the monitor to ensure that any problems noted in the course 
of the trial are resolved. The Investigator must maintain a comprehensive and centralized filing 
system of all study-related documentation that is suitable for inspection by the Sponsor or its 
designated monitors and by quality assurance auditors, or representatives of regulatory 
authorities.
8.2
Data Management Procedures
The Sponsor will provide CRF Completion Guidelines for eCRF data entry. Study specific 
data management procedures will be maintained in the data management plan. Queries 
resulting from edit checks and/or data verification procedures will be posted electronically in 
the eCRF.
8.3
Access to Source Data
The Investigator will permit the Sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect patient confidentiality are to be employed during 
monitoring. The eCRFs and related source documents will be reviewed in detail by the monitor 
at each site visit. Original source documents or certified copies are needed for review. This 
review includes inspection of data acquired as a requirement for participation in this study and 
other medical records as required to confirm that the information contained in the eCRFs, such 
as disease assessments, AEs, and concomitant medications, is complete and correct. Other 
study records, such as correspondence with the sponsor and the IRB/IEC and screening and 
drug accountability logs will also be inspected. All source data and study records must also be 
available for inspection by representatives of regulatory authorities.
8.4
Accuracy and Reliability of Data
Steps to be taken to assure the accuracy and reliability of data include:
●
The selection of qualified Investigators and appropriate study centers.
●
Review of protocol procedures with the Investigators and associated 
personnel prior to the study.
●
Periodic monitoring visits by the designated monitor(s).
●
eCRFs will be reviewed for accuracy and completeness by the designated 
monitor(s) during monitoring visits to the study centers. Any discrepancies 
will be resolved with the Investigator or designees as appropriate.
8.5
Quality Assurance Procedures
The Sponsor or its designee may conduct audits at the clinical site or other study-related 
facilities and organizations. Audit reports will be retained by the Sponsor as part of the written 
record.
08NYPB

	
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9.2
Study Endpoint Definitions
See Section 7.2 for definitions of the efficacy/response endpoints. 
9.3
Statistical and Analytical Plans
9.3.1
General Considerations
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. Continuous variables will be summarized by number of subjects and mean, 
standard deviation/standard error, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of subjects. Tests of statistical 
significance will be described in the SAP.
9.3.1.1
Subject Disposition
The number and percentage of subjects in study populations will be summarized by treatment 
group, separately for each stage. The subject disposition table will also include the number of 
subjects screened, randomized, and treated. No formal statistical comparisons will be 
performed.
Subjects who are screened but not randomized (screen failures) and the associated reasons for 
failure to randomize will be tabulated for all screened subjects. The number and percentage of 
subjects who complete the 12-week treatment period and of subjects who prematurely 
discontinue will be presented for each treatment group and pooled across treatment groups for 
the Safety Population. The reasons for premature discontinuation from treatment period as 
recorded in the eCRFs will be summarized.
9.3.1.2
Subject Characteristics
Demographic parameters (age, age group, sex, race, ethnicity, height, weight, body mass 
index) and other baseline characteristics will be summarized descriptively by treatment group 
for the intent-to-treat (ITT), full analysis set (FAS), per protocol (PP) analysis set, and safety 
analysis sets (SAF).
9.3.1.3
Protocol Deviations
Protocol deviations will be summarized by type in each treatment group. Both major and minor 
protocol deviations will be listed.
9.3.1.4
Prior and Concomitant Therapy
Prior medication is defined as any medication started before the date of study drug 
administration. A concomitant medication is defined as any medication taken on or after the 
date of study drug administration.
Prior and concomitant medications will be coded by drug name and therapeutic class using the 
World Health Organization (WHO) Drug Dictionary. Results will be tabulated by Anatomic 
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Therapeutic Class and preferred term. If a subject took a specific medication multiple times or 
took multiple medications within a specific therapeutic class, that subject will be counted only 
once for the coded drug name or therapeutic class.
9.3.1.5
Randomization and Blinding
Subjects will be randomized in a 4:1 ratio to a PT101 dose level/dosing regimen and placebo. 
The study will be conducted in a double-blind fashion, which will be described in the Clinical 
Trial Integrity Plan.
9.3.1.6
Adjustments for Covariates
Detailed methodology will be provided in the SAP.
9.3.1.7
Handling of Dropouts and Missing Data
Detailed methodology will be provided in the SAP.
9.3.1.8
Multiple Comparisons and Multiplicity
No multiplicity adjustments will be applied.
9.3.1.9
Data Transformations and Derivations
Time variables based on 2 dates (e.g., start date and end date) will be calculated as (end date –
start date + 1 [in days]) unless otherwise specified in the SAP.
Baseline values used in all statistical analyses will be the most recent non-missing 
measurement prior to the first dose of study drug unless otherwise specified in the SAP.
More detailed methodology will be provided in the SAP.
9.3.2
Analysis Sets
9.3.2.1
Intent-to-Treat Analysis Set
The ITT analysis set consists of all randomized subjects. Subjects will be included in the 
treatment group assigned at randomization regardless of the actual treatment received.
9.3.2.2
Full Analysis Set
The FAS consists of all randomized subjects who received any study drug (PT101 or placebo).
Treatment groups will be determined using the actual treatment received, regardless of the 
randomization treatment assignment.
08NYPB

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
Proportion of subjects achieving clinical remission, endoscopic improvement, 
clinical response, endoscopic remission, histologic remission, histologic response, 
mucosal healing at Week 12

Proportion of subjects achieving symptomatic remission and symptomatic response 
at assessed timepoints through Week 12
9.3.5
Exploratory Efficacy Analyses
MMRM may be used to compare change from baseline in partial Mayo Score beyond Week 12 
as well as change in PT101- and UC-associated biomarkers.
9.3.6
Pharmacokinetic and Immunogenicity Analyses
9.3.6.1
Pharmacokinetic Analyses
Serum concentrations of PT101 will be listed and summarized by treatment group using 
descriptive statistics (sample size, arithmetic mean, geometric mean, % coefficient of variation, 
standard deviation, median, minimum, and maximum). Concentration over time may also be 
plotted in semilogarithmic and linear formats. 
ADA to PT101 will be assessed using a standard 3-tier approach to measure binding antibody 
with a screening assay, ADA titer using a confirmatory assay, and neutralizing antibody to 
PT101 in subjects with confirmed positive titers. Data will be listed and summarized by 
treatment group as detailed in the SAP.
9.3.6.2
Biomarker Analyses
Relationships of biomarker parameters (e.g., baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and PK parameters will be explored. Relationships and 
associated data that are determined to be of interest will be summarized. Details will be 
described separately in the SAP.
9.3.7
Safety Analyses
The safety analyses will be performed using the SAF. The safety parameters will include AEs 
and SAEs, vital sign measurements, ECG findings and clinical laboratory values. The primary 
safety analysis will include all data available for all subjects through Week 12.
9.3.7.1
Extent of Exposure
Duration of treatment will be summarized and listed. Duration of treatment, number of doses, 
and total dose will be summarized. Dose modifications will also be summarized.
9.3.7.2
Adverse Events
An overview of AEs will provide a tabulation of the incidence of all AEs, treatment-emergent 
AEs, treatment-related AEs, Grade 3 and higher AEs, SAEs, treatment-related SAEs, deaths, 
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and AEs leading to study treatment discontinuation. Adverse events will be defined as 
treatment emergent if they are newly occurring or worsen following study treatment.
AEs will be listed and summarized by Medical Dictionary for Regulatory Activities 
(MedDRA), preferred term, severity, and relationship to study drug. In the event of multiple 
occurrences of the same AE with the same preferred term in 1 subject, the AE will be counted 
once as the occurrence. The incidence of AEs will be tabulated by preferred term and treatment 
group. AEs leading to premature discontinuation of study drug will be summarized and listed 
in the same manner.
9.3.7.3
Deaths and Serious Adverse Events
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal outcome 
will be listed.
9.3.7.4
Clinical Laboratory Results
Laboratory values (e.g., chemistry, hematology, and urinalysis) may be presented graphically 
by visit. Summary statistics may be tabulated as appropriate by scheduled visit. Laboratory 
values will be listed with grade per NCI CTCAE and flagged when values are outside the 
normal reference range.
9.3.7.5
Other Safety Analyses
Vital Signs
Vital signs will be presented graphically for each vital sign by scheduled visit. Summary 
statistics and change from baseline and/or predose to postdose may be tabulated where 
appropriate.
ECG
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
may be summarized for each scheduled ECG, and shifts from baseline may be tabulated.
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R1); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements.
10.1 Informed Consent
The Investigator is responsible for presenting the risks and benefits of study participation to 
the patient in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during the 
study, if required. The Investigator will ensure that documented informed consent, including 
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optional genetic analysis and future research, is obtained from each subject, or legally 
acceptable representative, if applicable to this study, by obtaining the signature and date on the 
informed consent document prior to the performance of protocol evaluations or procedures.
If informed consent is obtained from a legally acceptable representative for a subject who is 
unable to provide informed consent at study entry (if applicable), but the subject is later able 
to provide informed consent, the Investigator must obtain documented informed consent from 
the subject.
10.2 Ethical Review
The investigator will provide the Sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at the 
investigative site(s). The name and address of the reviewing ethics committee are provided in 
the investigator file.
The Investigator will supply the following to the site’s IRB/IEC:
●
Protocol and amendments
●
Informed consent document and updates
●
Clinical Investigator’s Brochure and updates
●
Relevant curricula vitae, if required
●
Required safety and SAE reports
●
Any additional submissions required by the site’s IRB/IEC
The Investigator must provide the following documentation to the Sponsor or its designee:
●
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol.
●
The IRB/IEC approvals of any amendments to the protocol or revisions to the informed 
consent document.
●
The IRB/IEC receipt of safety and SAE reports, as appropriate.
10.3 Regulatory Considerations
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations.
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10.3.1 Investigator Information
The contact information and qualifications of the Principal Investigator and Subinvestigators 
and name and address of the research facilities are included in the investigator file.
10.3.2 Protocol Amendments and Study Termination
Any Investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The Investigator is responsible for 
enrolling subjects who have met protocol eligibility criteria. Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies.
The Sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or ET.
10.4 Study Documentation, Privacy and Records Retention
To protect the safety of subjects in the study and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and medical records 
in the subjects’ files as original source documents for the study. If requested, the Investigator 
will provide the Sponsor, its licensees and collaborators, applicable regulatory agencies, and 
applicable IRB/IEC with direct access to original source documents or certified copies.
Records containing subject medical information must be handled in accordance with local and 
national laws, rules, and regulations and consistent with the terms of the informed consent 
document for the study. eCRFs and other documents to be transferred to the Sponsor should 
be completed in strict accordance with the instructions provided by the Sponsor, including the 
instructions regarding the coding of subject identities.
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov.
All study records containing subject details will identify the subject by initials (where 
permitted) and the assigned subject identification number. Subject information collected will 
comply with the applicable local laws and requirements for the protection of privacy of 
individually identifiable health information, such as the General Data Protection Regulation 
(GDPR) of the European Union.
10.5 Clinical Trial Agreement
Payments by the Sponsor to Investigators and institutions conducting the trial, requirements 
for Investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement.
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11 REFERENCES
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Bousvaros A (2010). Use of immunomodulators and biologic therapies in children with 
inflammatory bowel disease. Expert Rev Clin Immunol 6, 659-666.
Bradley GM, and Oliva-Hemker M (2012). Pediatric ulcerative colitis: current treatment 
approaches including role of infliximab. Biologics 6, 125-134.
Carter MJ, Lobo AJ, and Travis SP (2004). Guidelines for the management of inflammatory 
bowel disease in adults. Gut 53 Suppl 5, V1-16.
Castela E, Le Duff F, Butori C, et al. (2014). Effects of low-dose recombinant interleukin 2 to 
promote T-regulatory cells in alopecia areata. JAMA Dermatol 150, 748-751.
Chang JT (2020). Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 383, 2652-
2664.
Chaparro M, Trapero-Marugán M, Moreno-Otero R, et al. (2009). Azathioprine plus ribavirin 
treatment and pancytopenia. Alimentary Pharmacology and Therapeutics 30, 962-963.
Fanton C, Furie R, Dixit N, et al.  (2020)  Selective expansion of regulatory T cells in patients 
with systemic lupus erythematosus by a novel IL-2 conjugate, NKTR-358.  Poster session 
presented at: American College of Rheumatology (ACR) Convergence  2020 Nov 5-9 [online 
meeting].  Abstract 1824.
Danese S, and Fiocchi C (2011). Ulcerative colitis. N Engl J Med 365, 1713-1725.
Harbord M, Eliakim R, Bettenworth D, et al. (2017). Third European Evidence-based 
Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. 
J Crohns Colitis 11, 769-784.
Hartemann A, Bensimon G, Payan CA, et al. (2013). Low-dose interleukin 2 in patients with 
type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. The Lancet 
Diabetes & Endocrinology 1, 295-305.
He J, Zhang X, Wei Y, et al. (2016). Low-dose interleukin-2 treatment selectively modulates 
CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med 22, 991-993.
Irvine EJ, Feagan B, Rochon J, et al. (1994). Quality of life: a valid and reliable measure of 
therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse 
Prevention Trial Study Group. Gastroenterology 106, 287-296.
Jairath V, Jeyarajah J, Zou G, et al. (2019). A composite disease activity index for early drug 
development in ulcerative colitis: development and validation of the UC-100 score. Lancet 
Gastroenterol Hepatol 4, 63-70.
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Jauregui-Amezaga A, Geerits A, Das Y, et al. (2017). A Simplified Geboes Score for 
Ulcerative Colitis. J Crohns Colitis 11, 305-313.
Jess T, Rungoe C, and Peyrin-Biroulet L (2012). Risk of colorectal cancer in patients with 
ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol 
Hepatol 10, 639-645.
Klatzmann D, and Abbas AK (2015). The promise of low-dose interleukin-2 therapy for 
autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283-294.
Koreth J, Matsuoka K, Kim HT, et al. (2011). Interleukin-2 and regulatory T cells in graft-
versus-host disease. N Engl J Med 365, 2055-2066.
Ma C, Sedano R, Almradi A, et al. (2021). An international consensus to standardize 
integration of histopathology in ulcerative colitis clinical trials. Gastroenterology.
Magro F, Lopes J, Borralho P, et al. (2020). Comparing the Continuous Geboes Score With 
the Robarts Histopathology Index: Definitions of Histological Remission and Response and 
their Relation to Faecal Calprotectin Levels. J Crohns Colitis 14, 169-175.
Mosli MH, Feagan BG, Zou G, et al. (2017). Development and validation of a histological 
index for UC. Gut 66, 50-58.
Neuenschwander B, Branson M, and Gsponer T (2008). Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med 27, 2420-2439.
Ng SC, Shi HY, Hamidi N, et al. (2018). Worldwide incidence and prevalence of inflammatory 
bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 
2769-2778.
Ordás I, Eckmann L, Talamini M, et al. (2012). Ulcerative colitis. Lancet 380, 1606-1619.
Pai RK, Khanna R, D'Haens GR, et al. (2019). Definitions of response and remission for the 
Robarts Histopathology Index. Gut 68, 2101-2102.
Rosenzwajg M, Churlaud G, Mallone R, et al. (2015). Low-dose interleukin-2 fosters a dose-
dependent regulatory T cell tuned milieu in T1D patients. J Autoimmun 58, 48-58.
Rosenzwajg M, Lorenzon R, Cacoub P, et al. (2018). Immunological and clinical effects of 
low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann 
Rheum Dis.
Saadoun D, Rosenzwajg M, Joly F, et al. (2011). Regulatory T-cell responses to low-dose 
interleukin-2 in HCV-induced vasculitis. N Engl J Med 365, 2067-2077.
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Tchao N,  Amouzadeh H, Sarkar N, et al. (2021)  Efavaleukin alfa, a novel IL-2 mutein, 
selectively expands regulatory T cells in patients with SLE.   Poster session presented at: 
American College of Rheumatology (ACR) Convergence  2021 Nov 5-9 [online meeting].  
Abstract 1734.
Tung J, Loftus Jr EV, Freese DK, et al. (2006). A population-based study of the frequency of 
corticosteroid resistance and dependence in pediatric patients with Crohn's disease and 
ulcerative colitis. Inflammatory Bowel Diseases 12, 1093-1100.
Turner D, and Griffiths AM (2011). Acute severe ulcerative colitis in children: a systematic 
review. Inflamm Bowel Dis 17, 440-449.
Ungaro R, Mehandru S, Allen PB, et al. (2017). Ulcerative colitis. Lancet 389, 1756-1770.
Ware JE, Jr., and Sherbourne CD (1992). The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care 30, 473-483.
Yalcin I, and Bump RC (2003). Validation of two global impression questionnaires for 
incontinence. Am J Obstet Gynecol 189, 98-101.
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APPENDIX 2:
GUIDANCE ON CONTRACEPTION
ACCEPTABLE METHODS FOR HIGHLY EFFECTIVE BIRTH CONTROL
Male subjects, who are sexually active with a pregnant or breastfeeding woman, choose Option 1 or 2 
Option 1: Male condom with spermicide and cervical cap
Option 2: Male condom with spermicide and diaphragm 
Female subjects who are of childbearing potential AND male subjects who are sexually active with women of 
childbearing potentiala, choose any TWO of the following methods:

Hormonal methods of contraception (excluding progestin-only pills)

Intrauterine device with failure rate < 1%

Tubal ligation

Vasectomy (at least 90 days from the date of surgery with a semen analysis documenting azoospermia)

A barrier method (male or female condom with spermicide, cervical cap with spermicide, diaphragm 
with spermicide
a
A woman of childbearing potential is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed 
menopause. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of 
other biological, physiological, or pharmacological causes. 
UNACCEPTABLE METHODS OF CONTRACEPTION

Abstinence (including periodic abstinence)

No method

Withdrawal

Rhythm

Any barrier method without spermicide

Spermicide only

Progestin-only pills

Concomitant use of female and male condoms
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APPENDIX 3:
MAYO SCORING SYSTEM
Stool frequencya, d:
0 = Normal number of bowel movements 
1 = 1 to 2 bowel movements more than normal
2 = 3 to 4 bowel movements more than normal
3 = 5 or more bowel movements more than normal
Subscore, 0 to 3
Rectal bleedingb, d:
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy:
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, absent vascular pattern, any friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessmentc:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
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The Mayo Score ranges from 0 to 12, with higher scores indicating more severe disease
a Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency
b The daily bleeding score represents the most severe bleeding of the day
c The physician’s global assessment acknowledges the 3 other criteria, the subject’s recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical findings and the subject’s 
performance status
d The modified Mayo Score calculated at the Screening and Week 12 visits must use the SF and RB Mayo 
subscores recorded on the eDiary (or paper diary) over the 3 consecutive days prior to the endoscopy (excluding 
the bowel preparation day)
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APPENDIX 4:
ORIGINAL GEBOES SCORING SYSTEM
Grade 0: Architectural changes
0.0 No abnormality
0.1 Mild abnormality
0.2 Mild/moderate diffuse or multifocal abnormalities
0.3 Severe diffuse or multifocal abnormalities  
Grade 1: Chronic inflammatory infiltrate 
1.0 No increase
1.1 Mild but unequivocal increase
1.2 Moderate increase
1.3 Marked increase 
Grade 2A: Eosinophils in lamina propria
2A.0 No increase
2A.1 Mild but unequivocal increase
2A.2 Moderate increase
2A.3 Marked increase 
Grade 2B: Neutrophils in lamina propria
2B.0 No increase
2B.1 Mild but unequivocal increase
2B.2 Moderate increase
2B.3 Marked increase
Grade 3: Neutrophils in epithelium 
3.0 None
3.1 < 5% crypts involved
3.2 < 50% crypts involved
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3.3 > 50% crypts involved 
Grade 4: Crypt destruction 
4.0 None
4.1 Probable: local excess of neutrophils in part of the crypts
4.2 Probable: marked attenuation
4.3 Unequivocal crypt destruction 
Grade 5: Erosions and ulcerations
5.0 No erosion, ulceration or granulation tissue
5.1 Recovering epithelium + adjacent inflammation
5.2 Probable erosion: focally stripped
5.3 Unequivocal erosion
5.4 Ulcer or granulation tissue
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APPENDIX 5:
ROBARTS HISTOPATHOLOGY INDEX
RHI =1 x chronic inflammatory infiltrate level (4 levels) + 2 x lamina propria neutrophils 
(4 levels) + 3 x neutrophils in epithelium (4 levels) + 5 x erosion or ulceration (4 levels after 
combining Geboes 5.2 and 5.2). The RHI ranges from 0 to 33.
Chronic Inflammatory Infiltrate Level
0 = no increase
1 = mild but unequivocal increase
2 = moderate increase
3 = marked increase
Lamina Propria Neutrophils
0 = none
1 = mild but unequivocal increase
2 = moderate increase
3 = marked increase
Neutrophils in Epithelium 
0 = none
1 = < 5% crypts involved
2 = < 50% crypts involved
3 = > 50% crypts involved
Erosion or Ulceration
0 = no erosion, ulceration or granulation tissue
1 = recovering epithelium + adjacent inflammation
1 = probable erosion – focally stripped
2 = unequivocal erosion
3 = ulcer or granulation tissue
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APPENDIX 6:
COMPOSITE UC-100
Composite UC-100= (1 + 16 × Mayo Clinic stool frequency subscore [0 to 3] + 6 × Mayo 
Clinic endoscopic subscore [0 to 3] + 1 × RHI score [0 to 33])
The UC-100 ranges from 1 (no disease activity) to 100 (severe disease activity).

Mayo Clinic stool frequency subscore (Appendix 3)

Mayo Clinic endoscopic subscore (Appendix 3)

RHI score (Appendix 5) 
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APPENDIX 7:
DRUG-INDUCED LIVER INJURY GUIDANCE DOCUMENT
PURPOSE
The purpose of this appendix is to provide guidance regarding clinical follow-up and 
systematic data gathering and reporting on potential cases of drug induced liver injury (DILI) 
that meet specific agency-specified criteria (‘Hy’s Law’ criteria as discussed below) as being 
predictive of a drug’s ability to cause severe liver injury. The data collected will be used by 
the Sponsor or the Investigator to create narratives for regulatory agency reporting.
INTRODUCTION
Drug-induced hepatotoxicity is one of the most common causes of termination of drug 
development, a major reason for refusal of market authorization and for restricted use, and the 
single most important cause of the withdrawal of market authorization for products (Björnsson 
2006). Thus, drug-induced hepatotoxicity is a major concern during the discovery, 
development to post-authorization phases of the product life cycle (excerpted from Premarket 
Evaluation of Hepatotoxicity of Health Products, Ministry of Public Health, Canada, April 
2012).
As stated in the United States Food and Drug Administration (FDA) Guidance for Industry -
Drug-Induced Liver Injury: Premarketing Clinical Evaluation; hepatocellular injury (usually 
detected by serum aminotransferase elevations [AT]) can be caused by drugs that rarely, if 
ever, cause severe DILI (e.g. aspirin, tacrine, statins, and heparin) as well as by drugs that do 
cause such injury.  
The most specific predictor of a drug’s potential for severe hepatotoxicity, is the occurrence of 
hepatocellular injury (AT elevation) accompanied by increased serum total bilirubin (TBL), 
not explained by any other cause, such as viral hepatitis or exposure to other hepatotoxins, and 
without evidence of cholestasis, together with an increased incidence of AT elevations in the 
overall trial population compared to control. Increased plasma prothrombin time, or its 
international normalized ratio (INR), a consequence of reduced hepatic production of Vitamin 
K-dependent clotting factors, is another potentially useful measure of liver function that might 
suggest the potential for severe liver injury.
Recognition of the importance of altered liver function, in addition to liver injury, began with 
Hyman Zimmerman’s observation that drug-induced hepatocellular injury (i.e. AT elevation) 
accompanied by jaundice (i.e. TBL elevation) had a poor prognosis, with a 10 to 50 percent 
mortality from acute liver failure (in pretransplantation days) (Zimmerman 1978, 1999). This 
became known as "Hy's Law". This guidance describes the recommended process for 
monitoring and evaluation of subjects meeting the laboratory criteria for potential Hy’s Law 
defined as:

1) an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value 
that is greater than or equal to three times (3X) the upper limit of normal (ULN) and

2) an elevated TBL lab value that is greater than or equal to two times (2X) ULN and
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
3) at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
It should be noted that the guidance provided here specifically pertains to potential Hy’s 
Law cases as defined above. Due to the significant potential implications of a Hy’s Law case 
for the health of study subjects as well as for the safety profile of the investigational agent or 
agents being evaluated, study investigators must follow these guidelines for evaluation of the 
study subject, and investigation for potential alternate etiologies.        
It should also be noted that it is often appropriate to conduct additional evaluation for an 
underlying etiology in the setting of abnormalities of liver blood tests including AST, ALT, 
bilirubin, and alkaline phosphatase that are suggestive of DILI but do not meet criteria for a 
potential Hy’s Law case. In these situations, investigators should initiate appropriate evaluation 
and monitoring based on their judgment, using the guidelines below. They should 
communicate with the sponsor’s medical monitor as soon as possible. In these cases, the 
decision to proceed with additional evaluation will be made through consultation between the 
study investigators and the sponsor medical monitor. 
CLOSE OBSERVATION RECOMMENDATIONS
The following steps should be taken when a subject is observed to have an elevated AST or 
ALT lab value that is greater than or equal to 3X ULN and an elevated TBL lab value that is 
greater than or equal to 2X ULN and, at the same time, an ALP lab value that is less than 2X 
ULN, as a result of within-protocol-specific testing or unscheduled testing. 
Treatment with PT101 should be stopped if the laboratory criteria for potential Hy’s Law 
are met (Section 3.1.7 Individual Stopping Rules).  
Initiate close observation, defined below, and continue performing follow-up to resolution. 
Close observation is defined as follows: 

Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
study drug has been discontinued and the subject is asymptomatic.

Obtain a detailed history of symptoms and prior or concurrent diseases. (See Section 
4.1).

Obtain additional pertinent history informing potential alternate etiologies for the liver 
enzyme and bilirubin elevations (see below). 

Complete Stage 1 workup for potential alternate etiologies for the liver enzyme and 
bilirubin elevations (see below). 

Consider gastroenterology or hepatology consultation. 
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Note: if the etiology of the observed laboratory abnormalities becomes clear in the course of 
evaluation, the evaluation may be abbreviated as appropriate and agreed upon by the study 
investigator and sponsor medical monitor.  
EVALUATION OF POTENTIAL HY’S LAW CASES
When a subject meets criteria for being a potential Hy’s Law case (as defined above), it is 
important to thoroughly assess the subject’s history, hepatic risk factors, clinical condition and 
hepatic function until resolution (normal or baseline levels). This information is both critical 
for effect of evaluation and management of an active potential Hy’s Law case, and for 
supporting optimal assessment of drug safety.   
Accrued data pertinent to the evaluation of the potential Hy’s Law case should be recorded in 
source documents and in appropriate CRFs.  
Key elements of the evaluation to be addressed and documented in assessment
Consistent with regulatory guidance (see references) the following information must be 
gathered during evaluation of a potential Hy’s Law case, even if the subject in question is 
known to be receiving control treatment. Information should be updated as data accrues 
throughout the evaluation.  
1.  Study drug treatment including the following:
a. Time and dates from start of drug administration to start of the illness (initial 
detection of pertinent laboratory abnormalities and/or physical symptoms or signs).
b. Time and date of interruption of drug administration
2.  Narrative free text describing relevant medical history and the course of the illness.  
This should include the following elements and should clearly address timeframe (including 
onset and duration of symptoms, signs, and relevant risk factors in medical history):    
a. Pertinent history: Including history of present illness and potentially relevant past 
medical history including potential risk factors for liver disease of alternate etiologies 
(unrelated to study drug). See Table 7 and Table 8 below.    
b. Pertinent physical examination findings. See Table 7 below.    
c. Outcomes including treatment, recovery, hospitalization, liver transplant and death 
Note: The history and physical examination elements noted in Table 7 and Table 8 should be 
specifically addressed as pertinent positive or negative findings
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Table 7:
Symptoms and signs to assess during evaluation of a potential Hy’s Law 
case  
Category
Examples of Signs and Symptoms
Blood/lymphatic
Susceptibility to bleeding
Circulatory
spider nevi, abdominal varicosities, edema
Digestive/hepatic
Anorexia/appetite loss, diarrhea, bloody or black stool, light-colored stools, nausea, 
vomiting, vomiting of blood, right upper quadrant abdominal pain, enlarged and tender 
liver, jaundice, enlarged spleen, ascites
Immune
Fever
Integumentary
Rash, pruritus
Muscular
Muscle aches and pains
Nervous
Changes in mental status or level of consciousness
Urinary
Dark urine
Miscellaneous
Fatigue, malaise, weight gain, other (identify):
General 
Obesity (record weight and height)
Table 8:
Medical history elements to assess in evaluation of a potential Hy’s Law 
case.
Category
Examples of Confounding Variables
Subject medical history
Prior history of liver injury or disease, including but not limited to 
Gilbert's syndrome, autoimmune disorders, cancer, Wilson's disease, 
NASH, alcoholic or infectious hepatitis, biliary tract disease, 
hypoxic/ischaemic hepatopathy
Family history 
Autoimmune disorder, cancer, Gilbert’s syndrome, Wilson’s disease
Substance use/abuse
Alcohol, illegal drugs, illegal intravenous (IV) drugs 
Prior & Concomitant Medications:  
Review all non-study medications 
and therapies, including: over-the-
counter (OTC), prescription. As 
appropriate, ask the subject to bring 
products/packaging to site and 
review contents.
History of recent of concomitant acetaminophen (APAP)/paracetamol 
use, excessive nonsteroidal anti-inflammatory drug (NSAID) intake, 
use of non-study drug or therapy that can cause liver damage or 
idiosyncratic adverse drug reactions
History of prior exposure to the investigational drug or similar drugs 
that could potentially have predisposed to an immune/allergic reaction 
upon exposure in the study   
Herbal and nutritional supplements
Herbal, complementary therapies, and nutritional supplements
Adulteration of products
Information on potential contamination or adulteration of food or 
other ingested products (such as nutritional supplements)
Chemical exposure
Occupational or in other situations
Potential exposure to infectious 
agents 
Infectious hepatitis, transfusion, travel (last 3 years), tattoos, sexually 
transmitted diseases, new sexual partner, shared needles
Special Diet
Special diet started since randomization. Unusual foods (e.g. foraged 
mushrooms) or special diets. Consumption of seasonal foods.
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Category
Examples of Confounding Variables
Other
Recent physical trauma, excessive exercise, or other prolonged 
physical exertion
3. All pertinent data including results of all evaluations for alternate etiologies. This 
should include all data, positive and negative, collected under Stage 1 and 2 evaluations (see
below).  
Note- laboratory data should be captured with laboratory normal ranges, and should include 
both protocol-scheduled laboratory evaluations as well as all unscheduled evaluations.  
Data collected on multiple occasions over time should ideally be displayed in a chart or graph.
If applicable, request copies of hospital discharge summaries, consultation reports, pathology 
reports, special studies (e.g. imaging or biopsy), etc.
4. Summary assessment of evaluation for potential etiologies: This should include the 
investigator’s summary impression regarding potential etiology of the observed liver function 
test abnormalities and status of the ongoing evaluation.   
5. Medical status and treatment plan: This should include the investigator’s summary 
impression regarding subject medical status and the treatment plan.
Evaluation for potential Hy’s Law cases if there are no evident alternate etiologies
Note: If a clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 
testing may not be required. In this case, consultation with the Sponsor medical monitor is 
required.
Stage 1 workup: should be performed within 48-72 hours: 

A detailed medical history and physical examination should be performed, including 
the elements noted in Table 7 and Table 8.    

Review aminotransferase values obtained prior to and during the study or 
administration of study medication.

Consultation with a hepatologist/gastroenterologist should be strongly considered
Perform the following laboratory tests:

Liver safety laboratories: ALT, AST, bilirubin (total and direct), alkaline phosphatase 
(ALP), gamma-glutamyl transferase (GGT)

Prothrombin Time (PT) / international normalized ratio (INR) 
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
Creatine phosphokinase (CPK)

Albumin

Complete blood count including platelet count and white blood cell count with an 
automated differential. Specific attention should be paid to eosinophil count as 
hypereosinophilia may be associated with idiosyncratic drug reactions. 

Toxicology 
screen 
for 
drugs 
of 
abuse 
(including 
ethanol) 
and 
for 
acetaminophen/paracetamol level should also be sent. Investigators may order 
additional toxicology tests as clinically indicated.

Viral hepatitis serologies (obtain appropriate consent prior to testing, if required 
locally)
o
A (IgG, IgM)
o
B (HepBs Ag, Hep Bs Ab, Hep Bc Ab)
o
C (RNA)
o
Cytomegalovirus (CMV): Viral PCR and serologies (IgG, IgM)   
o
Epstein-Barr Virus (EBV): Viral PCR and serologies (IgG, IgM)

Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent prior to 
testing, if required locally)

Appropriate samples should be collected and stored for potential viral PCR testing for 
the following viruses: hepatitis E, herpes simplex, varicella and parvovirus. These 
samples should not be submitted for analysis unless testing for these pathogens is 
triggered under Stage 2 workup, or there is a specific suspicion.       

Obtain a right upper quadrant ultrasound. If ultrasound is not available, MRI or CT 
scan may be used to image liver and biliary tract.   
Stage 2 workup: Unless otherwise agreed upon by the study investigator and sponsor 
medical monitor, Stage 2 tests should be drawn within one (1) week of receiving the Stage 
1 workup results and the results of Stage 1 evaluation are negative.
Notes: 
• A specific test may be performed earlier if the investigator determines that the clinical 
presentation leads to a certain diagnosis.
• If no etiology for the liver safety test abnormalities has been identified and evaluation 
is 
progressing 
to 
Stage 
2 
workup, 
consultation 
with 
a 
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hepatologist/gastroenterologist must occur unless both the study investigator and 
sponsor medical monitor agree that there is a compelling reason that this is 
unnecessary.   
Stage 2 workup should be guided by information accrued during Stage 1 workup as well as 
expert input from a hepatologist/gastroenterologist:
The following laboratory tests and evaluations may be considered, as appropriate, for 
evaluation of a potential Hy’s Law case.  

Serologies for the following infectious agents (contain appropriate local consent):
o
Viral hepatitis D (if subject has hepatitis B)
o
Viral hepatitis E   
o
Herpes simplex
o
Toxoplasmosis
o
Varicella
o
Parvovirus

Assessments for inherited liver diseases. Ensure appropriate consent is obtained for 
any genetic testing.
o
Hemochromatosis

Iron Studies: serum ferritin, iron, total iron binding capacity

Genetic test if necessary to confirm a diagnosis. A genetic test will 
generally not be necessary if iron studies are normal.
o
Gilbert’s disease: genetic testing if there is a suspicious history and total and 
direct bilirubin measurements do not support a clear diagnosis
o
Wilson’s disease: ceruloplasmin and 24hr urinary copper
o
Alpha-1-antitrypsin deficiency: serum alpha-1-antitrypsin concentration and 
protease inhibitor (PI) typing
o
Cystic fibrosis: genetic testing
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
Tests for autoimmune hepatitis
o
Antinuclear antibody (ANA) 
o
Anti-smooth muscle antibodies
o
Anti-liver-kidney microsomal antibodies
o
Anti-soluble liver antigen antibodies
o
Anti-actin antibodies

Testing for primary biliary cirrhosis: Anti-mitochondrial antibody (if ALP or TBL 
>ULN)

Celiac disease screening including anti-tissue transglutaminase (TTG) antibody, IgA, 
and anti-endomysial (EMA) antibody if clinically indicated.  

Consider screening for cystic fibrosis if clinically indicated.   
If laboratory tests or ultrasound evidence of biliary tract obstruction, consider obtaining ERCP 
or MRCP
CONTACTS
If you have any questions, please refer to your Sponsor contact list for the following Alimentiv 
or Pandion personnel:
- Clinical Research Associate or Subsidiary Monitor
- Medical Monitor
REFERENCES

Drug-Related Hepatotoxicity, Victor J. Navarro and John R. Senior, N Engl J Med 
2006;354:7314-9

Drug-induced liver injury:Hy’s rule revisited, Einar Björnsson MD, PhD, Clinical 
Pharmacology & Therapeutics, Vol. 79, Issue 6, June 2006.

Premarket Evaluation of Hepatotoxicity of Health Products, Ministry of Public Health, 
Canada, April 2012
o
https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-
products/applications-submissions/guidance-documents/hepatotoxicity-pre-
market-evaluation.html
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o
FDA Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009
o
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf 

Zimmerman HJ 1978 Hepatotoxicity, The Adverse Effects of Drugs and Other 
Chemicals on the Liver, Drug-induced liver disease (Appleton-Centry-Crofts, New 
York), pp 351-5.

Zimmerman HJ 1999 Hepatotoxicity, The Adverse Effects of Drugs and Other 
Chemicals on the Liver, Drug-induced liver disease (Lippincott Williams & Wilkins, 
Philadelphia), 2, pp 428-33.
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APPENDIX 8: 
12-LEAD ELECTROCARDIOGRAM ABNORMALITY 
CRITERIA
Potentially Significant 
Findings Leading to 
Screen Failure 
Potentially Significant 
Postrandomization Findings 
(clarification on action to 
take)
RHYTHM
Sinus Tachycardia
110 bpm
HR > 110 bpm and HR 
increase of ≥25 bpm from 
baseline, that is sustained for 
90 minutes or longer
Sinus Bradycardia
< 40 bpm
HR < 40 bpm and HR 
decrease of ≥5 bpm from 
baseline
Sinus Pause/Arrest
> 2.0 seconds
> 2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature 
Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR 
< 40 bpm
Junctional Rhythm with HR 
< 40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular 
Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
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Potentially Significant 
Findings Leading to 
Screen Failure 
Potentially Significant 
Postrandomization Findings 
(clarification on action to 
take)
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms + Increase of 
15 ms; or PR Increase of >
25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB 
as Defined Above
New Onset RBBB (Not 
Including Rate-related)
ICRBBB (QRS < 120 ms)
No Exclusion
Nothing
Short PR/Preexcitation 
Syndrome
Delta Wave + PR < 120 ms
Delta Wave + PR < 120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 
10 ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 
60 ms From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 
60 ms From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P 
Mitrale or P Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH 
Plus Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
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Potentially Significant 
Findings Leading to 
Screen Failure 
Potentially Significant 
Postrandomization Findings 
(clarification on action to 
take)
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive 
of Myocardial Ischaemia 
In 2 or more contiguous
leads
In 2 or more contiguous leads
T-wave Inversions 
Suggestive of Myocardial 
Ischaemia 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; mm=millimeter; 
ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using Fridericia 
formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1
08NYPB

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1<3%

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Amendment 8; 13-May-2022
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APPENDIX 10:
INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR STATEMENT
This study will be conducted in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation (ICH) E6 Good Clinical Practice (GCP) 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations.
I have read the protocol, including all appendices, and I agree it contains all necessary details 
for me and my staff to conduct this study. I will conduct this study as outlined herein. I will 
provide study personnel under my supervision access to all materials provided by Pandion 
Therapeutics. I will ensure my staff are appropriately informed of their obligations.
_________________________
_______________________
Principal Investigator Name
Signature
______________
__________
Date
Site Number
_________________________________
___________________________
Institution Name
Address of Institution
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APPENDIX 11:
DOCUMENT HISTORY
Version
Date
Original
12-Mar-2021
Amendment 1
11-May-2021
Amendment 4
17-Dec-2021
Amendment 8
13-May-2022
08NYPB

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