Conditions: Chronic Graft Versus Host Disease
Keywords: GVHD ponesimod
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
Chronic graft versus host diseasre (GVHD) is a serious reaction that might occur in a person (the host) who has received cells or organs (graft) from another person because the graft attacks the host's cells. Currently there are no approved therapies for chronic GVHD in the USA, and patients with chroninc GVHD are treated with immunosuppressant drugs. T-lymphocytes (a type of white blood cells) are likely to play a role in the development of chronic GVHD. Due to the capacity of ponesimod to block the traffic of T-lymphocytes, ponesimod may be a new therapeutic approach to treat chroninc GVHD.

The main objective of this study is to assess the effectiveness and safety of several doses of ponesimod in subjects with chronic GVHD who did not respond to standard available treatments.

Detailed description:

Arms:
arm 1: Study treatment consists of 3 consecutive periods: 5 mg ponesimod treatment period (including up-titration), 10 mg treatment period (including up-titration) and a 20 mg treatment period.

Interventions: intervention 1: Ponesimod
Intervention descriptions: intervention 1: Oral film-coated tablets at the doses of 2, 3, 4, 5, 6, 7, 8, 9, 10, and 20 mg. One tablet of ponesimod at any dose will be taken orally once daily.

Protocol document:
Prot_SAP_000.pdf: 
Ponesimod / ACT-128800 
Chronic Graft versus Host Disease 
Protocol AC-058C202 
A Phase 2, open-label, single-arm, intra-subject dose-escalation study to investigate 
the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in 
subjects with symptomatic moderate or severe chronic GVHD inadequately 
responding to first or second line therapy 
Study Phase: 
NCT Number: 
Date: 
Version and History: 
2 
NCT02461134 
5 July 2016 
Final Version 4 
Amendment 2, Final Version 3, 21 May 2015 
Amendment 1, Final Version 2, 28 January 2015 
Final Version 1, 16 December 2014 
Confidentiality statement 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed 
without the consent of Actelion Pharmaceuticals Ltd.


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SPONSOR CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Trial Physician  
 
Daniele D’Ambrosio, MD, PhD 
 
 
Fax 
 
e-mail 
  
MEDICAL HOTLINE 
Toll phone number:  
 
  
 
1 (800) 540-5687 (USA) 
  
 
+ 41 61 227 05 63 (Switzerland) 
 
 
Site-specific toll telephone numbers and toll-free numbers for the Medical Hotline can 
be found in the Investigator Site File. 
 
 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
 
 
Clinical Science Program Head 
Daniele D’Ambrosio, MD, PhD 
 
Clinical Trial Statistician 
 
 
Clinical Project Statistician 
 
 
Drug Safety Physician 
 
 
 
NATIONAL PRIMARY INVESTIGATORS 
 
 
 
 
National Institutes of Health 
 


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CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
 
 
CENTRAL ENROLLMENT 
 
 
 
A list of site-specific contact details for CROs can be found in the Investigator Site 
File. 
 
 
 
 


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SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Ponesimod / ACT-128800 
Indication 
Chronic graft versus host disease 
Protocol number, study title  
AC-058C202, A Phase 2, open-label, single-arm, intra-subject dose-escalation study to 
investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod 
in subjects with symptomatic moderate or severe chronic GVHD inadequately responding 
to first or second line therapy 
I approve the design of this study.  
 
 


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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Ponesimod / ACT-128800 
Indication 
Chronic graft versus host disease 
Protocol number, study title  
AC-058C202, A Phase 2, open-label, single-arm, intra-subject dose-escalation study to 
investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod 
in subjects with symptomatic moderate or severe chronic GVHD inadequately responding 
to first or second line therapy 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
electronic Case Report Form (CRF), and any other protocol-related documents. I fully 
understand that any changes instituted by the investigator(s) without previous agreement 
with the sponsor would constitute a protocol deviation, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. I will obtain approval by an Institutional Review 
Board or Independent Ethics Committee (IRB/IEC) prior to study start and signed informed 
consent from all subjects included in this study. If an amendment to the protocol is 
necessary, I will obtain approval by an IRB/IEC and ensure approval by regulatory 
authorities (if applicable) have been obtained before the implementation of changes 
described in the amendment. I will allow direct access to source documents and study 
facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and agree to 
inspection by regulatory authorities or IRB/IEC representative. I will ensure that the study 
treatment(s) supplied by the sponsor are being used only as described in this protocol. I 
confirm herewith that the sponsor is allowed to enter and utilize my professional contact 
details and function in an electronic database for internal purposes and for submission to 
Health Authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Site Principal 
Investigator 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................16 
SUBSTANTIAL GLOBAL AMENDMENT 3 .................................................................20 
PROTOCOL SYNOPSIS AC-058C202 ............................................................................26 
1 
BACKGROUND .........................................................................................................54 
1.1 
Chronic graft versus host disease .................................................................54 
1.1.1 
Epidemiology ....................................................................................54 
1.1.2 
Pathogenesis ......................................................................................54 
1.1.3 
Current treatments .............................................................................55 
1.1.4 
Unmet medical need .........................................................................56 
1.2 
Sphingosine 1-phosphate receptors ..............................................................60 
1.2.1 
S1P and GVHD: preclinical evidence ..............................................60 
1.3 
Ponesimod, selective modulator of S1P1 ......................................................61 
1.3.1 
Nonclinical studies ............................................................................61 
1.3.2 
Clinical studies ..................................................................................62 
1.3.2.1 
Clinical pharmacology .................................................. 62 
1.3.2.2 
Pharmacodynamics in humans ...................................... 62 
1.3.2.3 
Efficacy in humans ........................................................ 63 
1.3.2.4 
Safety and tolerability ................................................... 64 
1.4 
Rationale and purpose of the study ...............................................................65 
2 
STUDY OBJECTIVES ...............................................................................................65 
2.1 
Main objectives .............................................................................................65 
2.2 
Exploratory objectives ..................................................................................66 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................66 
3.1 
Study design .................................................................................................66 
3.2 
Study periods ................................................................................................66 
3.2.1 
Screening Period ...............................................................................66 


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3.2.2 
Core Treatment Period ......................................................................66 
3.2.3 
Core Safety Follow-up Period / Follow-up Period 1 ........................67 
3.2.4 
Extension Treatment Period ..............................................................67 
3.2.5 
Extension Safety Follow-up Period (Follow-up Period 2) ...............68 
3.3 
Study design rationale ..................................................................................68 
3.4 
Site personnel and their roles ........................................................................71 
3.4.1 
Principal investigator and sub-investigator .......................................71 
3.4.2 
Cardiac safety assessor .....................................................................71 
3.4.3 
Clinical coordinator / study nurse .....................................................72 
3.4.4 
Ophthalmologist ................................................................................72 
3.4.5 
Pulmonary function laboratory technician or expert ........................72 
3.4.6 
Pulmonologist ...................................................................................72 
3.5 
Study Committees .........................................................................................73 
3.5.1 
Study Monitoring Committee ...........................................................73 
3.5.2 
Ophthalmology Safety Board ...........................................................73 
4 
SUBJECT POPULATION ..........................................................................................73 
4.1 
Subject population description .....................................................................73 
4.2 
Rationale for the selection of the study population ......................................74 
4.3 
Inclusion criteria ...........................................................................................74 
4.3.1 
Women of child-bearing potential ....................................................75 
4.4 
Exclusion criteria ..........................................................................................76 
4.5 
Medical history .............................................................................................80 
4.6 
Extension Treatment Period inclusion criteria .............................................83 
4.7 
Extension Treatment Period exclusion criteria .............................................83 
5 
TREATMENTS ..........................................................................................................83 
5.1 
Study treatment .............................................................................................83 
5.1.1 
Investigational treatment: description and rationale .........................84 
5.1.2 
Study treatment administration .........................................................84 
5.1.2.1 
Subject study treatment diary ........................................ 84 
5.1.2.2 
Titration ......................................................................... 85 
5.1.2.3 
Criteria to permit dose increases at Day 29 and Day 57 
(Core Treatment Period) ................................................ 87 
5.1.2.4 
Maintenance of ponesimod dose (Core and Extension 
Treatment Periods) ........................................................ 87 
5.1.3 
Blinding ............................................................................................88 
5.1.4 
Study treatment supply .....................................................................88 
5.1.4.1 
Study treatment packaging and labeling ....................... 88 
5.1.4.2 
Study treatment distribution and storage ....................... 89 


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5.1.4.3 
Study treatment dispensing ........................................... 89 
5.1.4.4 
Study treatment return and destruction ......................... 89 
5.1.5 
Drug accountability and compliance ................................................89 
5.1.5.1 
Drug accountability ....................................................... 89 
5.1.5.2 
Drug compliance ........................................................... 89 
5.1.6 
Ponesimod dose adjustments and interruptions ................................90 
5.1.7 
Cardiac monitoring for ponesimod initiation and re-initiation 
requiring re-uptitration ......................................................................90 
5.1.8 
Procedures for re-initiation of ponesimod in the event of 
interruption ........................................................................................91 
5.1.9 
Premature discontinuation of ponesimod .........................................96 
5.1.10 
Specific dose-reduction, interruption, or premature 
discontinuation criteria .....................................................................96 
5.1.10.1 
Cardiovascular ............................................................... 97 
5.1.10.2 
Hematologic .................................................................. 98 
5.1.10.3 
Hepatobiliary ................................................................. 99 
5.1.10.4 
Immune/infection ........................................................ 103 
5.1.10.5 
Ocular .......................................................................... 106 
5.1.10.6 
Reproductive/pregnancy .............................................. 106 
5.1.10.7 
Respiratory .................................................................. 106 
5.2 
Mandatory concomitant chronic GVHD treatment (Core Treatment 
Period only) ................................................................................................109 
5.2.1 
Immunosuppressant treatments other than ponesimod ...................109 
5.2.2 
Modifications to IS treatments ........................................................109 
5.3 
Previous and concomitant therapy ..............................................................110 
5.3.1 
Definitions ......................................................................................110 
5.3.2 
Reporting of previous HSCT and GVHD therapies .......................111 
5.3.3 
Reporting of concomitant therapy in the eCRF ..............................111 
5.3.4 
Allowed concomitant therapy .........................................................111 
5.3.5 
Forbidden concomitant therapy ......................................................111 
6 
STUDY ENDPOINTS ..............................................................................................112 
6.1 
Pharmacokinetic and pharmacodynamic endpoints ....................................112 
6.1.1 
Pharmacokinetic evaluations ..........................................................112 
6.1.2 
Pharmacodynamic evaluations .......................................................112 
6.1.3 
PK/PD relationship .........................................................................112 
6.2 
Safety endpoints .........................................................................................113 
6.2.1 
Overall safety endpoints .................................................................113 
6.2.2 
Absolute lymphocyte count ............................................................113 
6.2.3 
Cardiac rate and rhythm safety endpoints .......................................113 


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6.2.4 
Pulmonary function safety endpoints .............................................113 
6.2.5 
Other safety endpoints ....................................................................114 
6.3 
Efficacy endpoints (exploratory) ................................................................114 
6.3.1 
Complete overall response definition .............................................114 
6.3.2 
Partial overall response definition ..................................................115 
6.3.3 
Subject responder / non-responder definition .................................116 
6.3.4 
Other efficacy endpoints .................................................................116 
6.4 
Quality of life endpoints .............................................................................117 
7 
STUDY ASSESSMENTS .........................................................................................117 
7.1 
Screening/baseline assessments ..................................................................118 
7.1.1 
Informed consent (screening visit) .................................................118 
7.1.2 
Baseline demographics and disease characteristics ........................118 
7.1.3 
Study-concomitant therapies ...........................................................118 
7.2 
Pharmacokinetic and pharmacodynamic assessments ................................119 
7.2.1 
Pharmacokinetic assessments .........................................................119 
7.2.1.1 
Timing for sampling .................................................... 119 
7.2.1.2 
Procedures for sampling .............................................. 119 
7.2.1.3 
Labeling and shipment ................................................ 119 
7.2.1.4 
Bioanalysis .................................................................. 120 
7.2.2 
Pharmacodynamic assessments ......................................................120 
7.3 
Safety assessments ......................................................................................120 
7.3.1 
12-lead ECG ...................................................................................120 
7.3.2 
Blood pressure ................................................................................122 
7.3.3 
Spirometry ......................................................................................123 
7.3.4 
DLCO ...............................................................................................124 
7.3.5 
Chest X-ray .....................................................................................125 
7.3.6 
Test for tuberculosis ........................................................................125 
7.3.7 
Ophthalmological assessments .......................................................125 
7.3.8 
Optical Coherence Tomography .....................................................126 
7.3.9 
Weight and height ...........................................................................126 
7.3.10 
Physical examination ......................................................................127 
7.3.11 
Laboratory assessments ..................................................................127 
7.3.11.1 
Type of laboratory ....................................................... 127 
7.3.11.2 
Laboratory tests ........................................................... 128 
7.4 
Efficacy assessments ..................................................................................130 
7.4.1 
Organ-specific assessments (Chronic GVHD Activity 
Assessment Form A) .......................................................................130 
7.4.1.1 
Skin .............................................................................. 130 
7.4.1.2 
Mouth .......................................................................... 131 


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7.4.1.3 
Liver ............................................................................ 131 
7.4.1.4 
Lungs ........................................................................... 131 
7.4.1.5 
Eyes ............................................................................. 132 
7.4.1.6 
Joints and fascia ........................................................... 132 
7.4.1.7 
GI tract ......................................................................... 133 
7.4.2 
Clinician global reported ratings (Chronic GVHD Activity 
Assessment Form A) .......................................................................133 
7.4.2.1 
Clinician Overall Severity Scale. ................................ 133 
7.4.2.2 
Clinician None-Mild-Moderate-Severe Scale ............. 134 
7.4.2.3 
Clinician 7-Point Change Scale ................................... 134 
7.5 
Quality of Life assessments ........................................................................134 
7.5.1 
Lee Symptom Scale ........................................................................134 
7.5.2 
Patient-reported chronic GVHD symptoms (Chronic GVHD 
Activity Assessment Form B) .........................................................135 
7.5.2.1 
Skin itching .................................................................. 135 
7.5.2.2 
Skin and/or joint tightening ......................................... 135 
7.5.2.3 
Mouth sensitivity ......................................................... 135 
7.5.2.4 
Genital discomfort ....................................................... 136 
7.5.2.5 
Eyes ............................................................................. 136 
7.5.3 
Patient-reported global ratings (Chronic GVHD Activity 
Assessment Form B) .......................................................................136 
7.5.3.1 
Patient-Reported Overall Severity Scale ..................... 136 
7.5.3.2 
Patient-Reported Mild-Moderate-Severe Scale ........... 136 
7.5.3.3 
Patient-Reported 7-Point Change Scale ...................... 136 
7.6 
Exploratory biomarker assessments ...........................................................137 
7.6.1 
Blood lymphocyte subsets ..............................................................137 
7.6.1.1 
Sampling time .............................................................. 137 
7.6.1.2 
Sampling procedure ..................................................... 137 
7.6.1.3 
Labeling and shipment ................................................ 137 
7.6.1.4 
Bioanalysis .................................................................. 137 
7.6.2 
Plasma biomarkers ..........................................................................137 
7.6.2.1 
Sampling time .............................................................. 138 
7.6.2.2 
Sampling procedure ..................................................... 138 
7.6.2.3 
Labeling and shipment ................................................ 138 
7.6.2.4 
Bioanalysis .................................................................. 138 
7.6.3 
Exploratory biomarker samples ......................................................138 
7.6.3.1 
Sampling time .............................................................. 138 
7.6.3.2 
Sampling procedure ..................................................... 138 
7.6.3.3 
Labeling and shipment ................................................ 138 
7.7 
Total blood volume .....................................................................................139 


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8 
SCHEDULE OF VISITS AND ASSESSMENTS ....................................................139 
8.1 
Screening period .........................................................................................141 
8.1.1 
Visit 1 (screening) ...........................................................................141 
8.1.2 
Visit 2 Enrollment Day 1 (pre-dose) ...............................................142 
8.1.2.1 
Visit 2 – Day 1 – pre-dose assessments ...................... 142 
8.2 
Core Treatment Period ................................................................................143 
8.2.1 
Visit 2 – Enrollment Day 1 (post-dose) ..........................................143 
8.2.1.1 
Visit 2 - Day 1 - Enrollment and post-dose 
assessment ................................................................... 143 
8.2.2 
Visit 3 – Week 4 .............................................................................144 
8.2.3 
Visit 4 – Week 8 .............................................................................145 
8.2.4 
Visit 5 – Week 12 ...........................................................................146 
8.2.5 
Visits 6 and 7 - Weeks 16 and 20 ...................................................147 
8.2.6 
Visit 8 – EOT1 Visit .......................................................................147 
8.3 
Core Safety Follow-up Period / Follow-up Period 1 ..................................148 
8.3.1 
Visit 9 - 30-day post-Core Treatment Safety Follow-up visit 1 
(FU1) ...............................................................................................149 
8.3.2 
Visit 10 - 90-day post-treatment Safety Follow-up visit 2 
(FU2) ...............................................................................................149 
8.4 
Extension Treatment Period .......................................................................150 
8.4.1 
Visit 11 (EX-1) ...............................................................................150 
8.4.2 
Visits 12, 13, 15, and 16 (EX-2, EX-3, EX-5, and EX-6), 
Extension Weeks 4, 8, 16, and 20 ...................................................151 
8.4.3 
Visits 14, 17, 18, 19, 20, 21, and 22 (EX-4, EX-7, EX-8, EX-9, 
EX-10, EX-11, and EX-12), Extension Weeks 12, 24, 36, 48, 
60, 72, and 84 ..................................................................................152 
8.4.4 
Visit 23 (EX-13, EOT2) Extension Week 96 .................................153 
8.4.5 
Extension Safety Follow-up Period (Follow-up Period 2) .............154 
8.5 
Unscheduled visits ......................................................................................154 
8.5.1 
Visits for re-initiation of study drug ...............................................154 
8.5.2 
Unscheduled visits for reasons other than re-initiation of study 
drug .................................................................................................155 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ........................................................................................................................156 
9.1 
Study completion ........................................................................................156 
9.2 
Premature withdrawal from study ..............................................................156 
9.3 
Premature termination or suspension of the study ......................................157 
9.4 
Medical care of subjects after study completion / withdrawal from 
study ............................................................................................................158 


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10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .........................158 
10.1 
Adverse events ............................................................................................158 
10.1.1 
Definitions of adverse events ..........................................................158 
10.1.2 
Intensity of adverse events ..............................................................159 
10.1.3 
Relationship to study treatment ......................................................160 
10.1.4 
Adverse events associated to study design or protocol-
mandated procedures ......................................................................160 
10.1.5 
Reporting of adverse events ............................................................160 
10.1.5.1 
Subjects prematurely discontinued from the Core 
Treatment Period ......................................................... 160 
10.1.5.2 
Subjects not prematurely discontinued from the Core 
Treatment Period and not entering the Extension 
Treatment Period ......................................................... 160 
10.1.5.3 
All Subjects entering the Extension Treatment Period 160 
10.1.6 
Follow-up of adverse events ...........................................................160 
10.2 
Serious adverse events ................................................................................161 
10.2.1 
Definitions of serious adverse events .............................................161 
10.2.1.1 
Serious adverse events ................................................. 161 
10.2.1.2 
Serious adverse events associated with the study design 
or protocol-mandated procedures ................................ 161 
10.2.2 
Reporting of serious adverse events ...............................................162 
10.2.2.1 
During screening period .............................................. 162 
10.2.2.2 
During Core Treatment Period and Extension Treatment 
Period ........................................................................... 162 
10.2.2.3 
During the follow-up period for subjects prematurely 
discontinued from the Core Treatment Period ............ 162 
10.2.2.4 
During follow-up period for subjects not prematurely 
discontinued from the Core Treatment Period and not 
entering the Extension Treatment Period .................... 162 
10.2.2.5 
During follow-up period for all subjects entering the 
Extension Treatment Period ........................................ 162 
10.2.3 
Follow-up of serious adverse events ...............................................162 
10.2.4 
After the follow-up period ..............................................................162 
10.2.5 
Reporting procedures ......................................................................163 
10.3 
Pregnancy ...................................................................................................163 
10.3.1 
Reporting of pregnancy ..................................................................163 
10.3.2 
Follow-up of pregnancy ..................................................................164 
10.4 
Study safety monitoring ..............................................................................164 
11 STATISTICAL METHODS .....................................................................................165 


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11.1 
Analysis sets ...............................................................................................165 
11.1.1 
Screened analysis set ......................................................................165 
11.1.2 
Full analysis set ...............................................................................165 
11.1.3 
Per-protocol set ...............................................................................165 
11.1.4 
Safety set .........................................................................................166 
11.1.5 
PD analysis set ................................................................................166 
11.1.6 
PK analysis set ................................................................................166 
11.1.7 
Extension set ...................................................................................166 
11.1.8 
Usage of the analysis sets ...............................................................166 
11.2 
Variables .....................................................................................................167 
11.2.1 
Primary PD variable ........................................................................167 
11.2.2 
Safety variables ...............................................................................167 
11.2.3 
Exploratory efficacy variables ........................................................168 
11.2.4 
Other variables ................................................................................171 
11.2.5 
Variables in Extension Treatment Period .......................................172 
11.2.6 
Overall testing strategy of the PD variable .....................................172 
11.2.7 
Analysis of the primary PD variable(s) ..........................................172 
11.2.7.1 
Hypotheses and statistical model ................................ 172 
11.2.7.2 
Handling of missing data ............................................. 173 
11.2.7.3 
Main analysis of the primary PD variable (primary 
analysis) ....................................................................... 173 
11.2.7.4 
Supportive/sensitivity analyses ................................... 173 
11.2.7.5 
Subgroup analyses ....................................................... 174 
11.2.8 
Analysis of the efficacy variables ...................................................174 
11.2.9 
Analysis of the efficacy variables during the Extension 
Treatment Period .............................................................................174 
11.2.10 
Analysis of the safety variable(s) ....................................................175 
11.2.10.1 
Adverse Events ............................................................ 175 
11.2.10.2 
Absolute lymphocyte count ......................................... 176 
11.2.10.3 
Cardiac Safety ............................................................. 176 
11.2.10.4 
Pulmonary safety ......................................................... 177 
11.2.10.5 
Vital signs .................................................................... 178 
11.2.10.6 
Laboratory ................................................................... 178 
11.2.10.7 
Ocular safety ................................................................ 178 
11.2.11 
Analysis of (other) variable(s) ........................................................179 
11.2.11.1 
Quality of Life endpoints ............................................ 179 
11.2.11.2 
PK analysis .................................................................. 179 
11.2.11.3 
PD analysis .................................................................. 179 
11.2.11.4 
PK/PD relationship ...................................................... 179 
11.3 
Interim analyses ..........................................................................................179 


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11.4 
Sample size .................................................................................................180 
11.4.1 
Sample size for primary endpoint ...................................................180 
11.4.2 
Sample size assumptions ................................................................180 
11.4.3 
Sample size re-estimation ...............................................................182 
12 DATA HANDLING ..................................................................................................182 
12.1 
Data collection ............................................................................................182 
12.2 
Maintenance of data confidentiality ...........................................................182 
12.3 
Database management and quality control .................................................182 
13 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................183 
13.1 
Ethics and Good Clinical Practice ..............................................................183 
13.2 
Independent Ethics Committee / Institutional Review Board ....................183 
13.3 
Informed consent ........................................................................................184 
13.4 
Compensation to subjects and investigators ...............................................185 
13.5 
Protocol adherence/compliance ..................................................................185 
13.6 
Protocol amendments .................................................................................185 
13.7 
Essential documents and retention of documents .......................................185 
13.8 
Monitoring ..................................................................................................186 
13.9 
Investigator site file ....................................................................................187 
13.10 
Audit ...........................................................................................................188 
13.11 
Inspections ..................................................................................................188 
13.12 
Reporting of study results and publication .................................................188 
14 REFERENCES ..........................................................................................................190 
15 APPENDICES ...........................................................................................................197 
 


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LIST OF TABLES 
Table 1 
Visit and assessment schedule .......................................................... 50 
Table 2 
Overall response and survival rates for selected secondary agents .. 56 
Table 3 
Up-titration and dose-escalation schedule: Core Treatment Period . 85 
Table 4 
Up-titration schedule: Extension Treatment Period ......................... 86 
Table 5 
Common opportunistic infections in patients at least 30 days 
post-HSCT ...................................................................................... 104 
Table 6 
Suggested infection prophylaxis in chronic GVHD ....................... 105 
Table 7 
Total blood volume drawn per subject - Core Treatment Period and 
Follow-up Period 1 ......................................................................... 139 
Table 8 
Total blood volume drawn per subject - Extension Treatment Period 
and Follow-up Period 2 .................................................................. 139 
Table 9 
Definition of notable laboratory abnormalities for ponesimod ...... 209 
 
 
LIST OF FIGURES 
Figure 1 
Long-term success in withdrawing all IS treatment in patients 
initially treated with glucocorticoids ................................................ 58 
Figure 2 
Study periods: Screening through Follow-up Period 1 .................... 67 
Figure 3 
Study periods: Follow-up Period 1 through Follow-up Period 2 ..... 68 
 
 
LIST OF APPENDICES 
Appendix 1 
Additional subject eligibility guidance .......................................... 197 
Appendix 2 
Chronic GVHD Stage and Score forms ......................................... 199 
Appendix 3 
Guidance for initiating or dose increasing QT-prolonging drugs with 
known risk of Torsades de Pointes ................................................. 204 
Appendix 4 
Prohibited anti-arrhythmic or HR-lowering drugs ......................... 206 
Appendix 5 
Adverse events of special interest .................................................. 207 
Appendix 6 
Abnormalities for ECG, blood pressure and laboratory variables . 208 
Appendix 7 
Chronic GVHD Activity Assessment forms .................................. 212 
Appendix 8 
Lee Symptom Scale ........................................................................ 216 
Appendix 9 
Rule of 9s ....................................................................................... 217 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ADL  
Activities of daily living 
AE  
Adverse event 
ALC  
Absolute lymphocyte count 
ALG  
Anti-lymphocyte globulin 
ALT  
Alanine aminotransferase 
ARR  
Annualized relapse rate  
AST  
Aspartate aminotransferase 
ATG  
Anti-thymocyte globulin 
ATS  
American Thoracic Society 
AV  
Atrioventricular 
BOS  
Bronchiolitis obliterans syndrome 
BP  
Blood pressure 
bpm  
Beats per minute 
BSA  
Body surface area 
CDC  
The Centers for Disease Control and Prevention 
CI  
Confidence interval 
CMV  
Cytomegalovirus 
CNI  
Calcineurin inhibitor 
COPD  
Chronic obstructive pulmonary disease 
CRO  
Contract research organization 
CsA  
Cyclosporine 
CT  
Computed tomography 
CTCAE  
Common terminology criteria for adverse events 
Ctrough  
Trough concentrations 
CXR  
Chest X-ray 
DBO  
Diastolic blood pressure 
DDI  
Drug-drug interaction 
DLCO  
Diffusing capacity of lung for carbon monoxide 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 


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EDTA  
Ethylenediaminetetraacetic acid 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ERS  
European Respiratory Society 
ES  
Extension set 
EVL  
Everolimus 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
FEF  
Forced expiratory flow 
FEV1  
Forced expiratory volume in 1 second 
FFS  
Failure-free survival 
FU  
Follow-up 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
GI  
Gastrointestinal 
GVHD  
Graft versus host disease 
Hb  
Hemoglobin 
HIV  
Human immunodeficiency virus 
HLA  
Human leukocyte antigen 
HR   
Heart rate 
HSCT  
Hematopoietic stem cell transplantation 
i.v.  
Intravenous(ly) 
IB  
Investigator’s Brochure 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
IEC  
Independent Ethics Committee 
INR  
International normalized ratio 
IRB  
Institutional Review Board 
IRT  
Interactive response technology 
IS  
Immunosuppressant 


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ISF  
Investigator site file 
KCS  
Keratoconjunctivitis sicca 
kg  
Kilogram 
KPS  
Karnofsky Performance Score 
LOCF  
Last observation carried forward 
LSS  
Lee Symptom Scale 
MCP-Mod  
Multiple Comparison Procedure – Modeling 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg  
Milligram 
MMF  
Mycophenolate mofetil 
MMP-1  
Matrix metalloproteinase-1 
MOC  
Methods of contraception 
MPS  
Mycophenolate sodium 
mRNA  
Messenger RNA 
MS  
Multiple sclerosis 
MTX  
Methotrexate 
NIH  
National Institutes of Health 
NK  
Natural killer 
NRM  
Non-relapse mortality 
NYHA  
New York Heart Association 
o.d.  
Once daily 
OCT  
Optical coherence tomography 
OSB  
Ophthalmology Safety Board 
PASI  
Psoriasis Area and Severity Index 
PD  
Pharmacodynamic 
PDS  
Pharmacodynamic analysis set 
PFT  
Pulmonary function test 
PK  
Pharmacokinetic 
PKS  
Pharmacokinetic analysis set 
PML  
Progressive multifocal leukoencephalopathy 
PPS  
Per-protocol Set 


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P-ROM  
Photographic range of motion scale 
PTEN  
Phosphatase and tensin homolog 
QTcB  
QT corrected for heart rate on the basis of Bazett’s formula 
QTcF  
QT corrected for heart rate on the basis of Fridericia’s formula 
ROM  
Range of motion 
RRMS  
Relapsing remitting multiple sclerosis 
S1P  
Sphingosine 1-phosphate 
S1P1  
Sphingosine 1-phosphate receptor 1 
SAE  
Serious adverse event 
SAF  
Safety Set 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SIV  
Site initiation visit 
SMC  
Study Monitoring Committee 
SOC  
System organ class 
SOP  
Standard operating procedure 
SRL  
Sirolimus 
STD  
Standard deviation 
TAC  
Tacrolimus 
TB  
Tuberculosis 
TBL  
Total bilirubin 
ULN  
Upper limit of the normal range 
WBC  
White blood cell 
WOCBP  
Women of child-bearing potential 
 
 
 


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SUBSTANTIAL GLOBAL AMENDMENT 3 
Amendment rationale 
This amendment rationale applies to global protocol AC-058C202 Version 3 dated 21 May 
2015. The resulting amended global protocol is Version 4 dated 5 July 2016. 
The main reason for this amendment is to improve the AC-058C202 study eligibility 
criteria to recruit subjects who are more representative of the chronic graft versus host 
disease (GVHD) population in the real world. To accomplish this, while still ensuring 
safety of subjects included in the study, the eligibility criteria based on pulmonary function 
test results (i.e., spirometry and diffusing capacity of lung for carbon monoxide [DLCO]) 
have been changed, and the peripheral blood absolute lymphocyte count (ALC) eligibility 
threshold has been lowered. The exclusion criterion based on 1-s forced expiratory volume 
(FEV1) has been modified to exclude subjects with predicted normal value < 60% rather 
than < 75%, and exclusion criteria based on forced vital capacity (FVC) and DLCO results 
have been removed. The exclusion criterion based on ALC has been modified to exclude 
subjects with < 0.5 × 109 cells/L rather than < 0.8 × 109 cells/L. In line with these changes 
in eligibility criteria, adjustments were made to the guidance and criteria for interruption 
of study treatment in case of decreases in FEV1, FVC, or ALC occurring during treatment.  
The following rationale is provided to support these changes.  
Rationale for lowering ALC exclusion threshold to < 0.5 × 109 cells/L and ALC threshold 
for treatment interruption to < 0.1 × 109 cells/L 
Immune reconstitution is essential for the success of an allogeneic hematopoietic stem cell 
transplantation (HSCT), and a surrogate marker for immune reconstitution is ALC 
recovery. However, the rate of ALC recovery varies in allogeneic HSCT recipients and 
many patients will have low ALC several months after HSCT. Patients with chronic GVHD 
can be as early as 3–4 months after HSCT and they may receive multiple 
immunosuppressive treatments which may further decrease ALC. Although the presence 
of very low levels of ALC post-HSCT is associated with poor long-term outcomes 
[Kim 2015], subjects with ALC > 0.5 × 109 cells/L do not show a significant increase in 
non-relapse mortality (NRM) [Yamamoto 2014].  
Ponesimod is a selective and reversible sphingosine 1-phosphate receptor 1 (S1P1) 
modulator which causes a marked and sustained blood lymphocyte count reduction. This 
is a well described pharmacological effect of S1P1 modulators due to reversible inhibition 
of T and B lymphocyte egress from lymphoid organs [Brinkmann 2010]. In healthy 
subjects and patients with psoriasis or multiple sclerosis (MS), ponesimod has shown a 
clear dose dependent decrease of lymphocyte count with a mean decrease of approximately 
30%, 50%, 65% from baseline with 5, 10, or 20 mg, respectively [Ponesimod IB]. Based 


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on these data, treatment of chronic GVHD patients with pre-existing low ALC (e.g., < 0.8 
≥ 0.5 × 109 cells/L) with 20 mg ponesimod may result in decreased ALC < 0.2 × 109 cells/L. 
However, such decrease will be the result of a targeted and reversible sequestration of 
discrete subsets of T and B cells in lymphoid organs.  
In Phase 2 studies in MS and psoriasis patients, the overall rate of infections did not 
increase with ponesimod as compared to placebo, despite lymphocyte counts decreased 
< 0.5 × 109 cells/L in many subjects receiving placebo. Several studies with the 
non-selective S1P receptor modulator fingolimod as well as ponesimod have shown a 
predominant effect on naïve T cells and central memory CD4+ T cells with sparing of 
effector T cells [Mehling 2011, D’Ambrosio 2015]. Effector T cells, particularly CD8+, 
are thought to play a pivotal role in controlling viral infections. Preservation of effector 
T cell function may help to maintain control of viral replication and prevent the outbreak 
of infection. 
Despite sequestration of T and B lymphocytes, available data in MS patients treated with 
the non-selective S1P receptor modulator fingolimod indicate no association between 
lymphocyte count reduction and the risk of infections as well as preserved antibody 
response to non-live vaccines [Francis 2014, Kappos 2015]. In the initial clinical studies 
with fingolimod, treatment was to be interrupted when lymphocyte counts were 
< 0.1 × 109 cells/L but later this threshold was increased to < 0.2 × 109 cells/L. As a 
consequence, lymphocyte counts < 0.2 × 109 cells/L have been observed in a substantial 
number of MS patients treated with fingolimod and in these patients the rate of infections 
did not appear higher than in patients treated with placebo [Francis 2014].  
Importantly, and differently from fingolimod, lymphocyte count reduction by ponesimod 
is rapidly established, stable on treatment, and rapidly reversible after treatment 
discontinuation (within 1 week). Thus, in case of a clinically significant lymphopenia (e.g., 
ALC < 0.1 × 109 cells/L) or infection, ponesimod treatment may be interrupted and 
lymphocyte counts can be expected to return to the pre-treatment range within a few days, 
thus rapidly restoring the immune system function.  
It is also relevant to emphasize that in this open label study ALC values will always be 
visible to the investigator, together with absolute and differential white cell counts, and the 
protocol allows treatment interruption at any time if this is considered in the best interest 
of the patient at the discretion of the investigator.  
Taken together, these data justify lowering the ALC threshold for inclusion of subjects to 
< 0.5 × 109 cells/L from < 0.8 × 109 cells/L and also lowering the ALC threshold for 
interruption of ponesimod treatment to < 0.1 × 109 cells/L from < 0.2 × 109 cells/L, as these 
changes are expected to improve the external validity of the study without significantly 
increasing the risk for patients. 


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Rationale for changes to pulmonary function test exclusion criteria and for changes to the 
criteria for treatment interruption following bronchodilator challenge. 
A number of pulmonary complications can occur after an allogeneic HSCT, including 
infection, neoplasia, pulmonary edema, peri-engraftment respiratory distress syndrome, 
idiopathic pneumonia and diffuse alveolar hemorrhage. Additionally, recipients of 
allogeneic HSCT patients who develop chronic GVHD may develop the bronchiolitis 
obliterans syndrome (BOS), sclerosis of the chest wall, myositis, and muscle weakness. As 
a result of these complications pulmonary function test (PFT) abnormalities with 
obstruction, restriction, or diffusion impairment are common in patients with chronic 
GVHD.  
BOS is a serious irreversible obstruction, that does not respond to bronchodilators and is 
diagnosed by a decline in FEV1 and FEV1/FVC ratio < 0.7, and is associated with poor 
prognosis of chronic GVHD [Jagasia 2015]. Long-term observational data from 6-month 
survivors of allogeneic HSCT showed that obstruction, but not restriction or diffusion 
impairment, is associated with a significant increased mortality [Marras 2004].  
Although a patient may experience a diffusion impairment (measured by a decline in DLCO) 
after HSCT, BOS does not directly affect DLCO values and restrictive changes are not 
characteristics of this manifestation. In 2015, the National Institutes of Health (NIH) 
Chronic GVHD Consensus Response Criteria Working Group removed DLCO as an organ 
response measure for lung chronic GVHD. The working group recommends measuring 
changes in FEV1 and pulmonary symptoms only as response measures for clinical trials in 
chronic GVHD [Lee 2015]. 
Bronchial obstruction has been observed with the non-selective S1P receptor modulator 
fingolimod, which has been approved for the treatment of MS since 2010 [Francis 2010]. 
There are no contraindications to the use of fingolimod in patients with lung disease or 
pulmonary function abnormalities. After treatment of several thousand patients for several 
years, no specific safety signals have been detected with fingolimod and the clinical 
relevance of pulmonary function changes remains unclear. 
Similarly to fingolimod, ponesimod increases expiratory airflow resistance in a 
dose-dependent and reversible fashion. In MS patients, treatment with ponesimod 
20 mg once daily (o.d.) induced a mean decrease of FEV1 of approximately 6% while the 
mean decrease of FVC was less than 3%. These changes in pulmonary function were 
rapidly established, stable on treatment, and rapidly reversible (within 1 week) following 
treatment discontinuation and could also be reversed by administration of a short-acting β2 
agonist. In animal studies with ponesimod, there were no indications of irreversible 
structural or smooth muscle pulmonary changes. Furthermore, data from an ongoing, long-
term extension of the Phase 2 study in MS patients suggests that the decrease in FEV1 is 


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largely stable and remains reversible after several years of treatment with ponesimod 
[Actelion data on file]. 
Chronic GVHD patients with BOS are excluded from this study as the potential effect of 
ponesimod on this GVHD manifestation is unknown and both the disease and the drug may 
have an additive effect on the obstructive deficit. 
However, based on the above considerations, exclusion of subjects based on pre-existing 
low values of DLCO or FVC is not justified as this leads to the exclusion of a substantial 
number of patients with a restriction deficit or diffusion impairment who may actually 
benefit from ponesimod treatment with no increased risk. Similarly, decreasing the FEV1 
exclusion threshold from 75% to 60% of the normal predicted value while maintaining the 
exclusion for subjects with FEV1/FVC ratio < 0.7 will allow enrollment of subjects with 
restriction deficit but will exclude those with obstruction who may be more at risk.  
As for the change made to the exclusion threshold based on ALC, the changes made to the 
pulmonary function exclusion criteria will improve external validity of this trial.  
It is important to emphasize that spirometry and DLCO are assessed frequently during the 
study with a significant effort to increase accuracy of the measurements. Spirometry test 
results are used to guide subject’s management. Bronchodilator challenge and interruption 
of ponesimod treatment will continue to be performed whenever a relevant % decrease in 
normal predicted FEV1 and FEV1/FVC ratio are observed. However, the protocol-defined 
criteria that mandate bronchodilator challenge and ponesimod treatment interruption will 
be modified to reflect the change made in the inclusion criterion for FEV1 (60% of the 
normal predictive FEV1 value rather than 75%) and to still ensure that reversible 
obstructive changes, which may occur with ponesimod, are distinguished from the 
irreversible obstructive changes of BOS. These modifications to the protocol will continue 
to ensure early diagnosis of BOS and decreased risk of potential toxicity with ponesimod.  
Rationale for additional changes to the protocol 
Additional changes have been made to make the protocol less burdensome for subjects and 
investigators. These include allowing a serum pregnancy test prior to enrollment to confirm 
the first negative serum pregnancy test, reducing the washout duration for extracorporeal 
photopheresis (ECP), removing restrictions on topical immunosuppressant therapies, and 
removing the use of a central spirometry vendor. 
A second serum pregnancy test may be performed at least 7 days after the Visit 1 test to 
confirm the negative pregnancy test result. The 3 week period required between the Visit 1 
(screening) serum pregnancy test and the Visit 2 (Day 1) urine pregnancy test may be 
considered too long for women of child-bearing potential requiring a change in chronic 


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GVHD therapy. The subject may be enrolled as soon as the second serum pregnancy test 
negative results are available. 
The washout duration following ECP has been reduced from 30 days to 15 days. For 
chronic GVHD patients ECP is typically performed every two weeks until a partial 
response is achieved and then the treatment schedule may become less frequent 
[Dignan 2014]. Eligible subjects for this study are likely to be on a two week treatment 
schedule. Additionally, the active agent in ECP, 8-MOP, has a half-life less than 4 hours 
following cross-linking. Consequently, the washout period of 15 days is sufficient for ECP 
and is a convenient duration for eligible subjects to switch from ECP to a new therapy. 
The main objective of this study is to evaluate the safety, tolerability, and 
pharmacodynamic effect of ponesimod in patients with chronic GVHD. For the allowed 
concomitant topical calcineurin inhibitors (CNIs) and glucocorticoids, starting or 
increasing the dose will no longer be prohibited, but the protocol will recommend against 
changes in dose. Topical treatments have generally limited systemic immunosuppressive 
effects and it is often difficult to control the dose and application area of a topical treatment 
on a day-to-day basis. Therefore, it is reasonable to recommend no change rather than 
prohibit any change to concomitant topical CNIs/glucocorticoids in an effort to limit the 
confounding effects of these treatments.  
The central spirometry vendor will no longer be required for this protocol. Spirometry and 
DLCO testing can be performed using the equipment at the site’s pulmonary function 
facility. Typically, both spirometry and DLCO can be accomplished with a single PFT 
maneuver. Therefore, removing the central spirometry vendor reduces the burden of 
assessments for the subject by combining the spirometry and DLCO assessments where 
appropriate equipment is available. 
Other changes to the protocol include minor edits, corrections of typos, and clarifications 
including the responder definition in Section 6.3.3. 
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version. 
Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis: 
4.4 
Exclusion Criteria 


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5.1.10 
Specific dose-reduction, interruption, or premature discontinuation criteria 
5.2.2 
Modifications to IS treatments 
7.3.3 
Spirometry 
7.3.4 
DLCO 
 
Summary of previous amendments 
 
Amendment 
Date 
Main reason(s) 
1 
28 January 2015 
The main reason for this amendment was to update 
the protocol according to feedback from the FDA. 
2 
21 May 2015 
The main reason for this amendment was to add to the 
protocol: a longer safety follow-up period; an 
extension treatment period; and a second safety 
follow-up period. Subjects completing 24 weeks of 
ponesimod treatment will have the option to be 
treated with ponesimod for an additional 96 weeks, 
should they meet additional eligibility criteria. The 
protocol has been updated to refer to the initial 
24 weeks of treatment as the “Core Treatment Period” 
with the addition of the “Extension Treatment 
Period.” 
 
 


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PROTOCOL SYNOPSIS AC-058C202 
TITLE 
A 
Phase 
2, 
open-label, 
single-arm, 
intra-subject 
dose-escalation study to investigate the biological activity, 
safety, tolerability, and pharmacokinetics of ponesimod in 
subjects with symptomatic moderate or severe chronic 
GVHD inadequately responding to first or second line 
therapy 
OBJECTIVES 
Main objectives 
• To investigate the dose response in peripheral absolute 
lymphocyte count reduction with ponesimod in subjects 
with chronic graft versus host disease (GVHD) 
• To investigate the safety and tolerability of ponesimod 
in subjects with chronic GVHD 
Exploratory objectives 
• To investigate the efficacy of ponesimod in subjects 
with chronic GVHD 
DESIGN 
Prospective, 
multi-center, 
open 
label, 
single-arm, 
intra-subject, dose-escalation Phase 2 study. 
PERIODS 
Screening period 
• This period lasts up to 30 days prior to the day final 
eligibility is established and includes the screening visit 
and all baseline assessments. 
Core Treatment Period 
• The Core Treatment Period starts at the time of first 
intake of study drug, and continues until the end of 
treatment at Week 24.  
• Visits during the Core Treatment Period consists of an 
enrollment visit (Day 1) and visits at Weeks 4, 8, 12, 16, 
20, and 24.  
• The End-of-Treatment 1 (EOT1) visit takes place at 
Week 24, or earlier in case of premature discontinuation 
of study drug. In all cases, the EOT1 visit should take 
place not later than 7 days after the last dose of study 
drug.  
• All subjects will be treated according to local standard of 
care at investigator’s discretion after EOT1. 
Core Safety Follow-up Period 1 


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• All subjects will enter the core safety follow-up period 
after EOT1. 
• The follow-up period for subjects who were prematurely 
discontinued lasts for 30 days after the last dose of study 
drug and ends with the 30-day follow-up 1 (FU1) visit, 
which is also the End-of-Study (EOS) visit. 
• The follow-up period for subjects who were not 
prematurely discontinued lasts for 90 days after the last 
dose of study drug, and consists of the 30-day FU1 site 
visit and the 90-day follow-up 2 (FU2) visit, which is also 
the EOS visit. FU1 and FU2 are cancelled if the subject 
enrolls in Extension Treatment and visit EX-1 (Extension 
visit 1) occurs the day of or prior to the scheduled FU1 
visit. FU2 is cancelled if the subject enrolls in Extension 
Treatment and visit EX-1 occurs the day of or prior to the 
scheduled FU2 visit.  
Extension Treatment Period 
• Subjects who were not prematurely discontinued from 
the Core Treatment Period, and whose chronic GVHD 
was assessed by National Institutes of Health (NIH) 
response criteria to have progressed versus EOT1 disease 
activity, may be restarted on study drug and enter the 
Extension Treatment Period. The assessment of 
progression and the re-initiation of ponesimod must both 
occur at least 7 days after EOT1 and no later than 90 days 
after EOT1. (Note: subjects must not have been started 
on immunosuppressant (IS) therapy other than agents 
used during the Core Treatment Period). 
• The Extension Treatment Period starts the day 
ponesimod is restarted, on visit EX-1, and continues for 
96 weeks. Visits during the Extension Treatment Period 
will consist of visit EX-1 and visits at EX-Weeks 4, 8, 12, 
16, 20, 24, 36, 48, 60, 72, 84, and 96. 
• The End-of-Treatment 2 (EOT2) visit will take place at 
EX-Week 96 or earlier in case of premature 
discontinuation of study drug. In all cases, the EOT2 visit 
should take place not later than 7 days after the last dose 
of study drug.  


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• Subjects completing the EOT2 will be subsequently 
treated according to local standard of care at the 
investigator’s discretion. 
Extension Safety Follow-up Period 2 
• All subjects will enter the safety follow-up period after 
EOT2 (Follow-up Period 2), which will last for 30 days 
after the last dose of study drug and end with the 30-day 
follow-up 3 (FU3) visit. This is also the EOS visit for 
these subjects. 
STUDY 
DISCONTINUATION 
CRITERIA 
At any time during the treatment period, subjects meeting the 
study-specific criteria for premature discontinuation of study 
drug (described in Section 5.1.10) are to be prematurely 
discontinued from study drug and will perform EOT (1 or 2) 
and EOS visits. 
PLANNED DURATION 
Approximately 168 weeks 
First 
subject 
First visit 
Q2 
2015 
Last 
subject 
First visit 
Q2 
2016 
Last 
subject 
Last 
visit 
Q4 
2018 
SITE(S) 
/ COUNTRY(IES) 
Approximately 10 sites in the USA (planned).  
SUBJECTS / GROUPS 
30 subjects in 1 group 
INCLUSION CRITERIA 
FOR THE CORE 
TREATMENT PERIOD 
1. Signed informed consent prior to initiation of any 
study-mandated procedure. 
2. Males and females aged 18 to 70 years. 
3. Recipients of allogeneic hematopoietic stem cell 
transplant (HSCT) diagnosed with chronic GVHD. 
4. Currently receiving systemic IS therapy at enrollment, 
with no dose changes in the 14 days prior to enrollment, 
consisting of systemic glucocorticoids AND/OR one of 
the following systemic agents: cyclosporine (CsA), 
tacrolimus (TAC), mycophenolate mofetil (MMF), 
mycophenolate sodium (MPS), everolimus (EVL), 
sirolimus (SRL), or methotrexate (MTX). 
5. Subject needs a change of current systemic IS therapy, in 
the opinion of the investigator, based on all of the 
following conditions: 


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a) Symptomatic moderate or severe chronic GVHD 
per NIH global severity scoring assessed at 
screening. 
b) Glucocorticoid 
refractory, 
dependent, 
or 
intolerant status at screening [see Appendix 1 for 
guidance]. 
c) Evidence of GVHD progression at enrollment 
despite ≥ 4 weeks current systemic IS therapy, 
OR without evidence of GVHD improvement at 
enrollment despite ≥ 8 weeks current systemic IS 
therapy. Current systemic IS therapy must be the 
same as in inclusion criterion 4 [see Appendix 1 
for guidance]. 
6. Chronic GVHD manifestations involve at least one of the 
following organs: skin, mouth, eyes, joints and fascia, 
esophagus, upper or lower gastrointestinal (GI) tract. The 
qualifying manifestation should have an NIH chronic 
GVHD activity assessment score of at least 1 at 
enrollment [see Form A, Appendix 7]. 
7. Women of child-bearing potential (WOCBP) must have 
a negative serum pregnancy test at screening and a 
negative urine or serum pregnancy test prior to 
enrollment, and must agree to undertake urine pregnancy 
tests every 4 weeks during the study and up to the 
protocol defined EOS. 
8. WOCBP must agree to use acceptable methods of 
contraception during the study and up to the protocol 
defined EOS. 
EXCLUSION CRITERIA 
FOR THE CORE 
TREATMENT PERIOD 
Cardiovascular 
1. Resting heart rate (HR) < 50 bpm measured by 12-lead 
electrocardiogram (ECG) at enrollment (prior to study 
drug administration). 
2. Myocardial infarction within 24 weeks prior to screening 
or ongoing unstable ischemic heart disease. 
3. Cardiac failure (NYHA class III or IV) or any severe 
cardiac disease at time of screening. 
4. History or presence of valvular heart disease associated 
with symptoms or hemodynamic change. 


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5. History or presence of cardiac rhythm disorders 
(e.g., sino-atrial heart block, symptomatic bradycardia, 
atrial flutter or atrial fibrillation, ventricular arrhythmias, 
cardiac arrest). 
6. Presence of an increased QT corrected for HR on the 
basis of Fridericia’s formula (QTcF) interval > 470 ms 
(females), > 450 ms (males) measured by 12-lead ECG 
at screening or pre-dose on Day 1. 
7. History of syncope associated with cardiac disorders. 
8. Systemic arterial hypertension not controlled by 
medication as judged by the investigator. 
Hematologic 
9. Hemoglobin < 8.0 g/dL or need for red blood cell 
transfusion at screening. 
10. Absolute neutrophil count < 1.5 × 109/L 
(< 1500 cells/mm3) at screening. 
11. Absolute lymphocyte count < 0.5 × 109/L 
(< 500 cells/mm3) at screening. 
12. Platelet count < 50 × 109/L (< 50,000 cells/mm3) or need 
for platelet transfusion at screening. 
Hepatic 
13. ALT and/or aspartate aminotransferase (AST) ≥ 3.0-fold 
the upper limit of normal (ULN) at screening. 
14. Total bilirubin (TBL) > 1.5-fold ULN (unless in the 
context of known Gilbert’s Syndrome) at screening. 
15. Known chronic liver or biliary disease that is not due to 
chronic GVHD. 
Infection and infection risk 
16. Active or uncontrolled bacterial, viral, or fungal infection 
(except onychomycosis and dermatomycosis); positive 
hepatitis B surface antigen or hepatitis C antibody tests at 
screening. 
17. Cytomegalovirus (CMV) disease, including CMV 
pneumonia, CMV retinitis, and CMV gastroenteritis 
and/or subjects meeting institutional criteria for systemic 
therapy for CMV reactivation. (Subjects with positive 
CMV serology and/or CMV reactivation are not excluded 


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if they do not have CMV disease and do not require 
systemic therapy). 
18. Active or latent tuberculosis (TB), as assessed by chest 
X-ray performed at screening or within 90 days prior to 
screening, 
and 
interferon 
gamma 
release 
assay 
(QuantiFERON-TB-Gold®) at screening, except if there 
is documentation that the subject has received adequate 
treatment for TB previously. 
19. Congenital or acquired severe immunodeficiency or 
known human immunodeficiency virus (HIV) or positive 
HIV testing at screening. 
Malignancy 
20. New or recurrent malignancy or minimal residual 
disease. 
Metabolic 
21. Type 1 or 2 diabetes that is poorly controlled according 
to investigator judgment, or diabetes complicated with 
organ involvement such as nephropathy or retinopathy. 
Ophthalmologic 
22. Presence of macular edema. 
Pregnancy and breastfeeding 
23. Breastfeeding, pregnant women or women planning to 
become pregnant during the study. 
Pulmonary 
24. Subjects with a clinically significant pulmonary 
condition including asthma and chronic obstructive 
pulmonary disease (COPD) that is insufficiently 
controlled according to investigator judgment.  
25. Subjects 
with 
diagnosed 
bronchiolitis 
obliterans 
syndrome. 
26. Subjects with any hospitalization due to a clinically 
significant pulmonary condition including asthma or 
COPD exacerbation within 24 weeks prior to screening 
(with the exception of a fully resolved pulmonary 
infection).  


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27. Subjects with abnormal pulmonary function tests: forced 
expiratory volume in 1 second (FEV1) < 60% of predicted 
normal value or FEV1/forced vital capacity (FVC) ratio 
< 0.7 at screening. 
Renal 
28. Severe renal insufficiency defined as a calculated 
creatinine 
clearance 
< 
30 
mL/min/1.73 
m2 
(Cockroft-Gault) at screening. 
Treatments 
29. Systemic glucocorticoids at prednisone-equivalent dose 
> 1.0 mg/kg/day at screening. 
30. Treatment within 15 days prior to enrollment with: 
• Azathioprine 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin 
or any anti-arrhythmic or HR-lowering systemic 
therapy (a non-exhaustive list of drugs provided in 
Appendix 4) 
• CsA, TAC, MMF, MPS, EVL, SRL (with the 
exception of any therapy serving as a mandatory 
concomitant therapy, as per inclusion criterion 4 
and Section 5.2). 
• Extracorporeal photopheresis 
• Isotretinoin 
• Thalidomide 
31. Treatment within 30 days prior to enrollment with: 
• Acitretin  
• Cyclophosphamide 
• Etanercept 
• Imatinib 
• Vaccination with live vaccines 
32. Treatment within 45 days prior to enrollment with: 
• Pulse methylprednisolone 
• MTX (with the exception if MTX serves as a 
mandatory concomitant therapy, as per inclusion 
criterion 4 and Section 5.2). 


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33. Treatment within 60 days prior to enrollment with: 
• Basiliximab 
34. Treatment within 24 weeks prior to enrollment with: 
• Anti-lymphocyte globulin 
• Anti-thymocyte globulin 
• Belimumab  
• Mesenchymal stem cell therapy 
• Ofatumumab 
• Pentostatin 
• Rituximab 
35. Treatment within 36 weeks prior to enrollment with: 
• Hydroxychloroquine 
36. Treatment within 48 weeks prior to enrollment with: 
• Alemtuzumab 
• Clofazamine 
37. Treatment with any IS or immunomodulatory drug or 
technology not identified in items 30 to 37, unless 
discussed with the Sponsor to determine appropriate 
washout. Chemotherapy and radiation for conditioning 
treatment leading up to the stem cell transplant and 
growth factors are exempt and do not have to be 
discussed with the sponsor. 
Other Categories 
38. Karnofsky Performance Score < 60%. 
39. Known history of clinically significant drug or alcohol 
abuse. 
40. Known allergy to any of the ponesimod formulation 
excipients.  
41. Any other clinically relevant medical or surgical 
condition, which, in the opinion of the investigator, 
would put the subject at risk by participating in the study. 
42. Subjects 
unlikely 
to 
comply 
with 
protocol, 
e.g., uncooperative attitude, inability to return for 
follow-up visits, or known likelihood of not completing 
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subject unable to understand the nature, scope, and 
possible consequences of the study. 
INCLUSION CRITERIA 
FOR THE EXTENSION 
TREATMENT PERIOD 
1. Signed informed consent prior to initiation of any 
study-mandated procedure. 
2. Subject has completed the 24 weeks of treatment of the 
Core Treatment Period and the EOT1 visit. 
3. Subject has experienced disease progression 7 to 90 days 
after EOT1 visit, versus EOT1 chronic GVHD activity 
assessment, for at least one previously involved organ. 
Progression is per NIH Consensus Development Project 
response criteria and is defined in Section 6.3.2.  
4. WOCBP, as defined in Section 4.3.1, must have a 
negative urine pregnancy test at enrollment visit EX-1, 
and at all prior visits, and must agree to undertake 
monthly scheduled urine pregnancy tests during the study 
and up to the protocol defined EOS. 
5. WOCBP must agree to use acceptable methods of 
contraception during the study and up to the protocol 
defined EOS. 
EXCLUSION CRITERIA 
FOR THE EXTENSION 
TREATMENT PERIOD 
There are no exclusion criteria for the Extension Treatment 
Period. However:  
• Study drug specific dose-reduction, interruption, or 
premature discontinuation criteria remain in force for the 
duration of the study. These are described in 
Section 5.1.10. 
• Forbidden concomitant therapies remain in force for the 
duration of the study. These are described in 
Section 5.3.5. 
STUDY TREATMENTS 
Investigational treatment (study drug): ponesimod 
Ponesimod is supplied as its free base, in oral film-coated 
tablets at doses of 2, 3, 4, 5, 6, 7, 8, 9, 10, and 20 mg. One 
tablet of ponesimod at any dose will be taken orally once 
daily. 
Core Treatment Period 
For this dose-escalation study, subjects will receive three 
treatment courses, with each treatment course studying one 
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A 6 day up-titration scheme will be implemented from Day 1 
to Day 6 using a titration blister wallet, to reduce ponesimod 
first-dose effects. On-site subject monitoring will be required 
at enrollment on Day 1 [see Section 5.1.7]. A 4-day 
up-titration scheme will be implemented from Day 29 to 
Day 32 to gradually transition from the 5 mg to the 10 mg 
daily dose. The subject will have the dose escalated from 
10 to 20 mg on Day 57 (without gradual up-titration). The 
first day of the 4-day up-titration (Day 29) and the Day 57 
dose escalation do not require on-site monitoring. 
Criteria to permit dose increases at Day 29 and Day 57 
Subjects may have daily doses up-titrated from 5 mg to 
10 mg, starting on Day 29, and dose escalated from 10 mg to 
20 mg on Day 57, if the following are true: 
a) Subject has not met the study-specific criteria for 
interruption, 
dose 
reduction, 
or 
premature 
discontinuation of study treatment, described in 
Section 5.1.10. 
b) Subject does not have an ongoing grade 2 adverse 
event at least possibly related to study drug. 
c) Subject took ponesimod dose the day prior to the day 
of up-titration or dose-escalation. 
d) Investigator has reviewed and approved of the results 
of the Day 29 and/or Day 57 pre-dose assessments 
specified in Table 1. 
Extension Treatment Period 
Subjects will receive their last tolerated ponesimod dose 
(prior to EOT1) for 96 weeks, including up-titration. 
Study drug re-initiation after interruption (Core and 
Extension Treatment Periods) 
See Section 5.1.8 for guidance on re-initiation of ponesimod 
in the event of study drug interruption of any duration. 


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Systemic glucocorticoids (Core Treatment Period only) 
Glucocorticoid dosing should not be increased or decreased 
during the course of the study, with the following exceptions: 
• The investigator may see reason to initiate or increase the 
dose of systemic glucocorticoid to treat chronic GVHD 
flare or another condition. In this case, the investigator 
should consult with the sponsor prior to initiation or dose 
increase and the reason for dose increase should be 
documented. The subject may continue on ponesimod. 
The prednisone-equivalent dose should never exceed 
1 mg/kg/day. 
• Systemic glucocorticoid dosing may be lowered to avoid 
or prevent short- and long-term glucocorticoid toxicity. 
For subjects on longer term glucocorticoid therapy, it is 
recommended that the dose reduction rate does not 
exceed 10% of the dose per week. Glucocorticoid dosing 
may be increased following reduction, if medically 
indicated. 
• Systemic glucocorticoid dosing is not subject to 
restrictions during the Extension Treatment Period. 
Mandatory systemic IS other than ponesimod or systemic 
glucocorticoids (Core Treatment Period only) 
Systemic IS dosing (mg daily dose) should not be increased 
above baseline dose during the course of the study, with the 
following exception: 
• Systemic IS blood or serum level is below the therapeutic 
range that was defined for the subject at the time of entry 
into the study. The dose should be increased to restore 
blood or serum levels to within the defined therapeutic 
range. (IS that are not monitored with blood or serum 
level monitoring may never be increased above baseline 
dose.) 
Systemic IS dosing (mg daily dose) should not be lowered 
during the course of the study, with the following exceptions: 
• Adverse event (AE) or intolerance due to the systemic IS. 
The dose should be sufficiently lowered or discontinued, 
per investigator judgment. 


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• Systemic IS blood or serum level is above the therapeutic 
range that was defined for the subject at the time of entry 
into the study. The dose should be lowered to restore 
blood or serum levels to within the defined therapeutic 
range.  
 
Systemic IS dosing is not subject to restrictions during the 
Extension Treatment Period. 
Topical calcineurin inhibitors or glucocorticoids (Core 
Treatment Period only)  
• The sponsor recommends not starting or increasing 
dosage of topical calcineurin inhibitors (CNI) or 
glucocorticoid therapy during the course of the core 
study. 
• Topical CNI or glucocorticoid therapy dosing or area of 
application should not be decreased during the course of 
the core study, unless there is an AE or intolerance due to 
the topical drug. The dose should then be sufficiently 
lowered or discontinued, per investigator judgment. 
• Topical CNI or glucocorticoid dosing is not subject to 
restrictions during the Extension Treatment Period. 
CONCOMITANT 
THERAPY 
Mandatory concomitant therapy (Core Treatment 
Period only) 
Systemic glucocorticoids AND/OR one of the following 
systemic agents: CsA, TAC, MMF, MPS, EVL, SRL, or 
MTX. 
Allowed concomitant therapy (Core and Extension 
Treatment Periods) 
• Administration of intravenous (i.v.) atropine in the event 
of symptomatic bradycardia 
• Topical glucocorticoid  
• Topical CNI 
• Oral budesonide 
• QT-prolonging drugs with known risk of Torsades de 
Pointes should be used with caution, since ponesimod 


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may potentially enhance their effect on QT interval (list 
of drugs and guidance are provided in Appendix 3) 
• Short-acting ß2 agonists for respiratory symptoms and/or 
reduced pulmonary function during ponesimod treatment 
• Vaccination with non-live vaccines 
• Other treatments considered necessary for the subject’s 
benefit and not categorized as forbidden concomitant 
medications 
Forbidden concomitant therapy (Core and Extension 
Treatment Periods) 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin, or 
any other anti-arrhythmic or HR-lowering systemic 
therapy (a non-exhaustive list of drugs provided in 
Appendix 4) 
• IS or immunomodulatory treatments other than those 
prescribed per protocol 
• Mesenchymal stem cell therapy 
• Retinoids 
• Thoracoabdominal irradiation 
• Extracorporeal photopheresis 
• Vaccination with live vaccines 
• Any other investigational drug other than ponesimod. 
PHARMACOKINETIC 
AND 
PHARMACODYNAMIC 
ENDPOINTS 
Core Treatment Period Endpoints 
Pharmacokinetic (PK) evaluations 
• Trough concentrations of ponesimod at Day 1, Weeks 4, 
8, 12, 16, and 20 (all samples pre-dose), and Week 24 
• Ponesimod concentration 3 hours post-dose at Day 1 and 
Week 12 
Pharmacodynamic (PD) evaluations 
Primary PD endpoint 
• Change in peripheral absolute lymphocyte count from 
baseline to Week 4, Week 8 and Week 12 


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The primary endpoint assesses intra-subject dose response 
during the first 12 weeks of treatment. 
Other PD endpoints 
• Peripheral absolute blood lymphocyte count change from 
baseline (pre-dose on Day 1) to Weeks 4, 8, 12, 16, 20, 
24, and FU1, and change from pre-dose Week 12 to 3 
hours post-dose Week 12. 
• Peripheral absolute lymphocyte count reversibility from 
EOT1 to FU1 expressed as absolute change and percent 
change from baseline 
PK/PD relationship 
The PK and selected efficacy and safety variables will be 
correlated with the PD (peripheral absolute lymphocyte 
count and magnitude of reduction of lymphocyte count). If 
deemed appropriate, the PK will also be correlated with 
selected safety variables. 
Extension Treatment Period Endpoints 
The same endpoints, except for PK, will be assessed in the 
Extension Treatment Period as were assessed in the Core 
Treatment Period, however adjusted for the corresponding 
visit schedule. 
SAFETY ENDPOINTS 
Core Treatment Period Endpoints 
The treatment-emergent period is defined as the time from 
first study drug intake up to 30 days (inclusive) after last 
study drug intake. 
Overall safety endpoints 
• Treatment-emergent AEs, serious adverse events, and 
AEs of special interest [see Appendix 5] 
• AEs leading to premature discontinuation of study drug 
• Deaths 
Peripheral absolute lymphocyte count 
• Treatment-emergent 
absolute 
lymphocyte 
count 
< 0.2 × 109/L (< 200 cells/mm3) 


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Cardiac rate and rhythm safety endpoints 
• Treatment-emergent morphological ECG abnormalities 
(as defined by the ECG provider) 
• Change in 12-lead ECG variables (HR, PR, QRS, QT, QT 
corrected for HR on the basis of Bazett’s formula 
[QTcB], QT corrected for HR on the basis of Fridericia’s 
formula [QTcF]) from pre-dose to selected post-dose 
assessments (1 h, 2 h, 3 h, 4 h) on Day 1 and on day(s) of 
re-initiation of study drug 
• Notable abnormalities for selected 12-lead ECG 
variables (HR, PR, QT, QTc) at the 3-hour post-dose 
assessment on Day 1, pre-dose Weeks 4, 8, and 12 and 
Week 
24 
(notable 
abnormalities 
definition 
in 
Appendix 6) 
• Cardiac safety events will include: 
• Treatment-emergent QTc > 450 ms (male), > 470 ms 
(female), > 500 ms (male), and > 520 ms (female) 
• Treatment-emergent QTc increase from baseline 
> 30 ms, > 60 ms 
• Other treatment-emergent abnormalities observed by 
12-lead ECG 
• Treatment-emergent (serious) cardiac AEs of special 
interest 
Pulmonary function safety endpoints 
• Treatment-emergent decrease of FEV1 or FVC > 20% 
from baseline values 
• Treatment-emergent decrease of percent of predicted 
FEV1 or FVC > 20 percentage points from baseline 
values 
• Change in FEV1 and FVC from baseline, absolute and % 
of absolute change to all time points up to FU1 
• Among subjects with a decrease of > 200 mL and > 12% 
in FEV1 or FVC, respectively, from baseline to EOT1, 
reversibility is defined as a decrease of < 200 mL and 
< 12% in FEV1 or FVC, respectively, from baseline to 
last available follow-up 


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• Change from baseline to FU1 vs change from baseline to 
EOT1 in FEV1 or FVC (absolute and % of predicted) 
• Change in lung diffusion capacity as assessed by 
diffusing capacity of lung for carbon monoxide (DLCO), 
expressed in absolute change and % of predicted value 
from baseline to all time points up to FU1 
• Change from baseline to FU1 vs change from baseline to 
EOT1 in DLCO (absolute and % of predicted) 
• (Serious) pulmonary AEs of special interest  
• Withdrawal due to pulmonary reasons/AE 
Other safety endpoints 
• Treatment-emergent 
notable 
blood 
pressure 
abnormalities [definition in Appendix 6] 
• Treatment-emergent notable laboratory abnormalities 
[definition in Appendix 6] 
Extension Treatment Period Endpoints 
The same endpoints will assessed in the Extension Treatment 
Period as were assessed in the Core Treatment Period, 
however adjusted for the corresponding visit schedule. 
EFFICACY ENDPOINTS 
Core Treatment Period Endpoints 
NIH response endpoints 
• Achievement of a partial or complete overall response at 
24 weeks post-enrollment (per NIH Consensus 
Development Project response criteria) 
Definitions for the efficacy endpoint are based on the draft 
2014 NIH Consensus Guidelines [see Appendix 7]. 
Baseline or subsequent organ abnormalities that are not due 
to chronic GVHD are not evaluable for response (at the organ 
level). 
Complete overall response definition:  
A complete response is defined as resolution of all reversible 
manifestations due to chronic GVHD in all of the following 
organs at the Week 24 assessment, resulting in: 
• Skin: NIH Skin Score of 0 after previous involvement 


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• Mouth: NIH Modified Oral Mucositis Score of 0 after 
previous involvement 
• Liver: normal ALT, alkaline phosphatase, and TBL after 
previous elevation of one or more 
• Upper GI: NIH Upper GI Score of 0 after previous 
involvement 
• Lower GI: NIH Lower GI Score of 0 after previous 
involvement 
• Esophagus: NIH Esophagus Score of 0 after previous 
involvement 
• Lungs: normal FEV1 absolute value after previous 
involvement (normalization to FEV1 ≥ 80% predicted is 
considered a complete response) 
• Eyes: NIH Eye Score of 0 after previous involvement 
• Joint/fascia: Both NIH Joint and Fascia Score of 0 and 
photographic range of motion (P-ROM) score of 25 after 
previous involvement by at least one measure 
• Global: Clinician Overall Severity Score of 0 
Partial overall response definition:  
A partial overall response is defined as improvement in a 
measure for at least one organ without progression in 
measures for any other organ.  
The proposed general guideline for defining partial response 
in a specific organ requires a change in score from baseline 
as follows: 
• Skin: decrease in NIH Skin Score by at least 1 point 
• Mouth: decrease in NIH Modified Oral Mucositis Score 
by at least 2 points 
• Liver: decrease by 50% in ALT, alkaline phosphatase, or 
TBL 
• Upper GI: decrease in NIH Upper GI Score by at least 
1 point 
• Lower GI: decrease in NIH Lower GI Score by at least 
1 point 


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• Esophagus: decrease in NIH Esophagus Score by at least 
1 point 
• Lungs: increase by at least 10% predicted absolute value 
of FEV1, as long as initial FEV1 < 70% predicted 
• Eyes: decrease in NIH Eye Score by at least 1 point 
• Joint/fascia: decrease in NIH Joint and Fascia Score by 
1 or more points or increase in P-ROM score by 1 or 
more points for any site 
• Global: Clinician Overall Severity Score decreases by 
2 or more points on a 0–10 scale 
The proposed general guideline for defining progression in a 
specific organ requires a change in score from baseline as 
follows: 
• Skin: increase in NIH Skin Score by at least 1 point, 
except from 0 to 1 
• Mouth: increase in NIH Modified Oral Mucositis Score 
by at least 2 points 
• Liver: increase by ≥ 2 × ULN for ALT, alkaline 
phosphatase or TBL 
• Upper GI: increase in NIH Upper GI Score by at least 
1 point, except from 0 to 1 
• Lower GI: increase in NIH Lower GI Score by at least 
1 point, except from 0 to 1 
• Esophagus: increase in NIH Esophagus Score by at least 
1 point, except from 0 to 1 
• Lungs: decrease by at least 10% absolute value of FEV1, 
as long as final FEV1 < 70% predicted   
• Eyes: increase in NIH Eye Score by at least 1 point, 
except from 0 to 1 
• Joint/fascia: increase in NIH Joint and Fascia Score by 
1 or more points or decrease in P-ROM score by 1 or 
more points for any site 
• Global: Clinician Overall Severity Score increases by 2 
or more points on a 0–10 scale 
Subject responder / non-responder definition 


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The endpoint is reached if the subject is considered a partial 
or complete responder at Week 24. The remaining subjects 
will be considered as non-responders, this includes subjects 
with stable disease and subjects with mixed response 
(defined as complete or partial response in at least one organ 
accompanied by progression in another organ). 
Other exploratory efficacy endpoints 
• Need for rescue therapy for chronic GVHD 
o Rescue therapy is the addition of any new 
systemic or topical IS therapy or exceeding 
baseline dose for any systemic non-steroid IS or 
exceeding glucocorticoid dose equivalent to 
prednisone > 1 mg/kg/day 
• Partial or complete organ-specific response for the 
specific organ manifestation at Week 12 and Week 24 in 
subjects with a specific organ manifestation of chronic 
GVHD at study baseline 
o Affected organs limited to 2014 NIH consensus 
criteria organs of skin, eyes, mouth, esophagus, 
upper GI, lower GI, liver, lungs, and joints and 
fascia 
• Partial or complete overall response at Week 12 
post-enrollment 
• Complete response at Week 24 
• Partial or complete overall response at latest evaluable 
assessment during the core study (Week 12 and 24) 
• Average glucocorticoid daily dose over 24 weeks versus 
baseline dose 
• Percent glucocorticoid dose at Week 24 versus baseline 
Extension Treatment Period Endpoints 
The same endpoints will assessed in the Extension Treatment 
Period as were assessed in the Core Treatment Period, 
however adjusted for the corresponding visit schedule. 
QUALITY OF LIFE 
ENDPOINTS 
Core Treatment Period Endpoints 


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• Change from baseline to Week 12 and Week 24 in Lee 
Symptom Scale for chronic GVHD [Appendix 8] 
• Change from baseline to Week 12 and Week 24 in each 
of the subject-reported chronic GVHD symptoms (skin, 
eyes, mouth and genitals [Appendix 7 – Form B]). 
• Change from baseline to Week 12 and Week 24 in each 
of 
the 
patient-reported 
global 
ratings 
(Mild-Moderate-Severe Scale, Overall Severity Scale 
and 7-Point Change Scale [Appendix 7 – Form B]). 
Extension Treatment Period Endpoints 
The same endpoints will assessed in the Extension Treatment 
Period as were assessed in the Core Treatment Period, 
however adjusted for the corresponding visit schedule. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
Full Analysis set (FAS): The FAS includes all subjects who 
received at least one dose of study medication. 
Safety Set (SAF): The safety set is defined like the FAS and 
will be used for all safety-related outputs. 
Per-Protocol set (PPS): The per-protocol set is defined as 
subjects from the FAS without any major protocol 
deviations. Additional details of the definition of the PPS are 
described in Section 11.1.3 and in the statistical analysis 
plan. 
PD analysis set (PDS): The PD analysis set includes all 
subjects who received at least 4 weeks of study treatment and 
have at least one absolute lymphocyte count measurement 
between the Week 4 visit and Week 12 visit. The PD 
endpoints of this study will be analyzed based on the PD 
analysis set. 
PK analysis set (PKS): The PK analysis set includes all 
subjects from the safety set who provided at least one blood 
sample. All PK related data will be analyzed on the PK 
analysis set. 


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Extension set (ES): The extension set includes all subjects 
enrolled in the Extension Treatment Period and who received 
at least one dose of ponesimod in the Extension Treatment 
Period. 
Primary analysis variable (PD endpoint) 
The change in absolute lymphocyte count from baseline to 
Week 4, Week 8 and Week 12 in the Core Treatment Period 
is defined as:  
• 
𝑙𝑙𝑑𝑑 = absolute lymphocyte count for dose d – absolute 
lymphocyte count at baseline  
The change in absolute lymphocyte counts (𝑙𝑙𝑑𝑑) is assessed at 
Week 4 for the 5 mg dose, at Week 8 for 10 mg and at 
Week 12 for 20 mg in the Core Treatment Period.  
 
Overall testing strategy for the PD endpoint  
Null and alternative hypotheses 
The null hypothesis is that there is no dose response on the 
change from baseline in absolute lymphocyte count in the 
intra-subject dose escalation within the first 12 weeks of 
treatment and the alternative hypothesis is the existence of 
any intra-subject dose response within the first 12 weeks of 
treatment:  
𝐻𝐻0: 𝑙𝑙𝑑𝑑≥ 0 for all doses d = 5, 10, 20 mg 
vs 
𝐻𝐻1: 𝑙𝑙𝑑𝑑<  0 for at least 1 dose d = 5, 10, 20 mg 
To meet the objective of demonstrating existence of an 
intra-subject dose response on the absolute lymphocyte count 
reduction from baseline in subjects with GVHD, at least one 
of the null hypotheses must be rejected with a one-sided 
significance level of 5%. The type-1 error will be controlled 
via a hierarchical ordering of the tests: pairwise comparisons 
will be conducted in decreasing dose order. Within-subject 
t-tests will be performed at each dose level (assuming 
normally distributed data).  
Further t-tests will be performed across dose levels (5 mg vs 
10 mg, 5 mg vs 20 mg and 10 mg vs 20 mg). These tests, 


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performed at a one-sided significance level of 5%, will be 
considered as exploratory. 
In addition an Emax model will be fitted for the baseline, 
Week 4, Week 8 and Week 12 data. The data will be 
summarized with point-wise and model-based estimates, 
standard deviation (STD) and 95% confidence-interval on 
the reduction in absolute lymphocytes from baseline at the 
examined dose levels. A plot of the estimated dose-response 
curve with 95% credibility interval limits will be presented 
along with the observed response at each dose. 
The primary analysis will be performed on the PD analysis 
set and a sensitivity analysis will be performed on the FAS. 
A last observation carried forward approach (using the Week 
4 visit or later) will also be performed for subjects with a 
missing Week 8 or Week 12 assessment, based on the FAS. 
Exploratory efficacy endpoints 
The FAS is considered to be the main analysis set for the 
exploratory efficacy endpoints. Some analyses will be 
repeated on the PPS, if applicable. The exploratory efficacy 
endpoints will be analyzed descriptively. 
Safety endpoints 
Safety endpoints will mainly be analyzed descriptively on the 
safety set. Selected safety outputs might be analyzed by dose 
level and/or time-point. 
Extension endpoints 
The ES is considered to be the main analysis set for the safety 
and efficacy endpoints for the Extension Treatment Period. 
Quality of Life endpoints 
Analyses are described in Section 11. 
PK/PD endpoints 
Analyses are described in Section 11. 
SAMPLE SIZE 
ASSUMPTIONS 
Sample size based on PD endpoint 
The sample size of this single arm intra-subject 
dose-escalation study is based on simulations, comparing 


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lymphocyte data at baseline to Week 4 data of the estimated 
5 mg dose in the Core Treatment Period, using t-tests. 
Since no studies of subjects receiving ponesimod have been 
conducted in GVHD, historical data of the Actelion multiple 
sclerosis and psoriasis programs have been used to determine 
the sample size. As GVHD subjects are known to have 
reduced lymphocyte counts, assumptions were adjusted 
appropriately. Dose-response modeling techniques were 
applied to support the sample size estimation [details in 
Section 11]. 
Based on these simulations 30, subjects will be recruited in 
order to establish an intra-subject dose response and to 
collect sufficient safety data. The simulations were 
performed comparing the change of absolute lymphocyte 
counts at Week 4 (5 mg dose; mean: 0.85 × 109/L; STD 0.40) 
vs baseline (mean: 1.2 × 109/L; STD 0.60), applying t-tests 
with a one-sided alpha-level of 0.05. Based on those 
assumptions a power of around 85% is reached. As absolute 
lymphocyte counts are expected to be closest to baseline data 
for the 5 mg dose, the sample size of 30 subjects is expected 
to be sufficient for the 10 mg and 20 mg doses as well.  
SITE PERSONNEL 
To facilitate the performance of efficacy and safety 
assessments required by the protocol, it is essential that the 
site personnel have the appropriate medical expertise and that 
the roles are defined clearly up front. 
At each center, the study staff will consist of a/an:  
• Principal investigator; 
• Cardiac safety assessor (qualified physician evaluating 
cardiac safety assessments, may be the same person as 
principal investigator); 
• Clinical coordinator/study nurse; 
• Ophthalmologist; 
• Pulmonologist; 
• Pulmonary function laboratory technician or expert. 
It is recommended that the designated personnel remain 
unchanged throughout the entire course of the study and that 


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an adequately trained back-up is designated in case of 
absence of any of the staff listed above. 
STUDY COMMITTEES 
Study Monitoring Committee (SMC) 
• The SMC will ensure that the study is properly 
conducted, monitored, and that data are appropriately 
analyzed and interpreted. The SMC will review toxicity 
assessments for each subject. At any time, the SMC may 
interrupt enrollment or recommend termination of the 
study for safety reasons. The SMC will recommend the 
dose of ponesimod for further development in chronic 
GVHD. 
• The SMC core comprises at least two medical experts in 
the field of chronic GVHD and two medical experts from 
the sponsor (i.e., the project physician, and a drug safety 
physician with expert knowledge of the safety profile of 
ponesimod). 
• Additional permanent attendees of SMC meetings will 
include the study statistician, the clinical trial scientist 
and the clinical study coordinator.  
• The composition and operation of the SMC is described 
in the SMC charter. 
Ophthalmology Safety Board (OSB) 
• The OSB will review and evaluate any new or suspected 
cases of macular edema. 
• The 
OSB 
is 
composed 
of 
two 
independent 
ophthalmologists.  
• The composition and operation of the OSB is described 
in the OSB charter. 
STUDY EXTENSION 
Extension study 
Subjects successfully completing the 24 week Core 
Treatment Period and fulfilling eligibility criteria in 
Sections 4.6 and 4.7 may enter the 96 week Extension 
Treatment Period. 
 


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Table 1 
Visit and assessment schedule 
Periods 
Name 
SCREENING 
CORE TREATMENT PERIOD 
COURSE 1 
(up to 5 mg) 
COURSE 2 
(up to 10 
mg) 
COURSE 3 
(20 mg) 
 
Duration 
Up to 30 Days 
4 weeks 
4 Weeks 
16 Weeks 
Visits 
Number 
1 
2 
3 
4 
5 
Name 
Screening 
Enrollment 
W4 
W8 
W12 
Time 
Day −30 to −1 
Day 1 
Week 4 
Week 8 
Week 12 
Visit window 
 
 
± 3 days 
± 3 days 
± 7 days 
Informed consent* 
X 
 
 
 
 
Inclusion/exclusion criteria* 
X 
X 
Pre-dose 
 
 
 
Demographics* 
X 
 
 
 
 
Medical history* 
X 
 
 
 
 
Chronic GVHD Stage & Score*  
X 
 
 
 
 
Chronic GVHD Activity 
Assessment, Form A and B* 
 
X 
Pre-dose 
 
 
X 
Lee Symptom Scale* 
 
X 
Pre-dose 
 
 
X 
Chest X-ray 
X (1) 
 
 
 
 
Concomitant medications* 
X 
X 
X 
X 
X 
Physical examination*  
X 
 
 
 
X 
Body weight and height* 
X 
X 
(weight only) 
 
 
 
Systolic/diastolic blood 
pressure* 
X 
X See 
Section 5.1.7 
X (4) 
pre-dose 
X (4) 
pre-dose 
X 
pre-dose 
12-lead ECG (2)** 
X 
X See  
Section 5.1.7 
X (4) 
pre-dose  
X (4) 
pre-dose 
X 
pre-dose 
Ophthalmological examination 
X 
 
 
 
X 
OCT (3) 
X 
 
 
 
X 
Spirometry*/DLCO*  
X 
X 
Pre-dose 
X (4) 
pre-dose 
X (4) 
pre-dose 
X 
pre-dose 
Hematology**/Chemistry**/ 
Urinalysis 
X 
X  
pre-dose 
X (4) 
pre-dose 
/local and 
central lab 
X (4) 
pre-dose 
/local and 
central lab 
X 
pre-dose 
Tuberculosis test** 
X 
 
 
 
 
Viral serology** 
X 
 
 
 
 
Additional blood samples for 
exploratory biomarkers** 
 
X 
 
 
 
Pregnancy test*/** MOC* (5) 
X serum**  
X 
serum/urine* 
X urine* 
X urine* 
X urine* 
PK and PD** sampling 
 
X See 
Section 7.2.1 
X 
pre-dose 
X 
pre-dose 
X 
pre-dose & 
3 hr post-dose 
Study drug dispensing & 
accountability (6)** 
 
X 
X 
X 
X 
AEs & SAEs (7)* 
X 
X 
X 
X 
X 


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*Data collected in the eCRF     **Electronically transferred to the sponsor 
Table 1 
Visit and assessment schedule (continued) 
Periods 
Name 
Continued: CORE TREATMENT 
PERIOD, COURSE 3 (20 mg) 
UNSCHEDULED 
Applies to all periods in 
Table 1 
FOLLOW
-UP 
PERIOD 1 
 
Duration 
16 Weeks 
Variable 
30, 90 days 
Visits 
Number 
6 
7 
8 
R1, R2,… 
U1, U2, … 
9, 10 
Name 
W16 
W20 
W24 
(EOT1) 
Re-
initiation 
Un-
scheduled 
FU1, FU2 
(8) 
Time 
Week 16 
Week 20 
Week 24 
(earlier if 
prematurely 
discontinued
) 
Any day 
between 
Day 1 and 
EOT2 
Any day 
between 
Day 1 and 
EOS 
EOT1+30 & 
EOT1+90 
days 
Visit window 
± 7 days 
± 7 days 
± 7 days 
NA 
NA 
+ 7 days 
Chronic GVHD Activity 
Assessment, Form A and B* 
 
 
X 
 
 
X (9) 
Lee Symptom Scale* 
 
 
X 
 
 
X (9) 
Concomitant medications* 
X 
X 
X 
X 
X 
X 
Physical examination*  
 
 
X 
 
Optional 
 
Body weight and height* 
 
 
X 
(weight only) 
 
Weight 
optional 
 
Systolic/diastolic blood 
pressure* 
X 
pre-dose 
X 
pre-dose 
X 
X See 
Section 5.1.7 
X 
pre-dose 
X (FU1 
only) 
12-lead ECG (2)** 
X 
pre-dose 
X 
pre-dose 
X 
X See 
Section 5.1.7 
Optional; 
pre-dose 
X (FU1 
only) 
Ophthalmological 
examination 
 
 
X 
 
Optional 
 
OCT (3) 
 
 
X 
 
Optional 
 
Spirometry*/DLCO* 
 
 
X 
 
Optional 
X (FU1 
only) 
Hematology**/ 
Chemistry**/ 
Urinalysis 
X 
pre-dose 
X 
pre-dose 
X 
X 
pre-dose 
Optional 
X 
Additional blood samples for 
exploratory biomarkers** 
 
 
X 
 
 
X (FU1 
only) 
Pregnancy test*/MOC* (5) 
X urine 
X urine 
X urine 
X urine 
Optional 
urine 
X urine 
PK and PD** sampling  
X 
pre-dose 
X 
pre-dose 
X 
 
 
X  
(PD only) 
(FU1 only) 
Study drug dispensing & 
accountability (6)** 
X 
X 
X 
X 
 
 
AEs & SAEs (7)* 
X 
X 
X 
X 
X 
X 
*Data collected in the eCRF     **Electronically transferred to the sponsor 


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Table 1 
Visit and assessment schedule (continued) 
Periods 
Name 
EXTENSION TREATMENT PERIOD 
FOLLOW-
UP PERIOD 
2 
 
Duration 
96 Weeks 
30 Days 
Visits 
Number 
11 
12, 13, 14, 
15, 16 
17, 18, 19, 
20, 21, 22 
23 
24 
Name 
EX-1 (8) 
EX-2, 3, 4, 5, 
6 
EX-7, 8, 9, 
10, 11, 12 
EX-13 
FU3 (EOS) (8) 
Time 
EOT1 + 7 
days to EOT1 
+ 90 days 
(10) 
EX-Weeks 4, 
8, 12, 16, 20 
EX-Weeks 
24, 36, 48, 
60, 72, 84 
EX-Week 96 
(EOT2) 
EOT2 + 30 
days 
Visit window 
 
± 7 days 
± 7 days 
± 7 days 
+ 7 days 
Extension Treatment 
inclusion/exclusion criteria* 
X 
 
 
 
 
Chronic GVHD Activity 
Assessment, Form A and B* 
X 
X (Visit EX-4 
only) 
X 
X 
 
Lee Symptom Scale* 
X 
X (Visit EX-4 
only) 
X 
X 
 
Concomitant medications* 
X 
X 
X 
X 
X 
Physical examination*  
X 
X (Visit EX-4 
only) 
X 
X 
 
Body weight* 
X 
X (Visit EX-4 
only) 
X 
X 
 
Systolic/diastolic blood 
pressure* 
X See 
Section 5.1.7 
X  
(pre-dose) 
X  
(pre-dose) 
X  
X 
12-lead ECG (2)** 
X See  
Section 5.1.7 
X  
(pre-dose) 
X  
(pre-dose) 
X  
X 
Ophthalmological 
examination* 
 
X (Visit EX-4 
only) 
 
X 
 
OCT (3)* 
 
X (Visit EX-4 
only) 
 
X 
 
Spirometry*/DLCO*  
X 
pre-dose 
X (Visit EX-4 
only) 
pre-dose 
X 
pre-dose 
X 
X 
Hematology**/Chemistry**/ 
Urinalysis 
X 
pre-dose 
X 
pre-dose 
X 
pre-dose 
X 
X 
Pregnancy test*/MOC* (5) 
X urine 
X urine 
X urine (11) 
X urine 
X urine 
PK and PD** sampling 
X (PD only) 
pre-dose 
X (PD only) 
(Visit EX-4 
only) pre-
dose 
X (PD only) 
pre-dose 
X (PD only) 
X (PD only) 
Study drug dispensing & 
accountability (6)** 
X 
X 
X 
X 
 
AEs & SAEs (7)* 
X 
X 
X 
X 
X 
*Data collected in the eCRF     **Electronically transferred to the sponsor 
 


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Table 1 
Visit and assessment schedule (continued) 
Table notes  
Day 1 (date of first study drug intake) is to be used as the reference date for the purpose of calculating the 
subsequent visit dates (and time windows). 
(1) Any chest X-ray that has been performed within 90 days prior to screening can be used (in this case, no 
need to repeat chest X-ray at screening).  
(2) In the event of a CTCAE grade 2 QTc elevation identified on 12-lead ECG (QTc 481–500 ms), a 12-lead 
ECG must be repeated 3 hours post dose. The subject is prematurely discontinued if the repeated 
QTcF > 500 ms. 
(3) OCT is performed at indicated visits plus any visit in case of visual symptoms suggestive of macular edema. 
(4) Investigator must review all test results prior to permitting subject to start the 4-day up-titration at Visit 3 
and/or the dose escalation to 20 mg at Visit 4.  
(5) For women of child-bearing potential, the serum pregnancy test at Visit 1 must be performed at least 
3 weeks before a urine pregnancy test at Visit 2. A second serum pregnancy may be performed instead of 
the urine test as early as 7 days after the first serum pregnancy test, and enrollment can begin as soon as the 
negative result is available. Assess and reinforce continued use of MOC for women of child-bearing 
potential at every visit. 
(6) Subjects record study medication compliance in a diary. Study drug accountability must be performed by 
the study staff on the day of the visit and recorded on the Study Drug Dispensing and Accountability Log.  
(7) All AEs and SAEs that occur after signing the Informed Consent Form and up to 90 days after EOT1 (up 
to 30 days after EOT1 for prematurely discontinued subjects) and up to 30 days after EOT2 must be 
reported, as per Sections 10.1.5 and 10.2.2. 
(8) FU1 is cancelled if the subject enrolls in Extension Treatment and visit EX-1 occurs the day of, or prior to, 
the scheduled FU1 visit.  
FU2 is cancelled if the subject enrolls in Extension Treatment and visit EX-1 occurs the day of, or prior to, 
the scheduled FU2 visit. 
• 
If a subject discontinues study drug prematurely during the Core Treatment Period then visit FU1 is 
the EOS visit.  
• 
If a subject completes the 24 week Core Treatment Period and does not enroll in Extension Treatment, 
then visit FU2 is the EOS visit.  
• 
If a subject completes the 24 week Core Treatment Period and does enroll in Extension Treatment, 
then visit FU3 is the EOS visit.  
(9) Subjects who prematurely discontinued study drug do not undergo this assessment at FU1. 
(10) Subjects may be retreated with ponesimod at least 7 days after EOT1 (treatment course 3) and no later 
than 90 days after EOT1 if they successfully completed the first 24 weeks of the study and meet eligibility 
criteria as listed in Sections 4.6 and 4.7. 
(11) Monthly urine pregnancy tests must be done at home between quarterly visits EX-7, 8, 9, 10, 11, 12, and 
13. Subject will telephone the study site to convey results. See Section 7.3.11.2. 
AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; DLCO = diffusing capacity 
of lung for carbon monoxide; ECG = electrocardiogram; eCRF = electronic Case Report Form; 
EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; GVHD = graft versus host disease; 
MOC = methods of contraception; OCT = optical coherence tomography; PD = pharmacodynamics; 
PK = pharmacokinetics; QTc = corrected QT interval; QTcF = QT interval corrected according to Fridericia’s 
formula; SAE = serious adverse event 


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PROTOCOL 
1 
BACKGROUND 
1.1 
Chronic graft versus host disease 
Chronic graft versus host disease (GVHD) is a pleomorphic syndrome with 
autoimmune-like features. The disease can affect multiple sites, including the skin and 
subcutaneous connective tissues, lacrimal and salivary glands, oral mucosa, lungs, 
esophagus, joints, gastrointestinal (GI) tract and liver [Martin 2011]. Chronic GVHD is the 
most serious and common long-term complication of allogeneic hematopoietic stem cell 
transplantation (HSCT), and has a median time to onset of 4 to 6 months after 
transplantation, although up to 10% of cases may be diagnosed beyond 1 year [Lee 2008]. 
Chronic GVHD has distinctive signs and symptoms, which include sicca syndrome, 
obstructive bronchiolitis, and lichenoid or sclerotic skin changes, among others. Chronic 
GVHD also has signs and symptoms that are shared with acute GVHD, and these include 
erythematous skin rash, nausea, vomiting, diarrhea, and cholestatic liver disease 
[Weisdorf 2007]. 
Risk factors for chronic GVHD include use of a mobilized blood cell graft, a human 
leukocyte antigen (HLA)-mismatched or unrelated donor, older patient age, and especially 
a history of acute GVHD. The risk of this disease can be decreased by T-cell depletion 
from the graft or treatment of the recipient with anti-T-cell antibodies as part of the 
conditioning regimen prior to transplant [Martin 2011]. 
Chronic GVHD is a leading cause of late death in HSCT patients; however, at the same 
time, GVHD is associated with lower leukemia relapse rates. Data are conflicting regarding 
the correlation of this effect with GVHD severity [Garnett 2013]. 
1.1.1 Epidemiology 
Approximately 8000 allogeneic HSCT are now performed in the USA each year 
[Pasquini 2013]. Of these, approximately 35% are expected to develop chronic GVHD 
requiring systemic treatment, with a total incidence of approximately 3000 patients per 
year [Flowers 2011]. Based on reported rates of survival, recurrent malignancy and 
withdrawal of immunosuppression after resolution of chronic GVHD [Vigorito 2009], the 
total 
prevalence 
in 
the 
USA 
is 
estimated 
at 
less 
than 
10,000 
[NIH Design of Clinical Trials 2014]. 
1.1.2 Pathogenesis 
The pathophysiology of chronic GVHD is complex and involves both autoreactive and 
alloreactive T and B lymphocytes [Wolff 2011a, Antin 2011]. Several themes have 
emerged from different studies, which include: a potential role for regulatory T-cell 


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abnormalities in the development of chronic GVHD; thymic injury and dysfunction from 
chemotherapy, radiation, and/or acute GVHD leading to loss of self-tolerance; the observed 
presence of autoantibodies (anti-nuclear, -mitochondrial, -parietal, -smooth muscle, or -
parotid) present in some chronic GVHD patients; elevated levels of B-cell activating factor 
in chronic GVHD patients [Linhares 2013]; and contribution of transforming growth factor 
and platelet-derived growth factor pathways [Nishimori 2013]. T- and B-cell pathways 
may present potential targets for treating chronic GVHD [Linhares 2013]. 
1.1.3 Current treatments 
Symptomatic mild chronic GVHD may often be managed with local therapies alone, 
whereas patients with moderate or severe chronic GVHD are candidates for systemic 
immunosuppressant (IS) therapy [Jagasia 2015, Filipovich 2005]. Duration of IS therapy 
is determined by clinical response, with median duration estimated at 2 to 3 years 
[Stewart 2004]. 
Currently, there are no approved therapies for chronic GVHD in the USA. However, 
glucocorticoids, with or without the concomitant administration of calcineurin inhibitors 
(CNI), are considered standard treatments [Teshima 2009, Linhares 2013], are the most 
common treatments [Weisdorf 2007], and their use is based on data from randomized trials 
[Wolff 2011a]. The required intensity and duration of initial treatments for chronic GVHD 
are not well established [Wolff 2011a].  
Generally, the prednisone or methylprednisolone starting daily dose should not exceed 1.0 
mg/kg body weight and is followed by tapering over several months [Wolff 2011a]. 
Glucocorticoid tapering is stopped or the dose is increased with the recurrence or 
exacerbation of chronic GVHD symptoms [Martin 2009].  
CNIs are often co-administered with glucocorticoids as first-line therapy, and may 
ameliorate steroid-related side effects but are unlikely to provide an additional survival 
advantage [Koc 2002]. CNIs are worth considering for severe chronic GVHD 
[Wolff 2011a], and one approach is co-administration of CNIs with glucocorticoids, with 
CNI doses decreased only after glucocorticoids have been stopped [Martin 2011]. 
Approximately 50% of patients receiving initial therapy do not have a sustained response. 
There is no standard second-line therapy, with approximately 40 drugs having been studied 
in poorly standardized Phase 2 trials or reported in retrospective case analyses 
[Linhares 2013]. Many of these drugs, while studied as second-line therapy, have been 
used almost exclusively in combination with glucocorticoids [Wolff 2011a]. Results of a 
survey on second-line treatment of chronic GVHD indicated that the following agents were 
frequently used in at least 5 of the 30 responding centers, located in Germany, Austria, and 
Switzerland: steroids (30/30), cyclosporine (22/30), photopheresis (13/30), mycophenolate 


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mofetil (13/30), tacrolimus (9/30), mycophenolic acid (8/30), sirolimus (6/30), and pulse 
dose of steroids (5/30) [Wolff 2011a]. 
1.1.4 Unmet medical need 
Although chronic GVHD has been associated with a reduced risk of recurrent malignancy 
after HSCT, survival is not improved. Patients with chronic GVHD have an increased risk 
of infections and a 30–50% risk of mortality during the first 5 years after diagnosis 
[Martin 2011]. 
The prognosis of patients with glucocorticoid refractory chronic GVHD appears to be 
especially poor [Teshima 2009, Wolff 2011a]. There is a lack of agreement on the 
definition of glucocorticoid refractory [Greinix 2007], although one proposed working 
definition includes failure to improve after at least 2 months or progression after 1 month 
of standard glucocorticoid-based IS therapy [Lee 2008]. Another proposed definition 
consists of the following criteria: (1) progression on prednisone at 1 mg/kg/day for 
2 weeks, (2) stable disease on ≥ 0.5 mg/kg/day of prednisone for 4-8 weeks, and 
(3) inability to taper prednisone below 0.5 mg/kg/day [Wolff 2011a]. Table 2 shows 
reported response and survival rates for a variety of secondary agents, which were typically 
studied in patients with glucocorticoid-refractory or -resistant chronic GVHD. Results 
were highly variable, with large proportions (> 35%) of patients having failed to 
demonstrate overall response in most studies. Survival ranged from 53% at 1 year to 85% 
at 2 years. Due to the lack of robust data, and especially in the setting of 
glucocorticoid-refractory disease, it is recommended that patients are enrolled in clinical 
trials whenever possible [Garnett 2013]. 
Table 2 
Overall response and survival rates for selected secondary agents 
Agent 
Published overall 
response rates* 
Survival 
Mycophenolate mofetil 
46–75% (N=21-26) 
85% at 2 years 
High-dose corticosteroids 
48% (N=56) 
88% at 1 year 
Extracorporeal 
photopheresis 
61% (N=71) 
53% at 1 year 
Sirolimus 
63% (n=35) 
50% at 15 months 
2-deoxycoformycin 
53% (N=58) 
78% at 1 year 
Tacrolimus 
35% (N=39) 
Not reported 
Rituximab 
65–70% (N=21-38) 
76% at 2 years 
Thalidomide 
20–38% (N=23-80) 
41% at 2 years 
Source: Adapted from Lee 2008. *Definitions of response vary. 


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Glucocorticoid-dependent patients likely represent another subgroup with sub-optimal 
outcomes. Although there are no accepted definitions for glucocorticoid dependence in 
chronic GVHD, the ongoing University of California Davis study UCDCC#229 utilizes 
the following: chronic GVHD manifestations requiring a glucocorticoid dose of prednisone 
> 0.25 mg/kg/day (0.5 mg/kg by mouth every other day) for at least 12 weeks1. A recent 
Fred Hutchinson Cancer Research Center study provides insight into the unmet medical 
need for these patients. This observational study of 400 consecutive relapse-free subjects 
who received initial systemic treatment of moderate or severe chronic GVHD was designed 
to (among various objectives) determine whether the dose of prednisone at 6 or 12 months 
of treatment is associated with long-term success in withdrawing IS treatment due to 
resolution of GVHD [Inamoto 2014a]. Data was reported for up to 48 months. For those 
patients with failure-free survival (FFS) at 12 months, lower glucocorticoid doses were 
associated with successful withdrawal of all IS treatment [Figure 1]. FFS was defined as 
the absence of treatment change, NRM, and recurrent malignancy during initial systemic 
treatment. Furthermore, subsequent overall survival was slightly better among patients 
taking doses ≤ 0.3 or ≤ 0.2 mg/kg/day at 6 months compared with those taking respectively 
higher doses. 
 
 
                                                 
 
 
1 Retrieved from https://ccresources.ucdmc.ucdavis.edu/csr/ctsu/clinicaltrial/2158/?displayelig=y 


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Figure 1 
Long-term success in withdrawing all IS treatment in patients initially treated with glucocorticoids 


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Percent withdrawal of IST 
during initial treatment 
Months from initial treatment 
Percent withdrawal of IST 
during initial treatment 
Months from initial treatment 
Percent withdrawal of IST 
during initial treatment 
Months from initial treatment 
Results were analyzed according to prednisone 
(PDN) doses at 12 months after initial treatment. 
Withdrawal of all immunosuppressive treatment 
(IST) after resolution of GVHD among patients 
without recurrent malignancy was counted during 
initial treatment among patients initially treated 
with steroids. Patients with recurrent malignancy 
or with treatment change before 12 months were 
excluded. 
 
Source: Adapted from Inamoto Y et al. Blood 
2014;124:1363-1371 


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1.2 
Sphingosine 1-phosphate receptors 
Sphingosine 1-phosphate (S1P) plays a central role in lymphocyte trafficking [Cyster 2005, 
Brinkmann 2007, Brinkmann 2010, Schwab 2007]. S1P is synthesized and secreted by 
many cell types, including platelets, erythrocytes, and mast cells, and elicits a variety of 
physiological responses [Cyster 2005, Alvarez 2007]. Among other effects, lymphocyte 
egress from primary and secondary lymphoid organs is dependent on the interaction 
between S1P and the sphingosine 1-phosphate receptor 1 (S1P1). S1P1 agonists block 
lymphocyte migration out of lymphoid tissue into the lymphatic and vascular circulation, 
thereby reducing peripheral absolute lymphocyte count and preventing lymphocyte 
recruitment to sites of inflammation. Following withdrawal of an S1P1 agonist, the 
functional lymphocytes return to the circulation from their sites of sequestration. Other 
functions that do not rely on homing mechanisms, such as antibody generation by 
B lymphocytes, first-line immunological protection by granulocytes and monocytes, and 
antigen-dependent T cell activation and expansion, are not affected by this mechanism 
[Pinschewer 2000].  
S1P itself induces pleiotropic effects, which are mediated by a family of 
five G protein-coupled receptors, S1P1-S1P5, located on endothelial cells, vascular and 
cardiac smooth muscle cells, and cardiac myocytes [Alvarez 2007, Brinkmann 2007, 
Brinkmann 2010]. The first S1P receptor modulator, fingolimod (FTY720, Gilenya®), 
which has been approved by the FDA and the EMA for the treatment of MS, is not selective 
for S1P1, but interacts also with S1P3, S1P4, and S1P5 [Brinkmann 2007, Brinkmann 2010].  
1.2.1 S1P and GVHD: preclinical evidence 
Fingolimod, a non-selective S1P receptor modulator, has shown benefit in experimental 
acute GVHD in mice [Kim 2003, Katakoka 2005] and rats [Masabuchi 1996, Song 2006]. 
Due to the limited availability of bona fide chronic GVHD models in rodents [Chu 2008], 
a paucity of literature exists on the use of S1P1 modulators.  
One report documented the benefit of using fingolimod in both prevention and treatment 
in a sclerodermatous model of chronic GVHD in mice. Fingolimod treatment led to a 
significant decrease of body weight loss and inhibited skin and lung fibrosis. Best effects 
were observed when treatment with fingolimod was initiated at day 0 of disease induction 
[Huu 2013].  
Multiple mechanisms have been described to explain the efficacy of fingolimod in chronic 
GVHD. Most importantly, fingolimod inhibited the infiltration of T- cells and other 
mononuclear cells into the skin (the major organ studied in this report) but also 
normalization of PTEN, MMP-1 and p-Smad-3 expression (gene products involved in 
fibrosis [Nho 2006, Gu 2007]) in skin. Also, mRNA expression of cytokines/chemokines 


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were reduced and the number of regulatory myeloid and lymphoid cells increased after 
treatment with fingolimod [Huu 2013].  
1.3 
Ponesimod, selective modulator of S1P1 
Ponesimod, an iminothiazolidinone derivative, is an orally active, selective modulator of 
S1P1 that induces a rapid, dose-dependent, and reversible reduction in peripheral absolute 
lymphocyte count by blocking the egress of lymphocytes from lymphoid organs. T- and B-
cells are most sensitive to ponesimod-mediated sequestration. In contrast, monocytes, 
natural killer (NK) cell, and neutrophil counts are not reduced by ponesimod. The effect of 
ponesimod on circulating effector T-cells represents a promising therapeutic approach for 
diseases in which activated T-cells play a critical role.  
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.3.1 Nonclinical studies 
The main findings in the nonclinical studies conducted with ponesimod are: 
• Ponesimod causes a rapid and substantial reduction in circulating lymphocytes in rats 
and dogs, which is also rapidly and fully reversible. The effect correlates well with the 
plasma concentration of ponesimod. 
• Studies with ponesimod in animal models of T-cell-mediated diseases, such as MS, 
rheumatoid arthritis, type 1 diabetes and skin hypersensitivity, consistently indicated a 
therapeutic potential of ponesimod at oral doses that lower peripheral blood 
lymphocyte counts.  
• Ponesimod shows an oral bioavailability of 35–74%, low clearance, and a tissue 
distribution greater than total body water in rats and dogs. Plasma protein binding is 
high (≥ 98.9%) in rats, dogs, and humans. 
• Based on available nonclinical data, the potential for drug-drug interactions (DDI) is 
limited.  
• The metabolism of ponesimod is comparable in rats, dogs, and humans. The main 
metabolite, ACT-338375 (M13), is present in plasma of mice, rats, and dogs at levels 
similar to or higher than steady-state exposures in humans at 40 mg/day. 
• The main targets for ponesimod-related toxicity after treatment of up to 4 weeks were 
the lungs (mice, rats, and dogs) and the nervous system (clinical signs, dogs only). 
After 13, 26, and 52 weeks of treatment, the heart and skin were identified as additional 
target organs in dogs. No-observed-adverse-effect levels were established for all 
toxicologically relevant targets in rats, mice, and dogs after 4, 13, 26, and 52 weeks of 
treatment, and resulting safety margins are considered acceptable. 


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• Embryo-fetal toxicity studies in rats and rabbits indicated that ponesimod has 
embryotoxic and teratogenic potential. In rat fertility studies, ponesimod had no effects 
on female and male fertility and did not produce any testicular morphologic changes. 
Ponesimod has not been studied in nonclinical models of chronic GVHD, and no such 
studies are currently planned, due to the limited availability of models, alternative S1P 
class nonclinical data in acute and chronic GVHD [see Section 1.2.1], and extensive 
ponesimod safety and efficacy data obtained in both nonclinical studies and Phase 1 and 
Phase 2 studies in patients with autoimmune diseases. However, relevant to chronic 
GVHD, and in addition to the effect on circulating lymphocyte reduction, a decrease of 
local cytokines and chemokines has been demonstrated using ponesimod in animal models 
for skin inflammation and arthritis [Piali 2011]. Relative increases of regulatory T- and B-
cells were also observed using ponesimod in a model of diabetes [You 2013] and in Phase 
1 studies for ponesimod [D’Ambrosio 2015]. Ponesimod has also been demonstrated to 
inhibit the increase of IgA titers in a mouse model of lupus (data on file). 
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.3.2 Clinical studies 
Overall, more than 1000 subjects were exposed to ponesimod in the completed Phase 1 or 
Phase 2 clinical studies: 330 healthy male and female subjects, 24 subjects with hepatic 
impairment, and 16 subjects with renal impairment were exposed to single doses of 
ponesimod up to 75 mg and multiple doses up to 100 mg for up to 22 days; 304 subjects 
with moderate-to-severe chronic plaque psoriasis were exposed to ponesimod up to 40 mg 
once daily (o.d.) for up to 28 weeks, and 435 subjects with relapsing-remitting multiple 
sclerosis (RRMS) were exposed to ponesimod up to 40 mg o.d. for up to 4 years. 
1.3.2.1 Clinical pharmacology 
The pharmacokinetic (PK) profile of ponesimod is characterized by low variability. The 
terminal elimination half-life is about 32 h. There is approximately two-fold accumulation 
of the drug with repeated daily oral dosing, and steady state is achieved within 4–5 days. 
There is a good correlation between the plasma concentration of ponesimod and the 
peripheral blood absolute lymphocyte count. Food, age, race or sex do not appear to 
relevantly affect the PK and pharmacodynamics (PD) of ponesimod. The PK DDI potential 
of ponesimod is judged to be low based on current nonclinical and clinical data.  
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.3.2.2 Pharmacodynamics in humans 
Oral administration of ponesimod dose dependently reduces the circulating lymphocyte 
count in humans. The maximum reduction from baseline of approximately 65–80% is 
achieved after a single dose of ≥ 50 mg, or at steady-state, at 40 mg o.d. The nadir in 


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lymphocyte count is attained within 6–10 h following a given single dose. There is no 
evidence of tachyphylaxis of lymphocyte reduction. Peripheral blood counts of both T- and 
B-cells are reduced by ponesimod, while NK cells and neutrophils are not reduced. Food, 
race and/or gender do not appear to relevantly affect the PD of ponesimod. Upon 
discontinuation of ponesimod, the lymphocyte count generally returns to within the normal 
range within 1 week.  
The magnitude of lymphocyte-count reductions seen with ponesimod in subjects with MS 
were consistent with observations made after treatments of short duration in healthy 
subjects. In the Phase 2 dose-finding study AC-058B201 with subjects with RRMS, at 
Week 24, the mean reductions from baseline in lymphocyte count were 49.8%, 65.3% and 
68.6% in the ponesimod 10 mg, 20 mg, and 40 mg groups, respectively, compared to a 
mean increase of 3.3% in the placebo group. Lymphocyte count remained stable on 
treatment and returned to baseline levels within 1 week following ponesimod treatment 
discontinuation. 
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.3.2.3 Efficacy in humans 
Efficacy results are available for ponesimod in moderate-to-severe psoriasis and in RRMS. 
Study AC-058A200 was a randomized placebo-controlled study, and the primary objective 
was to demonstrate the efficacy of 20 mg ponesimod o.d. on mean Psoriasis Area and 
Severity Index (PASI) at Week 6 in plaque psoriasis subjects. Although PASI improved, 
the primary endpoint was not achieved. PASI improved in both ponesimod and placebo 
groups up to Week 4; thereafter, the rate of decrease appeared more pronounced in 
ponesimod groups. 
Study AC-058A201 was a randomized placebo-controlled study, and the primary objective 
was to demonstrate the efficacy of 20 and 40 mg ponesimod versus placebo at 16 weeks. 
There was a highly significant effect of both 20 and 40 mg doses over placebo in subjects 
achieving a 75% reduction in PASI score (primary analysis) and in Physician’s Global 
Assessment of ‘Clear’ or ‘Almost clear’ at Week 16.  
Study AC-058B201 was a randomized, placebo-controlled Phase 2b study, in which 
efficacy, safety, and tolerability of 10, 20, or 40 mg ponesimod administered for 24 weeks 
were investigated in subjects with RRMS. Treatment with ponesimod at all tested doses 
was associated with a statistically significant decrease in the cumulative number of new T1 
gadolinium-enhanced lesions at Weeks 12, 16, 20, and 24 (primary endpoint) compared to 
placebo. The observed effect was dose dependent, reaching a risk reduction versus placebo 
of 77% (p < 0.0001), 83% (p < 0.0001) and 43% (p < 0.05) in the 40, 20, and 10 mg 
groups, respectively, versus placebo. The study was not powered to detect a significant 


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effect of ponesimod on clinical endpoints like aggregate annualized relapse rate (ARR) or 
time to first confirmed relapse. Treatment with ponesimod was associated with a reduction 
in the aggregate ARR up to Week 24. The ARR reduction in the 40 mg dose group was 
52% (0.251 versus 0.525 for placebo; nominal p < 0.05), compared with 21% and 37% in 
the 20 mg and 10 mg groups, respectively. Treatment with ponesimod was associated with 
an increase in time to first confirmed relapse on treatment. The hazard ratio for subjects 
treated with 40 mg ponesimod was 0.42 (95% confidence interval [CI] 0.20–0.87, 
p = 0.0189). In the 20 mg and 10 mg groups, the hazard ratio was 0.79 (95% CI 0.43, 1.45) 
and 0.64 (95% CI 0.33, 1.22), respectively. 
Study AC-058B202 is a parallel-group, blinded extension to study AC-058B201. Subjects 
who completed 24 weeks of treatment with ponesimod in the core study were offered to 
continue treatment with ponesimod. Subjects who completed 24 weeks of treatment with 
placebo were randomized in a 1:1:1 ratio to either 10, 20 or 40 mg ponesimod daily. The 
results from an interim analysis of study AC-058B201/B202 with cut-off date of 31 
October 2013 have shown sustained low rates of magnetic resonance imaging and clinical 
disease activity with dose-dependent effects on relapse rate and disability accumulation.  
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.3.2.4 Safety and tolerability 
Clinical studies to date have identified transient changes in heart rate (HR) and 
atrioventricular (AV) conduction as the most prominent safety-related signal with 
ponesimod. Oral doses of ponesimod resulted in dose-dependent sinus rate reductions in 
all treated subjects; the changes were transient, with a nadir at approximately 
1.5–2.5 hours post-dose, and resolved largely within 6–10 hours after dosing. In some 
subjects, these HR reductions were accompanied by a transient effect on AV conduction 
with prolongation of the PR interval on the electrocardiogram (ECG) and, occasionally, 
second degree AV-block. The effects on HR and AV conduction diminish with repeated 
administration of ponesimod, indicating desensitization. To minimize the first-dose effects 
on HR and AV conduction, a dose up-titration regimen was successfully tested and is 
implemented in current clinical trials.  
Difficulty in inspiration (dyspnea) and related pulmonary function test (PFT) changes have 
also been detected in humans. Mild transient dyspnea/cough was noted frequently 2–6 h 
after an oral dose of 40 mg or higher. Symptoms resolved spontaneously upon 
discontinuation of treatment with ponesimod. Dose-dependent decreases from baseline in 
forced expiratory volume in 1 second (FEV1) were observed in the ponesimod groups. 
These decreases were established within the first few weeks, remained stable thereafter 
(including over long-term treatment), and were fully reversible following treatment 
discontinuation.  


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Elevations of aspartate transaminase (AST) and/or alanine aminotransferase (ALT) 
without any bilirubin increase have been noted with ponesimod; they have been reversible 
upon discontinuation of dosing. The changes were asymptomatic.  
Individual cases of macular edema associated with changes in visual acuity have been 
observed in subjects treated with ponesimod. These events resolved upon discontinuation 
of ponesimod. 
Nonclinical safety testing of ponesimod indicates an embryotoxic and teratogenic 
potential. Pregnant or lactating women are excluded from clinical trials, and women of 
child-bearing potential (WOCBP) must use reliable methods of contraception (MOC) and 
must not become pregnant during a clinical study and for at least 30 days after study drug 
discontinuation. A hormonal contraceptive is allowed as one of the required MOC, as the 
PK profile of hormonal contraceptives has been shown not to be substantially altered in the 
presence of ponesimod.  
More detailed information can be found in the Investigator’s Brochure [Ponesimod IB]. 
1.4 
Rationale and purpose of the study 
The central role of S1P in lymphocyte trafficking and the ability of an S1P receptor 
modulator to reduce the availability of circulating lymphocytes suggests a promising 
therapeutic approach for numerous immune system diseases [see Section 1.2]. 
The rationale for the study of ponesimod in the treatment of chronic GVHD is based on 
inhibition of T- and B-cell infiltration, reduction of local pro-inflammatory cytokines, 
relative increases of regulatory T-cells and possibly the reduction of antibody titers. Parts 
of these pathways were assessed in a model of sclerodermatous chronic GVHD using the 
non-selective S1P1 modulator fingolimod. Ponesimod has also demonstrated efficacy and 
a consistent safety profile in plaque psoriasis and RRMS, two conditions where 
lymphocytes are considered central to pathophysiology [see Section 1.3]. 
The purpose of this Phase 2 study is to explore dose response, safety and efficacy of 
ponesimod at 5, 10, and 20 mg daily doses in subjects with moderate or severe chronic 
GVHD who are glucocorticoid refractory, dependent, or intolerant and inadequately 
responding to the most recent line of therapy. 
2 
STUDY OBJECTIVES 
2.1 
Main objectives 
• 
To investigate the dose response in peripheral absolute lymphocyte count reduction 
with ponesimod in subjects with chronic GVHD 
• 
To investigate the safety and tolerability of ponesimod in subjects with chronic GVHD 


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2.2 
Exploratory objectives 
• 
To investigate the efficacy of ponesimod in subjects with chronic GVHD 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 
Study design  
This is a Phase 2 prospective, multi-center, open-label, intra-subject dose-escalation study. 
The study is designed to investigate the biological activity, safety, tolerability, and PK of 
ponesimod in subjects with symptomatic moderate or severe chronic GVHD inadequately 
responding to first- or second-line therapy.  
Approximately 30 subjects will be enrolled to receive ponesimod in escalating doses of 
5, 10 and 20 mg over the Core Treatment Period of 24 weeks. The study will be conducted 
at approximately 10 sites in the USA. Enrollment will proceed until the required number 
of subjects has been reached. Any subject in screening at the time of enrollment of the 30th 
subject may continue to enroll. Recruitment will be competitive across sites. Actelion may 
replace sites with no subject enrollment.  
Subjects completing the initial 24 weeks of the study will have the option to restart 
ponesimod for an extension treatment course of 96 weeks, should their chronic GVHD 
progress within a defined timeframe after stopping ponesimod at Week 24 of the study. 
3.2 
Study periods 
3.2.1 Screening Period 
This period starts up to 30 days prior to the day of enrollment and includes the screening 
visit and all baseline assessments occurring before the time of enrollment (Visit 1 and Visit 
2 pre-dose).  
3.2.2 Core Treatment Period 
The Core Treatment Period starts at enrollment, which occurs at the time of first study drug 
intake, and continues until the end of treatment at Week 24. Visits during the treatment 
period will consist of an enrollment visit (Day 1) and visits at Weeks 4, 8, 12, 16, 20, and 
24.  
The End-of-Treatment 1 (EOT1) visit will take place at Week 24 (Visit 8) or earlier in case 
of premature discontinuation of study drug. In all cases, the EOT1 visit should take place 
not later than 7 days after the last dose of study drug.  
Subjects who complete EOT1 will be subsequently treated according to local standard of 
care at the investigator’s discretion. 


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3.2.3 Core Safety Follow-up Period / Follow-up Period 1 
All subjects will enter the core safety follow-up period after EOT1 (Follow-up period 1), 
which will last for either 30 or 90 days. 
The follow-up period for subjects who were prematurely discontinued lasts for 30 days 
after the last dose of study drug and ends with the 30-day follow-up 1 (FU1) visit. This is 
the End-of-Study (EOS) visit for these subjects. WOCBP must continue to use acceptable 
MOC during this 30-day period. 
The follow-up period for subjects who were not prematurely discontinued lasts for 90 days 
after the last dose of study drug, and consists of the 30-day FU1 site visit and the 90-day 
follow-up 2 (FU2) visit, which is also the EOS visit. If the subject starts the study drug 
(and thus enters the Extension Treatment Period) prior to or on the day of scheduled FU1 
and/or FU2, then one or both of these visits are cancelled. WOCBP must continue to use 
acceptable MOC during this 90-day period. 
The study periods are depicted in Figure 2. 
Figure 2 
Study periods: Screening through Follow-up Period 1 
Screening 
Period 
Core Treatment Period (ponesimod) 
Follow up 
Period 1 
 
20 mg 
UT 
2 
10 mg  
UT 
1 
5 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 weeks 
4 weeks 
16 weeks 
1 - 30 days 
24 weeks 
90 days 
 
EOT1 
Visit 8 
90 day 
FU2  
Visit 10 
(EOS) 
 30 day 
FU1  
Visit 9 
(EOS) 
Screening 
Visit 1 
Enrollment 
Visit 2 (Day 1) 
EOT = End-of-Treatment; EOS = End-of-Study; FU = follow-up; UT 1 = 6-day up-titration; UT 2 = 4-day up-titration.  
3.2.4 Extension Treatment Period 
Subjects who completed the 24 weeks of study treatment (i.e., who were not prematurely 
discontinued from ponesimod) and whose chronic GVHD progressed after EOT1 may be 
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The Extension Treatment Period starts the day ponesimod is started, on visit EX-1 
(Visit 11) and can continue for up to 96 weeks. Visits during the Extension Treatment 
Period will consist of visit EX-1 and visits at EX-Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 
72, 84, and 96. 
The End-of-Treatment 2 (EOT2) visit will take place at EX-Week 96, EX-13 (Visit 23) or 
earlier in case of premature discontinuation of study drug. In all cases, the EOT2 visit 
should take place not later than 7 days after the last dose of study drug.  
Subjects completing the EOT2 will be subsequently treated according to local standard of 
care at the investigator’s discretion. 
3.2.5 Extension Safety Follow-up Period (Follow-up Period 2) 
All subjects will enter the safety follow-up period after EOT2 (Follow-up Period 2), which 
will last for 30 days after the last dose of study drug and end with the 30-day follow-up 3 
(FU3) site visit (Visit 24). This visit is the EOS visit for these subjects. WOCBP must 
continue to use acceptable MOC during this 30-day period. 
The study periods are depicted in Figure 3. 
Figure 3 
Study periods: Follow-up Period 1 through Follow-up Period 2 
Follow-up 
Period 1 
Extension Treatment Period 
Follow-up 
Period 2 
UT 
X 
Previously tolerated dose: 5, 10, or 20 mg 
 
 
 
 
Up to 90 days 
96 weeks 
30 days 
 
EOT2 
Visit 23 
EOT1 
Visit 8 
Enrollment 
EX-1 
Visit 11, (7-90 
days after EOT1) 
30 day 
FU3  
Visit 24 
(EOS) 
EOT1, 2 = End-of-Treatment 1, 2; EOS = End-of-Study; FU = follow-up; UTX = 6 or 14 day up-titration. 
3.3 
Study design rationale 
Ponesimod has demonstrated efficacy, safety, and tolerability at 10, 20, and 40 mg daily 
doses in RRMS and moderate-to-severe chronic plaque psoriasis. Furthermore, the 
magnitude of lymphocyte count reductions seen with ponesimod in RRMS subjects treated 


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over 2 years and psoriasis subjects treated for up to 28 weeks were consistent with 
observations made after short-term treatment in healthy subjects [Ponesimod IB, 
section 5.2.2]. 
Unique to chronic GVHD, and in contrast to other immune diseases, is the event of HSCT 
and subsequent immune system reconstitution. Most conditioning protocols destroy the 
patient’s immune system completely. After transplantation, donor monocytes are the first 
cells to engraft, followed by granulocytes, platelets, and NK cells. Clinical engraftment 
depends on achieving a sustained granulocyte count > 0.5 G/L and typically occurs 10 to 
25 days after HSCT. The number of most leucocyte subsets normalize quickly afterwards. 
However, transfer of the donor’s immunity is poor and T- and B-cell responses are 
incomplete for a long period after HSCT [Storek 2008]. Lymphocytes, the target of 
ponesimod, may have a markedly different homeostasis in chronic GVHD versus other 
studied diseases. 
In order to safely conduct the first study of ponesimod in chronic GVHD, an open-label 
dose-escalation trial is proposed. Ponesimod effects on lymphocyte count will be 
established at the lower doses of 5 mg and 10 mg daily, prior to final dose escalation to 20 
mg. This study seeks to expose subjects to the lower doses for an adequate time to establish 
the magnitude of dose response prior to allowing dose increases. Based on previous 
experience, maximal lymphocyte reduction occurs approximately 2 to 3 weeks after dose 
initiation, including up-titration [Ponesimod IB, section 5.2]; consequently, a one-month 
exposure duration (including up-titration) is assigned to the 5 mg and 10 mg daily doses 
each. Lymphocyte count will also be assessed 4 weeks after the final dose escalation to 20 
mg to assess dose response and ensure subject safety. 
Each chronic GVHD subject may have achieved different stages of immune reconstitution 
and lymphocyte homeostasis based on numerous variables, including time from transplant, 
conditioning regimen, age, and so on. Therefore, an intra-subject dose-escalation study is 
expected to provide the most meaningful results regarding ponesimod effects on 
lymphocyte count reduction in a study of modest sample size. 
Ponesimod will be given over 24 weeks, 16 weeks of which are at the 20 mg daily dose. 
This timeframe will permit further evaluation of safety, including infections and 
ponesimod effects on lung function. Frequent monitoring, with 4-week intervals between 
visits and testing at minimum, will serve to ensure safety. 
Efficacy will also be assessed. It is believed that improvement for many symptoms of 
chronic GVHD could be evident within the first four weeks of therapy 
[NIH Design of Clinical Trials 2014]; however, a response at 24 weeks is more 
meaningful. Currently, no standardized, validated global response measure has been 
developed 
for 
studies 
testing 
products 
for 
treatment 
of 
chronic 
GVHD 


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[NIH Design of Clinical Trials 2014]. Nevertheless, categorical criteria should be defined 
for response for each organ affected by GVHD, even if they have not been validated. 
Criteria for overall response should be unambiguous [Martin 2011]. This study employs 
updated draft NIH 2014 response criteria [NIH Therapeutic Response 2014], which were 
originally developed in 2005 [Pavletic 2006]. These criteria are based on international 
expert opinion.  
The study will require stable administration of background IS therapy, including 
glucocorticoids. The following are exceptions: (1) glucocorticoid dose reductions will be 
permitted to ameliorate safety concerns related to prolonged steroid exposure; 
(2) glucocorticoid dose increases (or initiation) will be permitted to treat chronic GVHD 
flare or another condition; however, the sponsor will need to be notified prior to a dose 
increase (or initiation). Stable administration of study drug and other concomitant IS agents 
facilitates the interpretation of study results in chronic GVHD [Martin 2011]. 
Subjects successfully completing the initial 24 week treatment period (i.e., subjects not 
prematurely discontinued from study drug) are followed for 90 days after stopping study 
drug. Should subject’s chronic GVHD progress after stopping ponesimod, they may restart 
ponesimod 7 to 90 days later. The rationale for the timeframe to restart is based on the 
following data: 
• Previous experience in humans shows that lymphocyte counts recover within 7 days of 
stopping ponesimod [Ponesimod IB, section 1.4]. (It would be difficult to attribute 
progression of chronic GVHD to cessation of ponesimod’s effect during the first 7 days 
after stopping, and difficult to justify restarting ponesimod in that period for that 
reason). 
• Previous experience in chronic plaque psoriasis patients suggests that the proportion of 
patients with relapse of psoriasis approaches a plateau within 12 weeks after cessation 
of ponesimod [figure 2 in Vaclavkova 2014]. 
Subjects may be retreated with ponesimod for 96 weeks. There is limited data to support a 
rationale for duration of therapy of an investigational agent in responders. However, 
resolution of chronic GVHD is known to occur slowly, with many patients requiring 
several years of immunosuppressive therapy [Martin 2009]. 
The 96 week Extension Treatment portion of the study will thus continue to make study 
drug available for subjects who were previously shown to benefit from ponesimod. This 
extended treatment period will also provide longer term safety, tolerability and efficacy 
data. In contrast to the initial 24 week treatment period, investigators will have greater 
flexibility in administering allowed concomitant background immunosuppressant therapy.  


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3.4 
Site personnel and their roles 
It is recommended that the designated personnel remain unchanged throughout the entire 
course of the study and that an adequately trained back-up be designated in case of absence 
of any of the staff listed below. 
At each site, the study staff will consist of:  
• 
A principal investigator 
• 
A cardiac safety assessor 
• 
A clinical coordinator/study nurse (if required) 
• 
An ophthalmologist 
• 
A pulmonologist  
• 
A pulmonary function laboratory technician or expert 
3.4.1 Principal investigator and sub-investigator 
The principal investigator is responsible for the overall conduct of the study at the site. It 
is her/his responsibility to explain the study and all its aspects to the subject and obtain 
her/his informed consent. The principal investigator will be responsible for subject clinical 
care and management, e.g., eligibility evaluation, supervision of study drug administration, 
monitoring of safety (including recording and treating of adverse events (AEs), physical 
examination, and routine laboratory results) and concomitant medications. The principal 
investigator may delegate duties to a sub-investigator but remains responsible for the 
overall conduct of the study at his/her site. The principal investigator and sub-investigator 
must be physicians experienced in treating chronic GVHD patients. 
The principal investigator or sub-investigator will assess efficacy via the chronic GVHD 
Activity Assessment [Appendix 7] according to the protocol schedule. 
3.4.2 Cardiac safety assessor 
The cardiac safety assessor must be a physician adequately trained and experienced in 
cardiology. He/she must be qualified and equipped to provide emergency treatment in cases 
of acute cardiac events. While the exams themselves may be performed by a delegate (e.g., 
study nurse), their review and interpretation must be performed by the physician. The 
investigator may perform this role if qualified. 
He/she is responsible for conducting all blood pressure (BP) and ECG assessments 
requested by the protocol during the study, including the close monitoring of the subject 
during the first 4 hours and up to 12 hours following study drug intake at Visit 2 (Day 1). 
He/she will independently assess eligibility for discharge or continued subject management 
on Visit 2 and on visits for re-initiation of study drug where post-dose monitoring will be 
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He/she will support the principal investigator in making a decision on eligibility of the 
subject prior to enrollment, and on providing adequate treatment in cases of cardiac events.  
Significant findings, which in view of the cardiac safety assessor meet the definition of an 
AE, must be reported to the principal investigator and recorded on the Adverse Event page 
of the electronic Case Report Form (eCRF). 
Any cardiac events of potential clinical concern must be assessed by the cardiac safety 
assessor for seriousness, and reported accordingly. 
3.4.3 Clinical coordinator / study nurse 
A clinical coordinator / study nurse may be required to assist the principal investigator / 
sub-investigator in all aspects of subject management. He/she will be responsible for 
scheduling visits and assessments as planned in the study protocol, recording concomitant 
medications, maintaining source documentation, and transcription of data into the eCRF. 
He/she will instruct the subjects on study drug administration, and collect, process, and 
send all blood and urine samples to the central laboratory. Additionally, he/she may be 
responsible for coordinating the conduct of PFTs, ophthalmological and cardiac 
examination, and the appropriate administration of the Patient-Reported Outcomes 
instruments. In the absence of a clinical coordinator / study nurse, the above tasks will be 
performed by the principal investigator or a sub-investigator. 
3.4.4 Ophthalmologist 
The ophthalmologist will review and interpret the ophthalmological examinations and 
optical coherence tomography (OCT) assessments as scheduled in the study protocol. In 
the event of suspected clinically significant findings (e.g., macular edema), unscheduled 
ophthalmology and OCT examination should be performed by the ophthalmologist, and 
the investigator will be notified for reporting of an AE. In the event of findings observed 
at any visit during the study, the ophthalmologist will conduct further examination, as per 
local standard practice, to rule out or confirm the diagnosis. 
3.4.5 Pulmonary function laboratory technician or expert 
The PFTs must be performed by experienced staff, such as a pulmonary function technician 
or expert according to the American Thoracic Society (ATS) / European Respiratory 
Society (ERS) guidelines [Miller 2005a] and study protocol schedule, in an established 
PFT unit. 
3.4.6 Pulmonologist 
A pulmonologist (or a physician adequately trained in pulmonology), will review PFT and 
diffusing capacity of lung for carbon monoxide (DLCO) results. If clinically significant 
alterations in PFTs or DLCO variables indicating a pulmonary condition that could result in 
increased risk for the subject are observed, he/she may be prematurely discontinued from 


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ponesimod at the discretion of the investigator. In the event of findings observed at any 
visit during the study, the pulmonologist will conduct further examination, as per local 
standard practice, to rule out or confirm the diagnosis. 
3.5 
Study Committees  
3.5.1 Study Monitoring Committee 
A Study Monitoring Committee (SMC), with a core comprising at least two medical 
experts in the field of chronic GVHD and two medical experts from the sponsor (i.e., the 
clinical project physician, and a drug safety physician with expert knowledge of the safety 
profile of ponesimod) will review toxicity assessments of each subject. At any time, the 
SMC may interrupt enrollment or recommend termination of the study for safety reasons. 
Additional permanent attendees of SMC meetings will include the clinical trial statistician, 
the clinical trial scientist and the clinical study coordinator. The SMC, governed by a 
charter, will ensure that the study is properly conducted, monitored, and that data are 
appropriately analyzed and interpreted. The SMC will recommend the dose of ponesimod 
for further development in chronic GVHD. 
3.5.2 Ophthalmology Safety Board 
An Ophthalmology Safety Board (OSB) composed of two independent ophthalmologists 
will review and evaluate any new or suspected case of macular edema. The composition 
and operation of the OSB is described in the OSB charter. 
4 
SUBJECT POPULATION 
4.1 
Subject population description 
This study will enroll male and female subjects aged 18 to 70 with chronic GVHD. Subjects 
will need a change of systemic IS therapy, in the opinion of the investigator. The need for 
a change will be based on the following: (1) subjects must have symptomatic moderate or 
severe chronic GVHD; (2) subjects must be glucocorticoid refractory, dependent, or 
intolerant; and (3) subjects must have inadequate response to their current systemic IS 
therapy according to the investigator’s judgment. The background IS therapy will be 
limited to commonly prescribed systemic first- and second-line therapies: glucocorticoids 
and/or one of the following: cyclosporine, tacrolimus, mycophenolate mofetil, 
mycophenolate sodium, everolimus, sirolimus, or methotrexate. 
Subjects with specified clinically significant medical conditions cannot enter the study. 
These include active or uncontrolled infections, new or recurrent malignancy, serious 
cardiac, pulmonary, or renal disease, and uncontrolled diabetes, among others. Subjects 
with Karnofsky Performance Score < 60 are excluded. 


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Subjects receiving IS other than allowed background therapy and specified rate and rhythm 
altering drugs, such as β-blockers, verapamil or digoxin, cannot enter the study.  
Eligible subjects must be able and willing to give informed consent for participation in the 
clinical study. 
4.2 
Rationale for the selection of the study population 
The study seeks to enroll chronic GVHD patients with high unmet need, which is 
established at several levels. 
Firstly, subjects must be symptomatic and have at least moderate severity chronic GVHD. 
Systemic therapy is typically indicated for chronic GVHD of at least moderate severity 
[Jagasia 2015]. 
Secondly, subjects should be glucocorticoid refractory, dependent, or intolerant. 
Glucocorticoids are standard first-line therapy for chronic GVHD, and it may be 
inappropriate to study ponesimod, initially, in subjects who could potentially benefit from 
glucocorticoids; however, approximately 50% of chronic GVHD patients do not have a 
sustained response to standard initial therapy, and the prognosis for patients considered to 
be glucocorticoid refractory or dependent is suboptimal [see Sections 1.1.3 and 1.1.4].  
Finally, subjects should be inadequately responding to their current therapy. Since chronic 
GVHD may take several weeks to respond to a new course of therapy, it could be 
inappropriate to start ponesimod shortly after the current course was initiated, or if subjects 
are improving on the current course. Therefore, investigators may enroll subjects in this 
ponesimod study if they judge subjects’ chronic GVHD to have progressed despite four 
weeks of the current course, or chronic GVHD to have not improved despite eight weeks 
of the current course. These criteria should be applied to first, second, or a subsequent line 
of current therapy, and have been adapted from general recommendations for indications 
for secondary treatment [Martin 2009]. 
With the exception of bronchiolitis obliterans syndrome (BOS), this study does not exclude 
any chronic GVHD manifestations from the patient population. However, due to safety 
considerations in this initial Phase 2 study, subjects with liver enzyme values, pulmonary 
function values, platelet counts, and other laboratory measures exceeding defined 
thresholds are excluded from enrollment. Thus, in addition to BOS, subjects with severe 
liver manifestations will not enter this study. 
4.3 
Inclusion criteria 
For inclusion into the study, all of the following inclusion criteria must be fulfilled. No 
waivers of any of the criteria for any subject are allowed: 
1. Signed informed consent prior to initiation of any study-mandated procedure. 


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2. Males and females aged 18 to 70 years. 
3. Recipients of allogeneic HSCT diagnosed with chronic GVHD. 
4. Currently receiving systemic IS therapy at enrollment, with no dose changes in the 
14 days prior to enrollment, consisting of systemic glucocorticoids AND/OR one of the 
following systemic agents: cyclosporine (CsA), tacrolimus (TAC), mycophenolate 
mofetil (MMF), mycophenolate sodium (MPS), everolimus (EVL), sirolimus (SRL), 
or methotrexate (MTX). 
5. Subject needs a change of current systemic IS therapy, in the opinion of the 
investigator, based on all of the following conditions: 
a. Symptomatic moderate or severe chronic GVHD per NIH global severity 
scoring assessed at screening [see Appendix 2 for NIH global severity scoring 
form]. 
b. Glucocorticoid refractory, dependent, or intolerant status at screening [see 
Appendix 1 for guidance]. 
c. Evidence of GVHD progression at enrollment despite ≥ 4 weeks current 
systemic IS therapy, OR without evidence of GVHD improvement at 
enrollment despite ≥ 8 weeks current systemic IS therapy. Current systemic IS 
therapy must be the same as in inclusion criterion 4 [see Appendix 1 for 
guidance]. 
6. Chronic GVHD manifestations involve at least one of the following organs: skin, 
mouth, eyes, joints and fascia, esophagus, upper or lower GI tract. The qualifying 
manifestation should have an NIH chronic GVHD activity assessment score of at least 
1 at enrollment [see Form A, Appendix 7]. 
7. WOCBP, as defined in Section 4.3.1, must have a negative serum pregnancy test at 
screening and a negative urine or serum pregnancy test prior to enrollment, and must 
agree to undertake urine pregnancy tests every 4 weeks during the study and up to the 
protocol defined EOS. 
8. WOCBP must agree to use acceptable MOC during the study and up to the protocol 
defined EOS. 
4.3.1 Women of child-bearing potential 
A woman is considered to be of child-bearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingo-oophorectomy or hysterectomy 
• Premature ovarian failure confirmed by a specialist 
• XY genotype, Turner syndrome, uterine agenesis 
• Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition) 


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WOCBP participating in the study must agree to use one of the following reliable MOC 
from the screening visit and up to the protocol defined EOS: 
• Two MOC, one from Group 1 and one from Group 2, defined as follows: 
o Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives 
or intrauterine devices. If a hormonal contraceptive is chosen from this group, 
it must be taken for at least 1 month prior to enrollment 
o Group 2: Female or male condoms, diaphragm or cervical cap 
OR 
• True abstinence from intercourse with a male partner only when this is in line with the 
preferred lifestyle of the subject 
OR 
• Permanent female sterilization (tubal occlusion/ligation at least 6 weeks prior to 
screening) 
OR 
• Sterilization of the male partner with documented post-vasectomy confirmation of the 
absence of sperm in the ejaculate 
4.4 
Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject: 
Cardiovascular 
1. Resting HR < 50 bpm measured by 12-lead ECG at enrollment (prior to study drug 
administration). 
2. Myocardial infarction within 24 weeks prior to screening or ongoing unstable ischemic 
heart disease. 
3. Cardiac failure (NYHA class III or IV) or any severe cardiac disease at time of 
screening. 
4. History or presence of valvular heart disease associated with symptoms or 
hemodynamic change. 
5. History or presence of cardiac rhythm disorders (e.g., sino-atrial heart block, 
symptomatic bradycardia, atrial flutter or atrial fibrillation, ventricular arrhythmias, 
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6. Presence of an increased QT corrected for HR on the basis of Fridericia’s formula 
(QTcF) interval > 470 ms (females), > 450 ms (males) measured by 12-lead ECG at 
screening or pre-dose on Day 1. 
7. History of syncope associated with cardiac disorders. 
8. Systemic arterial hypertension not controlled by medication as judged by the 
investigator. 
Hematologic 
9. Hemoglobin (Hb) < 8.0 g/dL or need for red blood cell transfusion at screening. 
10. Absolute neutrophil count < 1.5 × 109/L (< 1500 cells/mm3) at screening. 
11. Absolute lymphocyte count < 0.5 × 109/L (< 500 cells/mm3) at screening. 
12. Platelet count < 50 × 109/L (< 50,000 cells/mm3) or need for platelet transfusion at 
screening. 
Hepatic 
13. ALT and/or AST ≥ 3.0-fold the upper limit of normal (ULN) at screening. 
14. Total bilirubin (TBL) > 1.5-fold ULN (unless in the context of known Gilbert’s 
Syndrome) at screening. 
15. Known chronic liver or biliary disease that is not due to chronic GVHD. 
Infection and infection risk 
16. Active or uncontrolled bacterial, viral, or fungal infection (except onychomycosis and 
dermatomycosis); positive hepatitis B surface antigen or hepatitis C antibody tests at 
screening. 
17. Cytomegalovirus (CMV) disease, including CMV pneumonia, CMV retinitis, and 
CMV gastroenteritis and/or subjects meeting institutional criteria for systemic therapy 
for CMV reactivation. (Subjects with positive CMV serology and/or CMV reactivation 
are not excluded if they do not have CMV disease and do not require systemic therapy.) 
18. Active or latent tuberculosis (TB), as assessed by chest X-ray (CXR) performed at 
screening or within 90 days prior to screening, and interferon gamma release assay 
(QuantiFERON-TB-Gold®) at screening, except if there is documentation that the 
subject has received adequate treatment for TB previously. 
19. Congenital or acquired severe immunodeficiency or known human immunodeficiency 
virus (HIV) or positive HIV testing at screening. 
Malignancy 
20. New or recurrent malignancy or minimal residual disease. 


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Metabolic 
21. Type 1 or 2 diabetes that is poorly controlled according to investigator judgment or 
diabetes complicated with organ involvement such as nephropathy or retinopathy. 
Ophthalmologic 
22. Presence of macular edema. 
Pregnancy and breastfeeding 
23. Breastfeeding, pregnant women or women planning to become pregnant during the 
study. 
Pulmonary 
24. Subjects with a clinically significant pulmonary condition including asthma and 
chronic obstructive pulmonary disease (COPD) that is insufficiently controlled 
according to investigator judgment.  
25. Subjects with diagnosed BOS. 
26. Subjects with any hospitalization due to a clinically significant pulmonary condition 
including asthma or COPD exacerbation within 24 weeks prior to screening (with the 
exception of a fully resolved pulmonary infection).  
27. Subjects with abnormal PFTs: FEV1 < 60% of predicted normal value or FEV1/forced 
vital capacity (FVC) ratio < 0.7 at screening. 
Renal 
28. Severe 
renal 
insufficiency 
defined 
as 
a 
calculated 
creatinine 
clearance 
< 30 mL/min/1.73 m2 (Cockroft-Gault) at screening. 
Treatments 
29. Systemic glucocorticoids at prednisone-equivalent dose > 1.0 mg/kg/day at screening. 
30. Treatment within 15 days prior to enrollment with: 
• Azathioprine 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin or any anti-arrhythmic or 
HR-lowering systemic therapy (a non-exhaustive list of drugs provided in 
Appendix 4) 
• CsA, TAC, MMF, MPS, EVL, SRL (with the exception of any therapy serving 
as a mandatory concomitant therapy, as per inclusion criterion 4 and Section 
5.2). 
• Extracorporeal photopheresis 
• Isotretinoin 


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• Thalidomide 
31. Treatment within 30 days prior to enrollment with: 
• Acitretin  
• Cyclophosphamide 
• Etanercept 
• Imatinib 
• Vaccination with live vaccines 
32. Treatment within 45 days prior to enrollment with: 
• Pulse methylprednisolone 
• MTX (with the exception if MTX serves as a mandatory concomitant therapy, 
as per inclusion criterion 4 and Section 5.2). 
33. Treatment within 60 days prior to enrollment with: 
• Basiliximab 
34. Treatment within 24 weeks prior to enrollment with: 
• Anti-lymphocyte globulin (ALG) 
• Anti-thymocyte globulin (ATG) 
• Belimumab  
• Mesenchymal stem cell therapy 
• Ofatumumab 
• Pentostatin 
• Rituximab 
35. Treatment within 36 weeks prior to enrollment with: 
• Hydroxychloroquine 
36. Treatment within 48 weeks prior to enrollment with: 
• Alemtuzumab 
• Clofazamine 
37. Treatment with any IS or immunomodulatory drug or technology not identified in items 
30 to 37, unless discussed with the sponsor to determine appropriate washout. 
Chemotherapy and radiation for conditioning treatment leading up to the stem cell 
transplant and growth factors are exempt and do not have to be discussed with the 
sponsor. 


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Other Categories 
38. Karnofsky Performance Score (KPS) < 60%. 
39. Known history of clinically significant drug or alcohol abuse. 
40. Known allergy to any of the ponesimod formulation excipients.  
41. Any other clinically relevant medical or surgical condition, which, in the opinion of the 
investigator, would put the subject at risk by participating in the study. 
42. Subjects unlikely to comply with protocol, e.g., uncooperative attitude, inability to 
return for follow-up visits, or known likelihood of not completing the study including 
mental condition rendering the subject unable to understand the nature, scope, and 
possible consequences of the study. 
4.5 
Medical history 
Relevant medical history, as defined below, must be recorded in the eCRF: 
• Chronic medical conditions at any time in the past. 
• Cardiac, cardiovascular, pulmonary, immune, hepatic, and eye conditions at any time 
in the past. 
• New, significant acute medical conditions in the past 12 months prior to the study start. 
• Smoking status 
HSCT and GVHD history, as defined below, must be recorded in the eCRF including: 
• Diagnosis leading to HSCT (acute myelogenous leukemia, acute lymphoblastic 
leukemia, aplastic anemia, chronic lymphocytic leukemia, chronic myelogenous 
leukemia, hodgkin’s lymphoma, multiple myeloma, myelodysplastic syndrome, 
myeloproliferative 
disorder, 
non-hodgkins 
lymphoma, 
other 
cancer, 
other 
non-malignant disease). 
• Date of HSCT  
• HSCT-conditioning regimen (myeloablative, non-myeloablative, reduced-intensity, 
none) 
• HSCT-conditioning agents (ALG, ATG [for ALG, ATG, specify source: horse, rabbit, 
other]; busulphan, oral; busulphan, i.v.; campath; carmustine; cyclophosphamide; 
cytarabine/AraC; etoposide; fludarabine; melphalan ≤ 140 mg/m2; melphalan > 140 
mg/m2; total body irradiation ≤ 500cGy single dose / ≤ 800cGy fractionated; total body 
irradiation > 500cGy single dose / > 800cGy fractionated; no conditioning; other) 
• HSCT source (bone marrow, mobilized peripheral blood stem cells, cord blood, double 
cord) 


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• Allogeneic donor type (syngeneic; HLA-identical sibling; HLA-matched other relative; 
HLA-mismatched relative – 1 antigen mismatched [haplo-identical (yes, no)]; HLA-
mismatched relative – ≥ 2 mismatched [haplo-identical (yes, no)]; matched unrelated 
donor; mismatched unrelated donor). 
• For double cord only, second donor type (syngeneic; HLA-identical sibling; 
HLA-matched other relative; HLA-mismatched relative – 1 antigen mismatched 
[haplo-identical (yes, no)]; HLA-mismatched relative – ≥ 2 mismatched 
[haplo-identical (yes, no)]; matched unrelated donor; mismatched unrelated donor). 
• Donor gender (male, female; choose two genders if double cord: male/female, 
male/male, female/female). 
• Date of onset and resolution of acute GVHD. 
• Acute GVHD diagnosis based on evidence from a biopsy (yes, no). 
• Maximum overall grade of acute GVHD: I, II, III, or IV. 
• Maximum severity of skin involvement, acute GVHD 
o No skin acute GVHD / rash not attributable to acute GVHD 
o Stage 0 – no rash 
o Stage 1 – maculopapular rash, < 25% of body surface 
o Stage 2 – maculopapular rash, 25–50% of body surface 
o Stage 3 – generalized erythroderma 
o Stage 4 – generalized erythroderma with bullae formation and desquamation 
• Maximum severity of lower gastrointestinal tract, acute GVHD 
o No lower GI acute GVHD / diarrhea not attributable to acute GVHD 
o Stage 0 – no diarrhea 
o Stage 0 – diarrhea ≤ 500 mL/day 
o Stage 1 – diarrhea > 500 but ≤ 1000 mL/day 
o Stage 2 – diarrhea > 1000 but ≤ 1500 mL/day 
o Stage 3 – diarrhea > 1500 mL/day 
o Stage 4 – severe abdominal pain, with or without ileus 
• Maximum severity of upper gastrointestinal tract, acute GVHD 


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o No upper GI acute GVHD / persistent nausea or vomiting not attributable to 
acute GVHD 
o Stage 0 – no persistent nausea or vomiting 
o Stage 1 – persistent nausea or vomiting 
• Maximum severity of liver involvement, acute GVHD 
o No liver acute GVHD / bilirubin level not attributable to acute GVHD 
o Stage 0 – bilirubin < 2.0 mg/dL 
o Stage 1 – bilirubin 2.0–3.0 mg/dL 
o Stage 2 – bilirubin 3.1–6.0 mg/dL 
o Stage 3 – bilirubin 6.1–15.0 mg/dL 
o Stage 4 – bilirubin > 15.0 mg/dL 
• Other clinical involvement, acute GVHD (lung, other, none). 
• Current and past acute GVHD treatments (ALG, ATG [for ALG, ATG, specify source: 
horse, rabbit, other]; glucocorticoids, systemic; glucocorticoids, topical; CsA; extra-
corporeal photopheresis; tacrolimus [TAC]; anti-CD25 [zenapax, daclizumab, anti-
Tac]; campath; etanercept; infliximab; other in vivo monoclonal antibody; in vivo 
immunotoxin; MTX; MMF; MPS; SRL; EVL; ursodiol; other agent). 
• Date of onset of chronic GVHD 
• Onset of chronic GVHD was: 
o Progressive (acute GVHD progressed directly to chronic GVHD) 
o Interrupted (acute GVHD resolved, then chronic GVHD developed) 
o De novo (acute GVHD never developed) 
o Chronic GVHD flare (symptoms reactivated within 30 days of drug tapering or 
discontinuation) 
• Platelet count at diagnosis of chronic GVHD (expressed as × 109/L) 
• KPS at time of diagnosis of chronic GVHD. 
• Diagnosis was based on: histologic evidence / biopsy proven; clinical evidence; both; 
unknown. 
• Current and past chronic GVHD treatments (ALG, ATG [for ALG, ATG, specify 
source: horse, rabbit, other]; azathioprine; glucocorticoids, systemic; glucocorticoids, 
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anti-CD25 [zenapax, daclizumab, anti-Tac]; campath; etanercept; infliximab; other 
in vivo monoclonal antibody; clofazimine; MMF; MPS; psoralen and ultraviolet A; 
SRL; EVL; thalidomide; ursodiol; other agent). 
Concomitant baseline therapies, as defined in Section 5.3, will be recorded in the eCRF. 
4.6 
Extension Treatment Period inclusion criteria 
For inclusion into the Extension Treatment Period of the study, all of the following 
inclusion criteria must be fulfilled. No waivers of any of the criteria for any subject are 
allowed: 
1. Signed informed consent prior to initiation of any study-mandated procedure. 
2. Subject has completed the 24 weeks of treatment of the Core Treatment Period and the 
EOT1 visit. 
3. Subject has experienced disease progression 7 to 90 days after EOT1 visit, versus EOT1 
chronic GVHD activity assessment, for at least one previously involved organ. Progression 
is per NIH Consensus Development Project response criteria and is defined in Section 
6.3.2.  
4. WOCBP, as defined in Section 4.3.1, must have a negative urine pregnancy test at 
enrollment visit EX-1, and at all prior visits, and must agree to undertake monthly 
scheduled urine pregnancy tests during the study and up to the protocol defined EOS. 
5. WOCBP must agree to use acceptable MOC during the study and up to the protocol 
defined EOS. 
4.7 
Extension Treatment Period exclusion criteria 
There are no exclusion criteria for the Extension Treatment Period. However:  
• Study drug specific dose-reduction, interruption, or premature discontinuation criteria 
remain in force for the duration of the study. These are described in Section 5.1.10. 
• Forbidden concomitant therapies remain in force for the duration of the study. These 
are described in Section 5.3.5. 
5 
TREATMENTS 
5.1 
Study treatment 
The study treatment is the investigational drug ponesimod, administered during the Core 
and Extension Treatment Periods of the study.  
In the Core Treatment Period, study treatment consists of a 5 mg ponesimod treatment 
period (from Days 1 to 28 including up-titration), 10 mg ponesimod treatment period (from 
Days 29 to 56 including up-titration) and a 20 mg treatment period (from Days 57 to day 
before EOT1). 


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In the Extension Treatment Period, study treatment consists of the subject’s last tolerated 
dose administered throughout the Extension Treatment Period. The dose is either 5 mg, 
10 mg, or 20 mg. The Extension Treatment Period is 96 weeks long, including up-titration, 
and starts with the enrollment visit EX-1 and ends with the EOT2 visit.  
5.1.1 Investigational treatment: description and rationale 
Ponesimod is supplied as its free base, in oral film-coated tablets at the doses of 2, 3, 4, 5, 
6, 7, 8, 9, 10, and 20 mg. One tablet of ponesimod at any dose will be taken orally o.d.  
Core Treatment Period 
For this dose-escalation study, subjects will receive three treatment courses, with each 
treatment course studying one of the following ponesimod daily doses: 5, 10, and 20 mg. 
This is the first clinical trial of ponesimod in subjects with chronic GVHD, and will assess 
PK, PD, safety and efficacy of 5, 10 and 20 mg of ponesimod. Initially, subjects enrolling 
in the study will be treated for 4 weeks with 5 mg ponesimod (6-day up-titration, 22 days 
at 5 mg), followed by treatment for 4 weeks with 10 mg of ponesimod (4-day up-titration, 
24 days at 10 mg). For the remaining 16 weeks of the study the subjects will be treated 
with 20 mg ponesimod.  
From past clinical trial experience, 20 mg ponesimod has displayed an optimal benefit-risk 
balance in subjects with MS and psoriasis. For these reasons, 20 mg has been chosen as the 
maximum dose to be studied in this clinical trial. 
Extension Treatment Period 
Subjects who completed the Core Treatment Period (i.e., not prematurely discontinued 
from study drug) may enroll in the Extension Treatment Period should their chronic GVHD 
worsen after stopping study drug at Week 24/EOT1 visit (as per eligibility criteria in 
Sections 4.6 and 4.7). Subjects will be up-titrated to their last tolerated ponesimod dose 
(prior to EOT1) and will receive ponesimod for 96 weeks, including up-titration. 
5.1.2 Study treatment administration 
5.1.2.1 Subject study treatment diary 
Core Treatment Period 
Subjects will be given a device to record every time ponesimod is taken. Details of the 
diary and instructions for completing it will be provided to the investigator. Site personnel 
will instruct the subject on how to complete the diary prior to administration of the first 
dose of study medication on Day 1 (Visit 2). 
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Subjects will be given instructions on proper use of ponesimod (no device will be 
provided). 
5.1.2.2 Titration 
Core Treatment Period 
A 6-day up-titration will occur during study Days 1–6 using a titration blister wallet, to 
reduce ponesimod first-dose effects. On-site subject monitoring will be required at 
enrollment on Day 1 [see Section 5.1.7]. A 4-day up-titration will occur during study Days 
29–32 to gradually transition from the 5 mg to the 10 mg daily dose. The subject will have 
the dose escalated from 10 to 20 mg on Day 57 (without gradual up-titration). The first day 
of the 4-day up-titration (Day 29) and the Day 57 dose escalation do not require on-site 
monitoring. [See Table 3]. 
Table 3 
Up-titration and dose-escalation schedule: Core Treatment Period 
Treatment Course 
Study Day 
Ponesimod Daily Dose 
1 
6-day  
up-titration 
1 (Enrollment) 
2 mg (first dose given on-site 
with monitoring) 
2 
2 mg 
3 and 4 
3 mg 
5 and 6 
4 mg 
5 mg daily  
7 to 28 
5 mg 
2 
4-day  
up-titration 
29 (Week 4) 
6 mg 
30 
7 mg 
31 
8 mg 
32 
9 mg 
10 mg daily  
33 to 56 
10 mg 
3 
Dose escalation to 20 mg 
57 (Week 8) 
20 mg 
20 mg daily 
58 to day before EOT1 (Week 24) 
20 mg 
EOT1 = End-of-Treatment for the Core Treatment Period 
 
Extension Treatment Period 
A 6- or 14-day up-titration will occur starting at Visit EX-1 using a titration blister wallet, 
to reduce ponesimod first-dose effects. On-site subject monitoring will be required at 
enrollment at Visit EX-1 [see Section 5.1.7]. The choice of the 6- or 14-day up-titration 
will depend on the targeted dose: 5 mg, 10 mg, or 20 mg. The targeted dose is the subject’s 
previously tolerated ponesimod dose just prior to EOT1. [See Table 4]. 


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Table 4 
Up-titration schedule: Extension Treatment Period 
• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 5 mg dose is targeted.  
6 day up-titration scheme 
Day(s) 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 (Visit EX-1) 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 to EOT2 
5 mg 
No 
 
• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 10 mg dose is targeted.  
14 day up-titration scheme 
Day(s) 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 (Visit EX-1) 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 
5 mg 
No 
8 
6 mg 
No 
9 
7 mg 
No 
10 
8 mg 
No 
11 
9 mg 
No 
12, 13, and 14 
10 mg 
No 
15 to EOT2 
10 mg 
No 
 
• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 20 mg dose is targeted.  
14 day up-titration scheme 
Day(s) 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 (Visit EX-1) 
2 mg 
Yes 


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2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 
5 mg 
No 
8 
6 mg 
No 
9 
7 mg 
No 
10 
8 mg 
No 
11 
9 mg 
No 
12, 13, and 14 
10 mg 
No 
15 to EOT2 
20 mg 
No 
 
 
Core and Extension Treatment Periods 
Study drug dose up-titration, other than described above, is prohibited. Study drug dose 
reduction is permitted under some circumstances [see Section 5.1.10]. 
One tablet will be taken orally o.d., preferably in the morning, with or without food, and 
preferably at approximately the same time each day. The tablet will be swallowed as a 
whole. The last administration date and time of study drug before a visit and the 
administration date and time of study drug on the days of visits will be recorded in the 
eCRF. 
5.1.2.3 Criteria to permit dose increases at Day 29 and Day 57 (Core Treatment 
Period) 
Subjects may have daily doses up-titrated from 5 mg to 10 mg started on Day 29, or dose 
escalated from 10 mg to 20 mg on Day 57, if the following is true: 
a) Subject has not met the study-specific criteria for interruption, dose reduction, or 
premature discontinuation of study treatment, described in Section 5.1.10. 
b) Subject does not have an ongoing grade 2 adverse event at least possibly related to 
study drug. 
c) Subject took the correct scheduled study drug dose the day prior to the day of 
up-titration or dose escalation. 
d) Investigator has reviewed and approved of the results of the Day 29 and/or 
Day 57 pre-dose assessments specified in Table 1. 
5.1.2.4 Maintenance of ponesimod dose (Core and Extension Treatment Periods) 
One tablet of study drug will be taken orally o.d., preferably in the morning, either before, 
with or after breakfast. It is preferable that the tablet be taken each day at approximately 


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the same time. The tablet will be swallowed as a whole. During the Core Treatment Period 
only, the date and time of each study drug administration will be recorded by the subject 
in a diary. 
On the day of the study visits, study drug must be administered only after the completion 
of the scheduled pre-dose safety assessments (systolic BP [SBP] and diastolic BP [DBP], 
ECGs, PFTs, laboratory tests) and PK sampling.  
5.1.3 Blinding 
Not applicable. 
5.1.4 Study treatment supply 
Manufacture, labeling, packaging and supply of study treatments will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP) and any local or 
national regulatory requirements. 
All treatment supplies are to be used only in accordance with this protocol and not for any 
other purpose. 
5.1.4.1 Study treatment packaging and labeling 
5.1.4.1.1 Study treatment packaging 
Study treatment is provided as film-coated tablets and supplied in the following childproof 
bottles and childproof blister wallets: 
• 
6-day up-titration wallet containing two 2 mg tablets; two 3 mg tablets; two 4 mg 
tablets. 
• 
4-day up-titration wallet containing: one 6 mg tablet; one 7 mg tablet; one 8 mg 
tablet; one 9 mg tablet. 
• 
14 day up-titration wallet containing: two 2 mg tablets; two 3 mg tablets; two 4 mg 
tablets; one 5 mg tablet; one 6 mg tablet; one 7 mg tablet; one 8 mg tablet; one 9 mg 
tablet; three 10 mg tablets. 
• 
5 mg maintenance bottle containing thirty-six 5 mg tablets. 
• 
10 mg maintenance bottle containing thirty-six 10 mg tablets. 
• 
20 mg maintenance bottle containing thirty-six 20 mg tablets. 
5.1.4.1.2 Study treatment labeling 
Study treatment is labeled to comply with the applicable laws and regulations.  


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5.1.4.2 Study treatment distribution and storage  
Treatment supplies must be kept in an appropriate, secure area and stored according to the 
conditions specified on the medication labels. Ponesimod must not be stored above 25 °C 
(recommended storage is 15–25 °C).  
5.1.4.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used and unused study 
treatment blister wallets and/or bottles at each protocol-scheduled visit. An accurate record 
of the date and amount of study treatment dispensed to each subject must be available for 
inspection at any time.  
5.1.4.4 Study treatment return and destruction  
On an ongoing basis and/or on termination of the study, the monitor will collect used and 
unused bottles or blister wallets, which will be sent to the warehouse, where Actelion or a 
deputy will check treatment reconciliation. 
5.1.5 Drug accountability and compliance 
5.1.5.1 Drug accountability 
Records of study drug dispensed and returned, dosages administered, and intervals between 
visits are kept during the study. Study treatment accountability must be performed by the 
study staff on the day of the visit and before providing further study treatment, in order to 
ensure that the subject is compliant with study requirements. Study treatment 
accountability is checked by the monitor during site visits and at the end of the study. 
5.1.5.2 Drug compliance 
Core Treatment Period 
Subjects’ compliance with study drug intake will be monitored using a diary. On each day, 
the subjects will be asked to enter the date, time, number of tablets taken, and the unique 
bottle or blister wallet identifying number from which the tablets were taken from. In 
addition, during the up-titration, the position of the well on the blister wallet will be 
recorded in order to monitor that study drug tablets were taken in the correct sequence [see 
Section 5.1.2.1]. 
The study drug accountability performed by the site at each visit [see Section 5.1.5.1] will 
be used to crosscheck the subject’s compliance as indicated in the diary. Identified 
discrepancies will be reconciled by the site. Subjects will be asked to explain the observed 
discrepancies. Interruptions with known dates will be recorded accordingly in the study 
drug log [see Section 5.1.6]. Study drug intake requirement will be re-explained to the 
subject each time an interruption is observed. 


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Extension Treatment Period 
The study drug accountability performed by the site at each visit [see Section 5.1.5.1] will 
allow to assess the subject compliance. Interruptions with known dates will be recorded 
accordingly in the study drug log [see Section 5.1.6]. Study drug intake requirements will 
be re-explained to the subject each time an interruption is observed. 
5.1.6 Ponesimod dose adjustments and interruptions 
Ponesimod up-titration, other than described in Section 5.1.2, is prohibited. Ponesimod 
dose reduction is permitted under some circumstances [see Section 5.1.10]. 
Ponesimod interruption should be avoided. If ponesimod intake is interrupted by the 
subject for any reason, he/she must immediately inform the investigator. 
Ponesimod may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of ponesimod are described in Section 5.1.10. 
Detailed guidance on how to re-initiate ponesimod in the event of drug interruption is 
provided in Section 5.1.8. 
Ponesimod dose adjustments / interruptions must be recorded in the eCRF. 
5.1.7 Cardiac monitoring for ponesimod initiation and re-initiation requiring 
re-uptitration 
Subjects must undergo cardiac monitoring at the site on Day 1 (Visit 2 - ponesimod 
initiation) and EX-1 (Visit 11 - ponesimod treatment initiation in the extension).  
Subjects must also undergo cardiac monitoring at the site on the first day of any ponesimod 
re-initiation requiring up-titration. 
Cardiac monitoring is overseen by the cardiac safety assessor and consists of the following: 
• 
Pre-dose: 12-lead ECG; systolic/diastolic BP measurement. 
• 
Hourly post-dose, starting 1 hour post-dose: 12-lead ECG; systolic/diastolic BP 
measurement. ECG and BP are recorded hourly until the subject is discharged from 
monitoring. 
• 
Discharge from monitoring at least 4 hours post-dose, as per “Discharge from 
Cardiac Monitoring Criteria” below. 


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Discharge from Cardiac Monitoring Criteria 
After the collection of the 12-lead ECG and systolic/diastolic BP measurement at 
4 hours post-dose and up to 12 hours post-dose, the subject may be discharged from 
the clinic and continue on ponesimod as soon as all of the following are met:  
• ECG-derived resting HR > 45 bpm on the last ECG. If ECG-derived resting 
HR < 50 bpm on the last ECG, then HR at last ECG must be higher than at least one 
HR recorded on any prior post-dose ECG. 
• SBP > 90 mmHg. 
• QTcF < 481 ms on the last ECG. 
• Increase in QTcF on the last ECG versus pre-dose ECG must be < 60 ms. 
• No persisting significant ECG abnormality (e.g., QT prolongation, AV block second 
degree or higher) or ongoing AE requiring continued hospitalization or prohibiting 
study continuation as an outpatient. 
Should the subject not meet the criteria for discharge at 12 hours post-dose, he/she 
must be discontinued from ponesimod. Subjects who are discontinued may be 
discharged from the monitored setting only after the following criteria are met: 
• Vital signs return to near baseline values. 
• No persisting ECG abnormality (e.g., AV block second degree or higher). 
• No ongoing AE requiring continued hospitalization. 
• Absence of any other medical indication to remain in the monitoring setting. 
5.1.8 Procedures for re-initiation of ponesimod in the event of interruption 
Under no circumstances should a subject take more than one tablet per day. 
 
Terminology 
• Interruption: a day or the days where subject did not take a prescribed ponesimod 
dose. 
• Re-initiation: the day a ponesimod dose is taken following an interruption.  
• Re-initiation with up-titration: Re-initiation of a gradually increasing ponesimod 
dose regimen that reaches a target dose over several days. Not all re-initiations 
include up-titrations. 
 
If ponesimod intake is interrupted by the subject for any reason, the subject must 
immediately inform the investigator. The investigator and subject must adhere to the 
mandatory procedures described here regarding re-initiation. 


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Mandatory procedures for the following five interruption scenarios: 
Scenario 1: Subject missed taking 1 to 3 consecutive doses, with first dose missed 
on study Day 2–6. (Scenario 1 applies to Core Treatment Period only.) 
• Ponesimod must be re-initiated within 3 days of last missed dose, otherwise 
ponesimod is prematurely discontinued. 
• The following up-titration scheme using a titration blister wallet needs to be applied: 
6 day up-titration scheme 
Re-initiation Day 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7, 8, … 
5 mg 
No 
 
• Re-initiation with up-titration for scenario 1 is allowed only once during the study, 
otherwise ponesimod is prematurely discontinued.  
 
 
Scenario 2: Subject missed taking ≥ 4 consecutive doses, with first dose missed 
during study Days 2–56. (Scenario 2 applies to Core Treatment Period only.) 
• Subjects may only be re-initiated on ponesimod as per protocol and per investigator 
judgment, and according to the up-titration schemes in Scenario 4 below. Subsequent 
dose escalation from 5 mg to 10 mg or from 10 mg to 20 mg, whichever is relevant, 
is prohibited. 
 
 


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Scenario 3: Subject missed taking 1 to 3 consecutive doses any time after study 
Day 6. (Scenario 3 applies to both Core and Extension Treatment Periods.) 
• Dosing should be re-initiated at the same dose as the dose taken prior to ponesimod 
interruption, with the following exceptions (exceptions apply to the Core 
Treatment Period only): 
i. 
If the interruption occurs during Core Treatment Period Days 29–32 (up-
titration to 10 mg), the missed dose(s) is/are taken to complete remaining 
doses in the titration blister wallet 
ii. 
If the interruption includes Core Treatment Period Day 57 (dose-escalation to 
20 mg), the 10 mg dose is restarted, and a clinic visit is scheduled to conduct 
required assessments (e.g., ECG) prior to dose escalation to 20 mg 
• Ponesimod intake may be re-initiated by the subject at home. 
• Subjects must be instructed to contact the investigator immediately if they experience 
any symptoms of bradycardia (e.g., dizziness, vertigo, syncope). 
 


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Scenario 4: Subject missed taking ≥ 4 consecutive doses during study Days 57–148 
(Core Treatment Period) or at any time during the Extension Treatment Period. 
• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 5 mg dose is targeted. Ponesimod must be re-initiated within 10 days of 
last missed dose, otherwise ponesimod is prematurely discontinued (discontinuation 
applies to Core Treatment Period only). 
6 day up-titration scheme 
Re-initiation Day 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 to EOT1, 2 
5 mg 
No 
 
• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 10 mg dose is targeted. Ponesimod must be re-initiated within 10 days of 
last missed dose, otherwise ponesimod is prematurely discontinued (discontinuation 
applies to Core Treatment Period only). 
14 day up-titration scheme 
Re-initiation Day 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 
5 mg 
No 
8 
6 mg 
No 
9 
7 mg 
No 
10 
8 mg 
No 
11 
9 mg 
No 
12, 13, and 14 
10 mg 
No 
Day 15 to EOT1, 2 
10 mg 
No 
 
 
 


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• The following up-titration scheme using a titration blister wallet is applied if the 
ponesimod 20 mg dose is targeted. Ponesimod must be re-initiated within 10 days of 
last missed dose, otherwise ponesimod is prematurely discontinued (discontinuation 
applies to Core Treatment Period only). 
14 day up-titration scheme 
Re-initiation Day 
Ponesimod Daily Dose 
Given at site with 
monitoring 
1 
2 mg 
Yes 
2 
2 mg 
No 
3 and 4 
3 mg 
No 
5 and 6 
4 mg 
No 
7 
5 mg 
No 
8 
6 mg 
No 
9 
7 mg 
No 
10 
8 mg 
No 
11 
9 mg 
No 
12, 13, and 14 
10 mg 
No 
Day 15 to EOT1, 2 
20 mg 
No 
• Re-initiation with up-titration for scenario 4 is allowed only once during the Core 
Treatment Period, otherwise ponesimod is prematurely discontinued.  
• Re-initiation with up-titration for scenario 4 may be permitted more than once during 
the Extension Treatment Period if it is in the best interest of the subject. The 
investigator should discuss with Actelion. 
 
 
Scenario 5:  
Subject missed taking ≥ 4 consecutive doses during study Days 149–167. 
• Ponesimod is prematurely discontinued and an EOT1 visit is conducted. 


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5.1.9 Premature discontinuation of ponesimod 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator or Actelion. 
A subject has the right to prematurely discontinue study treatment at any time by 
withdrawal from treatment only or by withdrawal from treatment and any further 
participation in the study. 
The investigator should discontinue study treatment for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of the 
subject. 
Premature discontinuation of study treatment may also result from a decision by Actelion, 
e.g., in case of premature termination or suspension of the study [see Section 9.3]. 
The main reason and whether discontinuation of study treatment is the decision of the 
subject, the investigator or Actelion must be documented in the eCRF. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until the end of the safety follow-up period (30 days 
after study drug discontinuation), provided that the subject’s consent for this limited 
participation in the study has not been withdrawn. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study is described in Sections 9.2 and 9.4, respectively. 
5.1.10 Specific dose-reduction, interruption, or premature discontinuation criteria 
Ponesimod should be prematurely discontinued before initiating rescue IS therapy or 
other forbidden medications during the Core Treatment Period. Ponesimod should also 
be prematurely discontinued before initiating forbidden medications during the 
Extension Treatment Period. See Section 5.3.5. 
 
Ponesimod-specific dose reduction, interruption, or premature discontinuation criteria are 
presented for a variety of conditions and scenarios grouped according to the following 
organ systems. These criteria apply during both the Core and Extension Treatment Periods:  
(1) 
Cardiovascular 
(2) 
Hematologic 
(3) 
Hepatobiliary 
(4) 
Immune/infection 


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(5) 
Ocular 
(6) 
Reproductive/pregnancy 
(7) 
Respiratory 
5.1.10.1 Cardiovascular 
Ponesimod must be discontinued if any of the following are true at any time: 
1) The following are observed and also documented by ECG at any time during the 
study: 
a) HR < 40 bpm, or 
b) HR < 60 bpm is sustained for at least 1 hour and is associated with symptoms of 
bradycardia (e.g., syncope, dizziness, or vertigo), or 
c) QTcF > 500 ms is observed at any time throughout the study. 
2) The subject does not meet the criteria for discharge from hospital on Day 1, EX-1 or 
on the first day of re-initiation of ponesimod following drug interruptions after 12 h 
post-dose monitoring. 
3) The subject needs to receive systemic chronic treatment with β-blockers, diltiazem, 
verapamil, digoxin, digitoxin, or any other anti-arrhythmic or HR-lowering therapy 
(non-exhaustive list of drugs provided in Appendix 4). 
4) Subject experiences de novo or worsening of pre-existing hypertension that cannot 
be adequately controlled by medications. 
 
Continuous ECG monitoring is recommended for subjects who meet ponesimod 
discontinuation criteria related to bradycardia or other arrhythmias. Subjects who are 
prematurely discontinued may be discharged from the monitored setting only after the 
following criteria are met: 
Mandatory discharge from the clinic/hospital criteria for subjects discontinued due 
to bradycardia or other arrhythmias: 
• 
Vital signs return to near baseline values. 
• 
No persisting ECG abnormality (e.g., AV block second degree or higher). 
• 
No ongoing AE requiring continued hospitalization. 
• 
Absence of any other medical indication to remain in the monitoring setting. 
 


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At Visits 3, 4, 5, 6 and 7 (Weeks 4, 8, 12, 16 and 20) in the Core Treatment Period 
and Visits EX-2, EX-3, EX-4, EX-5, EX-6, EX-7, EX-8, EX-9, EX-10, EX-11, and 
EX-12 (Extension Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, and 84) in the Extension 
Treatment Period, 12-lead ECG measurements are collected pre-dose. In the event 
of a grade 2 QTc elevation, a repeat 12-lead ECG must be collected 3 hours 
post-dose. If QTcF > 500 ms, the subject is prematurely discontinued from the 
study. In addition, a PK sample must be collected within 20 minutes after the 3 hour 
post-dose ECG. 
 
Any clinically relevant finding found after ponesimod initiation and during the follow-up 
period and meeting the definition of an AE will be recorded accordingly in the eCRF. 
5.1.10.2 Hematologic 
Ponesimod must be prematurely discontinued for any of the following laboratory 
findings at any time:  
• 
Confirmed neutrophil count < 0.5 × 109/L (< 500 cells/mm3). 
• 
Confirmed absolute lymphocyte count < 0.1 × 109/L (< 100 cells/mm3), and 
subject is receiving ponesimod 5 mg daily or less.  
 
Ponesimod must be prematurely discontinued or, alternatively, the dosage must be 
reduced (dose reduction) for the following laboratory finding at any time: 
• 
Confirmed absolute lymphocyte count < 0.1 × 109/L (< 100 cells/mm3), and 
subject is receiving ponesimod 10 mg or 20 mg.  
Confirmation will be done as follows: 
Whenever a neutrophil count < 0.5 × 109/L (< 500 cells/mm3) or an absolute lymphocyte 
count < 0.1 × 109/L (< 100 cells/mm3) is recorded by the central laboratory, an alert will 
be sent to the principal investigator and the sponsor. The site will immediately contact the 
subject and ask her/him to return to the site within 48 hours at the latest to repeat the test 
at trough level (pre-dose) by the central laboratory (unless the clinical situation mandates 
immediate local testing). If the repeat test confirms a neutrophil count < 0.5 × 109/L (< 500 
cells/mm3) or an absolute lymphocyte count < 0.1 × 109/L (< 100 cells/mm3), then 
ponesimod must be discontinued or dose reduced according to the criteria above. 
Monitoring for prematurely discontinued subjects 
Neutrophil or lymphocyte counts must be monitored at least once a week by the local 
laboratory until the neutrophil count has returned to ≥ 80% of the baseline value or the 
absolute lymphocyte count has returned to ≥ 0.5 × 109/L ( ≥ 500 cells/mm3) or ≥ 80% of 
the baseline value. Any clinically relevant finding found after ponesimod initiation and 


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during the follow-up period and meeting the definition of an AE will be recorded 
accordingly in the eCRF. 
Dose reduction and monitoring 
For those subjects qualifying for dose reduction, the previously tolerated dose is 
immediately instituted without dose interruption. For subjects currently on ponesimod 
10 mg, the 5 mg dose is restarted. For subjects on 20 mg, the 10 mg dose is restarted. 
Subjects remain on the lower dose for the remainder of the study, with no further 
dose-escalation. Lymphocyte counts are repeated at the next scheduled study visit after 
dose-reduction (or earlier per investigator judgment), and if the absolute lymphocyte 
count remains < 0.1 × 109/L (< 100 cells/mm3) ponesimod is discontinued. Hematologic 
monitoring for prematurely discontinued subjects is continued as per above. 
5.1.10.3 Hepatobiliary 
In case of abnormal liver tests or signs and symptoms suggestive of drug-induced liver 
injury, subjects will be closely observed, liver tests will be repeated, and ponesimod may 
need to be prematurely discontinued or interrupted. 
The central laboratory will send alerts to the principal investigator and the sponsor 
whenever any of the following hepatobiliary laboratory abnormalities are recorded during 
the study:  
• 
≥ Grade 2 elevation ALT (> 3 × ULN) 
• 
≥ Grade 2 elevation AST (> 3 × ULN) 
• 
≥ Grade 2 elevation blood bilirubin (same as TBL) (> 1.5 × ULN) 
The site will immediately contact the subject and ask him/her to return to the site within 
72 hours, at the latest, to repeat the test by the central laboratory (unless the clinical 
situation mandates immediate local testing). An inquiry should be made about symptoms.  


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Should repeat testing confirm continuing abnormality, the following will apply: 


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Ponesimod must be prematurely discontinued for any of the following:  
• 
Grade 4 ALT or AST elevation (> 20.0 × ULN). 
• 
Grade 4 blood bilirubin (same as TBL) elevation (> 10.0 × ULN). 
• 
Grade 2 or higher ALT or AST elevation ( > 3 × ULN) and (TBL > 2 × ULN or 
international normalized ratio [INR] > 1.5; corresponds to Hy’s Law). 
• 
Grade 2 or higher ALT or AST elevation ( > 3 × ULN) with the appearance of: 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%). 
• 
Grade 3 or higher ALT or AST elevation (> 5.0 × ULN) during study Days 2–56 
or study Days 149–168. 
• 
Grade 3 or higher TBL elevation (> 3.0 × ULN) during study Days 2–56 or study 
Days 149–168. 
• 
Grade 3 or higher ALT or AST elevation (> 5.0 × ULN) and subject is taking 
ponesimod 5 mg. 
• 
Grade 3 or higher TBL elevation (> 3.0 × ULN) and subject is taking ponesimod 
5 mg. 
 
Please see box “Monitoring for all subjects with confirmed ≥ grade 2 AST, ALT, or 
TBL elevations”. 


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Ponesimod is interrupted for any of the following: 
• 
Grade 3 ALT or AST elevation (> 5.0–20.0 × ULN) during study Days 57–148 
or during the Extension Treatment Period. 
• 
Grade 3 TBL elevation (> 3.0–10.0 × ULN) during study Days 57–148 or during 
the Extension Treatment Period. 
 
Procedure for interruption 
• 
Interrupt ponesimod for at least 7 days. 
• 
Perform a re-test of AST, ALT, TBL within 7 days. 
• 
If elevated values do not return to baseline levels within 7 days following 
treatment interruption, ponesimod is prematurely discontinued. Please see box 
“Monitoring for all subjects with confirmed ≥ grade 2 AST, ALT, or TBL 
elevations”. 
• 
If elevated values return to baseline levels within 7 days following treatment 
interruption, ponesimod is re-initiated with up-titration. 
 
Procedure for re-initiation with up-titration 
• 
Re-initiation occurs 8–10 days after ponesimod was interrupted. 
• 
The previously tolerated dose is targeted at re-initiation with up-titration. For 
subjects on ponesimod 10 mg at the time of interruption, the 5 mg dose is 
targeted. For subjects on 20 mg at the time of interruption, the 10 mg dose is 
targeted. Subjects remain on the lower dose for the remainder of the study, with 
no further dose-escalation. 
• 
Re-initiation and up-titration should be conducted in accordance with 
Section 5.1.8, scenario 4. 
 
Perform a re-test of AST, ALT, TBL at 5–7 and 10–12 days following re-initiation, 
and monthly thereafter. Recurrence of ≥ grade 3 AST, ALT, TBL results in 
premature discontinuation with follow-up monitoring.  
 
Please see box “Monitoring for all subjects with confirmed ≥ grade 2 AST, ALT, 
or TBL elevations”. 
 
 
 


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Monitoring for all subjects with confirmed ≥ grade 2 AST, ALT, or TBL elevations 
• 
Monitoring continues even after ponesimod discontinuation or interruption. 
• 
AST, ALT, and TBL are re-tested weekly, and more frequently if indicated, until 
laboratory abnormalities are no longer regarded as clinically relevant.  
• 
Follow-up monitoring, including more frequent visits, is provided until signs and 
symptoms have resolved or until medically indicated. 
• 
Further diagnostic work-up/consultation with a hepatologist or other specialist 
should be considered according to local practice and the clinical situation.  
 
Any clinically relevant finding found after ponesimod initiation and during the follow-
up period and meeting the definition of an AE will be recorded in the eCRF. 
 
5.1.10.4 Immune/infection 
Subjects must be prematurely discontinued from ponesimod at any time during the 
study in the event of an infection requiring discontinuation of treatment per 
investigator judgment. 
 
In the event of an infection, the subject should be treated as clinically indicated and, if 
medically appropriate, study drug discontinued at the discretion of the investigator. In case 
of study drug discontinuation, adequate treatment needs to be provided, and the subject 
must be monitored until complete resolution of the infection. 
If the infection resolves and the benefit/risk balance is considered acceptable for the subject 
to resume study treatment, ponesimod may be re-initiated at the discretion of the 
investigator. See Section 5.1.8 for re-initiation procedures. 
Given ponesimod effects on lymphocytes, heightened vigilance is required for 
opportunistic infections, with particular attention to be paid to viral infections. However, 
investigators and physicians following subjects should also be alert to potential systemic 
infections caused by fungi and bacteria. 
Table 5 highlights opportunistic infections common in patients at least 30 days following 
HSCT (and relevant for the patient population in this study). 


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Table 5 
Common opportunistic infections in patients at least 30 days 
post-HSCT 
Stage 
Infections 
Post-engraftment: 
approximately 30 to 100 
days post-transplant 
• Herpes viruses, especially CMV (Note: CMV causes 
pneumonia, hepatitis, and colitis and potentiates 
superinfection with opportunistic pathogens, 
particularly among patients with active GVHD) 
• Pneumocystis carinii 
• Aspergillus 
Late phase:  
approximately 100 days 
post-transplant 
• CMV 
• VZV 
• EBV-related post-transplant lymphoproliferative 
disease 
• CRV 
• Encapsulated bacteria (e.g., H. influenzae and S. 
pneumoniae). 
Adapted from: CDC 2000 
CMV = cytomegalovirus; CRV = community-acquired respiratory viruses; EBV = Epstein-Barr virus; 
GVHD = graft versus host disease; VZV = varicella zoster virus 
If an opportunistic infection should occur despite appropriate and tailored infection 
prophylaxis and if, in the judgment of the investigator, the opportunistic infection does not 
respond as expected to anti-infectives, the subject must discontinue ponesimod and must 
be referred to an expert in infectious diseases for further examination and treatment.  
The Centers for Disease Control and Prevention (CDC) recommendations for infection 
prophylaxis and immunizations for chronic GVHD patients can be obtained at: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm. Suggested prophylaxis [as 
adapted from Martin 2009] appears in Table 6. 


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Table 6 
Suggested infection prophylaxis in chronic GVHD 
Infection or Risk Scenario 
Prophylaxis (Comment) 
Pneumocystis pneumonia and 
encapsulated bacterial 
infections 
Antibiotic prophylaxis is strongly recommended for all patients 
until 6 months after resolution of chronic GVHD and 
discontinuation of all systemic IS treatment. 
Pneumococci and 
haemophilus influenzae B 
Vaccination with conjugate pneumococcal vaccine at 1 year 
after HSCT is strongly recommended. (Comment: chronic 
GVHD impairs splenic clearance of encapsulated organisms. 
Response to unconjugated vaccines is poor in patients at 1 year 
after HSCT). 
Recurrent bacterial infections 
in patients with serum 
immunoglobulin G 
concentrations < 400 mg/dL 
or deficiencies of IgG2 or 
IgG4 
Intravenous administration of gamma globulin may be 
indicated. 
Patients who are at risk of 
CMV infection 
Virologic surveillance of blood and pre-emptive antiviral 
therapy should be instituted whenever surveillance tests 
become positive, before the onset of overt CMV disease. 
(Comment: if feasible, CMV-seronegative recipients with 
CMV-seronegative donors should receive screened or 
leukocyte-depleted blood products). 
MMR, and other infections 
prevented with live virus 
vaccines  
Patients should not be given live virus vaccines such as MMR 
until at least 1 year after resolution of chronic GVHD and 
withdrawal of all IS treatment. 
VZV 
Long-term administration of valacyclovir or acyclovir is 
recommended to prevent reactivation of VZV in patients 
previously infected with this virus. 
The safety and efficacy of VZV vaccination after resolution of 
chronic GVHD has not yet been determined. 
Patients on glucocorticoid 
treatment: glucocorticoid 
treatment increases the risk of 
fungal infections 
Prophylactic administration of fluconazole can prevent certain 
types of candida infections, but this agent is not effective for 
prevention of invasive mold infections. (Comment: clinical 
trials will be needed to determine whether newer agents such 
as itraconazole, voriconazole, or posaconazole can prevent 
invasive mold infections during glucocorticoid treatment for 
patients with chronic GVHD). 
Adapted from: [Martin 2009] 
CMV = cytomegalovirus; GVHD = graft versus host disease; HSCT = hematopoietic stem cell transplantation; 
IS = immunosuppressant; MMR = measles, mumps, rubella; VZV = varicella zoster virus. 


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Particular vigilance is required for rare and unusual neurological symptoms, as their 
recognition is crucial for the early diagnosis of neurotropic herpes virus infections and 
progressive multifocal leucoencephalopathy (PML), caused by reactivation of John 
Cunningham virus. Neurological warning signs for PML include major changes in vision, 
unusual eye movements, loss of balance or coordination, disorientation, and confusion. As 
there is no known treatment for PML, rapid recognition is essential. Several cases of PML 
have been reported in patients with GVHD [Focosi 2007]. 
The thorough physical examination and blood tests on the routine visits should focus on 
any potential sign of skin, mucosal surface, GI tract, liver, hematological, or other 
abnormality and organ dysfunction suggesting a potential opportunistic infection.  
Subjects should be advised to be pro-active and alert in reporting any unusual neurological 
symptoms and any signs and symptoms indicative of systemic infections, such as fever, 
malaise and fatigue [Kappos 2011]. 
5.1.10.5 Ocular 
In the event of suspected clinically significant findings (e.g., macular edema), an 
unscheduled ophthalmology and OCT examination should be performed. The OSB will 
receive all information related to suspected cases of macular edema and will perform 
central review of OCT results and subject data. In the case of macular edema confirmed by 
the local ophthalmologist, the subject must be discontinued from study drug and will be 
managed and followed-up until resolution or until medically indicated. Any clinically 
relevant finding found after study drug initiation and during the follow-up period and 
meeting the definition of an AE will be recorded accordingly in the eCRF. 
5.1.10.6 Reproductive/pregnancy 
If a subject becomes pregnant while on ponesimod, ponesimod must be discontinued. 
Female subjects participating in the study and wishing to become pregnant during the study 
must discontinue ponesimod. 
5.1.10.7 Respiratory 
Subjects experiencing new or worsening persistent respiratory symptoms must be carefully 
evaluated. Lung infections are common in chronic GVHD, and should be suspected, 
especially in case of fever and cough. BOS is an uncommon and serious condition in 
chronic GVHD and is associated with irreversible pulmonary function decline which does 
not respond to bronchodilators. Ponesimod can cause pulmonary function decline which is 
reversible upon cessation of drug and which is also reversible with bronchodilators. 
Lung function testing, including spirometry, is assessed frequently in this study. 
Investigators may conduct unscheduled spirometry at any time, and should do so 
particularly in case of unexplained respiratory symptoms. Spirometry results may 


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require a subsequent bronchodilator challenge, the results of which may lead to premature 
ponesimod discontinuation and further diagnostic work up to exclude/diagnose BOS or 
other lung disease. 
Bronchodilator challenge is required if all of the following spirometry parameters 
are met at any time: 
• > 10% decrease from the study baseline FEV1, and 
• FEV1 < 60% predicted, and  
• FEV1/FVC < 0.7  
Further dose escalation is prohibited once these parameters have been met. 
 
Bronchodilator challenge 
Subjects undergo bronchodilator challenge to help distinguish pulmonary function 
decline due to ponesimod from potential BOS or other causes. 
Procedure for bronchodilator challenge 
• An initial PFT assessment is performed. 
• Then, four separate inhalations (puffs) of 100 μg salbutamol/albuterol are 
administered using a spacer device. 
• A second PFT assessment must be performed 30 minutes (± 15 minutes) after 
administration of salbutamol/albuterol. 
 
Ponesimod may be continued, without interruption, if all of the following 
parameters are met following bronchodilator challenge: 
• FEV1 ≥ 60% predicted, and 
• FEV1/FVC ≥ 0.7, and 
• FEV1 ≤ 10% decrease from study baseline and 
• Subjects on 5 mg are not experiencing respiratory symptoms (this parameter does 
not apply to subjects on 10 or 20 mg). 
For continuing subjects, refer to the box: “CONTINUATION (after successful 
bronchodilator challenge)”. 
If these parameters are not met, ponesimod must be prematurely discontinued and 
further 
assessment 
is 
required; 
refer 
to 
the 
box: 
“PREMATURE 
DISCONTINUATION (after failing bronchodilator challenge)”. 
 


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CONTINUATION (after successful bronchodilator challenge) 
Generally, subjects are continued on ponesimod at the current dose, and no further dose 
escalation is allowed. If following a successful bronchodilator challenge, the conditions 
for performing the bronchodilator challenge are met again, a new bronchodilator 
challenge is recommended but not required and may be performed at the discretion of 
the investigator. 
For those subjects on ponesimod 10 mg or 20 mg, immediate dose reduction to 5 mg or 
10 mg may be considered by the investigator if subjects have respiratory symptoms. 
Dose escalation is not allowed after dose reduction in this study.  
For subjects continuing ponesimod, spirometry testing is conducted at all subsequent 
scheduled visits. In case of a recurrent 10% decline versus study baseline in FEV1, or 
continuing or worsening respiratory symptoms following dose reduction, subjects must 
be prematurely discontinued. 
 
PREMATURE DISCONTINUATION (after failing bronchodilator challenge) 
If the subject fails the bronchodilator challenge, ponesimod as the cause of lung function 
decline is still not ruled out. Ponesimod effects on lung function reverse rapidly within 
a few days following cessation of drug intake. Therefore, a rapid and robust 
improvement in lung function is required to help confirm ponesimod induced lung 
function decline and simultaneously help exclude BOS (which is not reversible). 
Spirometry must be conducted 7 to 10 days following premature discontinuation. 
Pulmonary function decline is very likely due to ponesimod, and BOS is unlikely if: 
• FEV1 assessed 7 to 10 days post premature discontinuation returns to baseline 
FEV1. 
All prematurely discontinued subjects need follow-up monitoring and evaluation. 
See box: “MONITORING AND WORK-UP for prematurely discontinued 
subjects”. 
 
MONITORING AND WORK-UP for prematurely discontinued subjects 
In all cases of premature discontinuation, monitoring must be provided until respiratory 
AEs have resolved and changes in pulmonary function are no longer regarded as 
clinically relevant, or until medically indicated. 
Further diagnostic work-up and consultation with a pulmonologist or other 
specialist is required and should be in accordance with local practice if PFT 
abnormalities or respiratory symptoms persist. 


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The current recommended work-up for BOS includes PFT testing and expiratory 
computed tomography (CT). Because a new diagnostic technique for BOS termed 
parametric response mapping is currently under investigation, a high resolution (helical) 
CT of inspiration and expiration is encouraged if available. This technique will permit 
visual representation of lung affected by obstructive disease (BOS) versus lung tissue 
with normal aeration or restrictive disease, and may become a valuable measure in the 
future [Jagasia 2015]. 
 
Use of short-acting β2 agonist for subjects continuing on ponesimod 
Subjects experiencing respiratory symptoms or reduced pulmonary function during the 
course of the treatment with ponesimod and fulfilling criteria to continue study 
medication may be prescribed short-acting β2 agonist (to be used on an ‘as needed’ basis 
/ ‘PRN’ use), at the investigator’s discretion.  
 
For all subjects: any clinically relevant finding found after signing of informed consent and 
during the follow-up period and meeting the definition of an adverse event will be recorded 
accordingly in the eCRF. 
5.2 
Mandatory concomitant chronic GVHD treatment (Core Treatment 
Period only) 
Section 5.2 applies only to the Core Treatment Period.  
5.2.1 Immunosuppressant treatments other than ponesimod 
Along with the study drug ponesimod, subjects must be treated with systemic 
glucocorticoids AND/OR one of the following systemic agents: CsA, TAC, MMF, MPS, 
EVL, SRL, or MTX. 
5.2.2 Modifications to IS treatments 
Mandatory and allowed (e.g., topical IS) IS therapies make up the subject’s background 
chronic GVHD IS therapy during the study. The dose and frequency of these medications 
should be kept constant during the study.  
Systemic glucocorticoids 
Glucocorticoid dosing should not be increased or decreased during the course of the study, 
with the following exceptions: 
• The investigator may see reason to initiate or increase the dose of systemic 
glucocorticoid to treat chronic GVHD flare or another condition. In this case, the 
investigator should consult with the sponsor prior to initiation or dose increase and the 


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reason for dose increase should be documented. The subject may continue on 
ponesimod. The prednisone equivalent dose should never exceed 1 mg/kg/day. 
• Systemic glucocorticoid dosing may be lowered to avoid or prevent short- and 
long-term glucocorticoid toxicity. For subjects on longer term glucocorticoid therapy, 
it is recommended that the dose reduction rate does not exceed 10% of dose per week. 
Glucocorticoid dosing may be increased following reduction, if medically indicated. 
• Systemic glucocorticoid dosing is not subject to restrictions during the Extension 
Treatment Period. 
Mandatory systemic IS other than ponesimod or systemic glucocorticoids 
Systemic IS dosing (mg daily dose) should not be increased above baseline dose during the 
course of the study, with the following exception: 
• Systemic IS blood or serum level is below the therapeutic range that was defined for 
the subject at the time of entry into the study. The dose should be increased to restore 
blood or serum levels to within the defined therapeutic range. (ISs that are not 
monitored with blood or serum level monitoring may never be increased above baseline 
dose.) 
Systemic IS dosing (mg daily dose) should not be lowered during the course of the study, 
with the following exceptions: 
• AE or intolerance due to the systemic IS. The dose should be sufficiently lowered or 
discontinued, per investigator judgment. 
• Systemic IS blood or serum level is above the therapeutic range that was defined for 
the subject at the time of entry into the study. The dose should be lowered to restore 
blood or serum levels to within the defined therapeutic range.  
Topical CNIs or glucocorticoids  
• The sponsor recommends not starting or increasing dosage of topical CNI or topical 
glucocorticoid therapy during the course of the core study. 
• Topical CNIs or glucocorticoid therapy dosing or area of application should not be 
decreased during the course of the core study, unless there is an AE or intolerance due 
to the topical drug. The dose should then be sufficiently lowered or discontinued, per 
investigator judgment. 
5.3 
Previous and concomitant therapy 
Section 5.3 applies to both Core and Extension Treatment Periods. 
5.3.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the start of study (i.e., 
signing of initial informed consent).  


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All therapy that is study-concomitant (i.e., ongoing or initiated after signing of informed 
consent, and initiated before EOS visit) must be captured in the eCRF.  
5.3.2 Reporting of previous HSCT and GVHD therapies 
Previous HSCT and GVHD therapies will be collected as part of HSCT and GVHD history 
[see Section 4.5]. 
5.3.3 Reporting of concomitant therapy in the eCRF 
The use of all study-concomitant therapy (including contraceptives and traditional or 
alternative medicines, i.e., plant-, animal-, or mineral-based medicines) will be recorded in 
the eCRF. The generic name, start/end dates of administration (as well as whether it was 
ongoing at start of treatment and/or EOS), route, dose, frequency, and indication will be 
recorded in the eCRF. 
5.3.4 Allowed concomitant therapy 
• Administration of i.v. atropine in the event of symptomatic bradycardia 
• Topical glucocorticoid  
• Topical CNI 
• Oral budesonide  
• QT-prolonging drugs with known risk of Torsades de Pointes should be used with 
caution since ponesimod may potentially enhance their effect on QT interval (list of 
drugs and guidance are provided in Appendix 3) 
• Short-acting ß2 agonists for respiratory symptoms and/or reduced pulmonary function 
during ponesimod treatment 
• Vaccination with non-live vaccines (Note: although nonclinical data indicate no 
significant impairment of antibody response to immunization, no clinical data is 
currently available on vaccination efficacy under ponesimod treatment, therefore it is 
suggested that all planned/indicated vaccinations are completed more than 30 days 
before the start of treatment and, in case of vaccination during the study, titer control 
is recommended.) 
• Other treatments considered necessary for the subject’s benefit and not categorized as 
prohibited concomitant medications 
5.3.5 Forbidden concomitant therapy 
• IS or immunomodulatory treatments other than those prescribed per protocol 
• Retinoids 
• Thoracoabdominal irradiation 
• Mesenchymal stem cell therapy  


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• Extracorporeal photopheresis 
• Vaccination with live vaccines 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin or any other anti-arrhythmic or 
HR-lowering systemic therapy (a non-exhaustive list of drugs provided in Appendix 4) 
• Any other investigational drug 
 
6 
STUDY ENDPOINTS 
This section describes the Core Treatment Period endpoints only. Similar endpoints will 
be assessed for the Extension Treatment Period, however adjusted for the corresponding 
visit schedule. 
6.1 
Pharmacokinetic and pharmacodynamic endpoints 
6.1.1 Pharmacokinetic evaluations 
• Trough concentrations (Ctrough) concentrations of ponesimod at Day 1, and Weeks 4, 8, 
12, 16, and 20 (all samples pre-dose), and Week 24 
• Ponesimod concentration 3 hours post-dose at Day 1 and Week 12 
6.1.2 Pharmacodynamic evaluations 
Primary PD endpoint 
• Change in peripheral absolute lymphocyte count from baseline to Week 4, Week 8 and 
Week 12 
The primary endpoint assesses intra-subject dose response during the first 12 weeks of 
treatment. 
Other PD endpoints 
• Peripheral absolute blood lymphocyte count change from baseline (pre-dose on Day 1) 
to Weeks 4, 8, 12, 16, 20, 24, and FU1, and change from pre-dose Week 12 to 3 hours 
post-dose Week 12. 
• Peripheral absolute lymphocyte count reversibility from EOT1 to FU1 expressed as 
absolute change and percent change from baseline 
6.1.3 PK/PD relationship 
The PK and selected efficacy and safety variables will be correlated with the PD (peripheral 
absolute lymphocyte count and magnitude of reduction of lymphocyte count). If deemed 
appropriate, the PK will also be correlated with selected safety variables. 


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6.2 
Safety endpoints 
The treatment-emergent period is defined as the time from first study drug intake up to 
30 days (inclusive) after last study drug intake. 
6.2.1 Overall safety endpoints 
• Treatment-emergent AEs, serious adverse events (SAEs), and AEs of special interest 
[see Appendix 5] 
• AEs leading to premature discontinuation of study drug 
• Deaths 
6.2.2 Absolute lymphocyte count 
• Treatment-emergent absolute lymphocyte count < 0.2 × 109/L (< 200 cells/mm3) 
6.2.3 Cardiac rate and rhythm safety endpoints 
• Treatment-emergent morphological ECG abnormalities (as defined by the ECG 
provider) 
• Change in 12-lead ECG variables (HR, PR, QRS, QT, QT corrected for HR on the basis 
of Bazett’s formula [QTcB], QT corrected for HR on the basis of Fridericia’s formula 
[QTcF]) from pre-dose to selected post-dose assessments (1 h, 2 h, 3 h, 4 h) on Day 1 
and on day of re-initiation of study drug. 
• Notable abnormalities for selected 12-lead ECG variables (HR, PR, QT, QTc) at 
3 hours post-dose assessment on Day 1, pre-dose on Weeks 4, 8, and 12, and Week 24 
(notable abnormalities definition in Appendix 6). 
• Cardiac safety events will include:  
o Treatment-emergent QTc > 450 ms (male), > 470 ms (female), > 500 ms (male), 
and > 520 ms (female) 
o Treatment-emergent QTc increase from baseline > 30 ms, > 60 ms 
o Other treatment-emergent abnormalities observed by 12-lead ECG 
o Treatment-emergent (serious) cardiac AEs of special interest. 
6.2.4 Pulmonary function safety endpoints 
• Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values 
• Treatment-emergent decrease of percent of predicted FEV1 or FVC > 20 percentage 
points from baseline values 
• Change in FEV1 and FVC from baseline, absolute and % of absolute change to all time 
points up to FU1 


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• Among subjects with a decrease of > 200 mL and > 12% in FEV1 or FVC from baseline 
to EOT1, reversibility is defined as a decrease of < 200 mL or < 12% in FEV1 or FVC, 
respectively, from baseline to last available follow-up 
• Change from baseline to FU1 vs change from baseline to EOT1 in FEV1 or FVC 
(absolute and % of predicted) 
• Change in lung diffusion capacity as assessed by the DLCO, expressed in absolute 
change and % of predicted value from baseline to all time points up to FU1 
• Change from baseline to FU1 vs change from baseline to EOT in DLCO (absolute and 
% of predicted) 
• (Serious) pulmonary AEs of special interest  
• Withdrawal due to pulmonary reasons/AE 
6.2.5 Other safety endpoints 
• Treatment-emergent notable BP abnormalities [definition in Appendix 6] 
• Treatment-emergent notable laboratory abnormalities [definition in Appendix 6] 
6.3 
Efficacy endpoints (exploratory) 
The main efficacy endpoint is: 
• Achievement of a partial or complete overall response at 24 weeks post-enrollment 
Definitions for the efficacy endpoint are based on the draft 2014 NIH Consensus 
Development Project response criteria [NIH Therapeutic Response 2014]. Baseline or 
subsequent organ abnormalities that are not due to chronic GVHD are not evaluable for 
response (at the organ level). 
6.3.1 Complete overall response definition 
A complete overall response is defined as resolution of all reversible manifestations due to 
chronic GVHD in the following organs at the Week 24 assessment, resulting in: 
• Skin: NIH Skin Score of 0 after previous involvement 
• Mouth: NIH Modified Oral Mucositis Score of 0 after previous involvement 
• Liver: normal ALT, alkaline phosphatase, and TBL after previous elevation of one or 
more 
• Upper GI: NIH Upper GI Score of 0 after previous involvement 
• Lower GI: NIH Lower GI Score of 0 after previous involvement 
• Esophagus: NIH Esophagus Score of 0 after previous involvement 
• Lungs: normal FEV1 absolute value after previous involvement (normalization to FEV1 
≥ 80% predicted is considered a complete response) 


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• Eyes: NIH Eye Score of 0 after previous involvement 
• Joint/fascia: Both NIH Joint and Fascia Score of 0 and photographic range of motion 
(P-ROM) score of 25 after previous involvement by at least one measure 
• Global: Clinician Overall Severity Score of 0 
6.3.2 Partial overall response definition 
A partial overall response is defined as improvement in a measure for at least one organ 
without increase in measures for any other organ. A subject is considered as a partial 
responder at the Week 24 assessment, if there is a change of clinical benefit from baseline 
in at least one of the organs assessed (skin, mouth, liver, upper and lower GI, esophagus, 
lung, eye, and joint/fascia) and no progression in any other organ (stable NIH scores 
compared to baseline).  
The proposed general guideline for defining partial response in a specific organ requires a 
change in score from baseline as follows: 
• Skin: decrease in NIH Skin Score by at least 1 point 
• Mouth: decrease in NIH Modified Oral Mucositis Score by at least 2 points 
• Liver: decrease by 50% in ALT, alkaline phosphatase, or TBL 
• Upper GI: decrease in NIH Upper GI Score by at least 1 point 
• Lower GI: decrease in NIH Lower GI Score by at least 1 point 
• Esophagus: decrease in NIH Esophagus Score by at least 1 point 
• Lungs: increase by at least 10% predicted absolute value of FEV1, as long as initial 
FEV1 < 70% predicted 
• Eyes: decrease in NIH Eye Score by at least 1 point 
• Joint/fascia: decrease in NIH Joint and Fascia Score by 1 or more points or increase in 
P-ROM score by 1 or more points for any site 
• Global: Clinician Overall Severity Score decreases by 2 or more points on a  
0–10 scale 
The proposed general guideline for defining progression in a specific organ requires a 
change in score from baseline as follows: 
• Skin: increase in NIH Skin Score by at least 1 point, except from 0 to 1 
• Mouth: increase in NIH Modified Oral Mucositis Score by at least 2 points 
• Liver: increase by ≥ 2 × ULN for ALT, alkaline phosphatase or TBL 
• Upper GI: increase in NIH Upper GI Score by at least 1 point, except from 0 to 1 
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• Esophagus: increase in NIH Esophagus Score by at least 1 point, except from 0 to 1 
• Lungs: decrease by at least 10% absolute value of FEV1, as long as final FEV1 < 70% 
predicted 
• Eyes: increase in NIH Eye Score by at least 1 point, except from 0 to 1 
• Joint/fascia: increase in NIH Joint and Fascia Score by 1 or more points or decrease in 
P-ROM score by 1 or more points for any site 
• Global: Clinician Overall Severity Score increases by 2 or more points on a 
0–10 scale 
6.3.3 Subject responder / non-responder definition 
The endpoint is reached if the subject is considered a partial or complete responder at Week 
24. The remaining subjects will be considered as non-responders, this includes subjects 
with stable disease and subjects with mixed response (defined as complete or partial 
response in at least one organ accompanied by progression in another organ). 
In case of deviations from the planned schedule of prednisone treatment (with the exception 
of prednisone exceeding 1 mg/kg/day), the subject will still be eligible for the primary 
analysis. 
6.3.4 Other efficacy endpoints 
Other efficacy endpoints include: 
• Need for rescue therapy for chronic GVHD 
o Rescue therapy is the addition of any new systemic or topical IS therapy, or 
exceeding baseline dose for any non-steroid IS, or exceeding glucocorticoid 
dose equivalent to prednisone > 1 mg/kg/day 
• Partial or complete organ-specific response for the specific organ manifestation at 
Week 12 and Week 24 in subjects with a specific organ manifestation of chronic 
GVHD at study baseline 
o Affected organs limited to 2014 NIH consensus criteria organs of skin, eyes, 
mouth, esophagus, upper GI, lower GI, liver, lungs, and joints and fascia 
• Partial or complete overall response at 12 weeks post-enrollment 
• Complete response at Week 24 
• Partial or complete overall response at latest evaluable assessment during the core study 
(Week 12 and Week 24) 
• Average glucocorticoid daily dose over 24 weeks versus baseline dose 
• Percent glucocorticoid dose at Week 24 versus baseline 


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6.4 
Quality of life endpoints 
• Change from baseline to Week 12 and Week 24 in Lee Symptom Scale for chronic 
GVHD [Appendix 8] 
• Change from baseline to Week 12 and Week 24 in each of the patient-reported chronic 
GVHD symptoms (skin, eyes, mouth and genitals [Appendix 7 – Form B]) 
• Change from baseline to Week 12 and Week 24 in each of the patient-reported global 
ratings (Mild-Moderate-Severe Scale, Overall Severity Scale and 7-Point Change Scale 
[Appendix 7 – Form B]) 
7 
STUDY ASSESSMENTS 
All study assessments are performed by a qualified study staff member: medical, nursing, 
or specialist technical staff, and are recorded in the source and eCRF, unless otherwise 
specified. Study assessments performed during unscheduled visits will also be recorded in 
the eCRF.  
If the principal investigator delegates any study procedure/assessment for a subject, 
e.g., ECG, blood sampling etc., to an external facility, he/she should inform Actelion to 
whom these tasks are delegated. The set-up and oversight will be agreed upon with 
Actelion. The supervision of any external facilities remains under the responsibility of the 
principal investigator. 
Calibration or service certificates for the following devices used to perform study 
assessments must be available prior to the enrollment of the first subject:  
• Temperature measurement devices for study medication storage area and lab sample 
storage (i.e., freezer) 
• Spirometer; in addition, a copy of the calibrations check (syringe check) of the day of 
measurement must be stored and a log of calibration check results must be maintained 
at the site [see Section 7.3.3]. 
• OCT 
• DLCO gas analyzer; in addition, a copy of the calibrations check of the day of a test 
must be stored, and a log of calibration results must be maintained at the site. In 
addition, frequent testing involving the same healthy subject control (biological quality 
check) or a DLCO simulator will ensure continuous monitoring of the gas analyzer 
measurement accuracy over time [see Section 7.3.4]. 
• ECGs 
• BP monitoring device 


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7.1 
Screening/baseline assessments 
7.1.1 Informed consent (screening visit) 
Prior to performing any study-specific procedures or assessments at Visit 1 (screening) or 
Visit 11 (Extension Treatment Period – Visit EX-1), the subject must provide written 
informed consent to participate in the study. If the signing of informed consent and 
performance of the first study-specific procedures or assessments take place on the same 
day, it must be clear from the source documents that informed consent was obtained prior 
to any study-specific procedures being performed. If a study-specific procedure or 
assessment has been performed as part of routine care of the subject and the results are 
available prior to the subject’s signing of informed consent, such procedure or assessment 
may be used to assess eligibility and does not have to be repeated. In such cases, it must be 
clear from the source document when and for which reason the assessment was done prior 
to the signing of the informed consent.  
It is the responsibility of the investigator to explain the study in all its aspects to the subject 
and obtain her/his informed consent. The informed consent process will be documented in 
the investigator site file. The language used in the oral and written information about the 
trial, including the informed consent form (ICF), will be provided in a language that is fully 
understandable to the subject.  
For subjects who provide informed consent but are subsequently not enrolled into the 
study, the reasons for not being enrolled will be recorded in the eCRF. 
7.1.2 Baseline demographics and disease characteristics 
Baseline demographics (sex, age, ethnicity, body weight, and height) are to be recorded in 
the eCRF at Visit 1. Complete, clinically relevant medical history and current conditions 
are to be documented in the eCRF, as well as smoking status and disease characteristics 
including the date of first chronic GVHD symptoms, date of chronic GVHD diagnosis [see 
Section 4.5], and chronic GVHD stage and score [Appendix 2]. Complications or 
symptoms associated with chronic GVHD within the last 24 months prior to the study will 
be collected in the medical history of the eCRF. 
7.1.3 Study-concomitant therapies 
All study-concomitant therapy (including contraceptives and traditional and alternative 
medicines, i.e., plant-, animal-, or mineral-based medicines) taken by the subject from the 
signing of informed consent until the end of their participation in the study (i.e., EOS) will 
be recorded in the Concomitant Therapies pages of the eCRF. This includes all ongoing 
therapies and those initiated or stopped during this period. The corresponding generic 
name, indication, route, dose, dates of initiation and discontinuation will be recorded. 


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7.2 
Pharmacokinetic and pharmacodynamic assessments 
These assessments are done to investigate PK and PD effects of ponesimod. 
7.2.1 Pharmacokinetic assessments 
7.2.1.1 Timing for sampling 
PK samples will be collected during this study for all subjects, in order to provide 
information about study drug exposure in the target population.  
At Visit 2 (Day 1), blood samples are collected pre-dose and then hourly (+/−20 minutes) 
post-dose, at the same time ECG measurements are taken, for a minimum of 4 and up to a 
maximum of 12 collections, depending on the number of ECG measurements taken. The 
ECG assessment schedule for Visit 2 (Day 1) is described in Sections 7.3.1 and 5.1.7. 
Placement of a peripheral venous catheter may facilitate these frequent blood collections. 
Blood samples will also be collected pre-dose at Visits 3, 4, 5, 6, and 7 (Weeks 4, 8, 12, 
16, and 20) and Visit 8 (EOT1). PK samples will also be drawn 3 hours (+/−20 minutes) 
post-dose at Visit 5 (Week 12).  
7.2.1.2 Procedures for sampling 
Up to 3 mL of blood must be collected in tubes containing ethylenediaminetetraacetic acid 
(EDTA). Immediately following collection of the required blood volume, the tubes must 
be slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into 
solution, and immediately cooled on ice. Within 30 minutes of collection, the tubes must 
be centrifuged at approximately 1500 g for 10 minutes at 2 to 8 °C. When a centrifuge that 
can be cooled is not available, the blood samples and the bucket of the centrifuge must be 
cooled on ice prior to centrifugation. The plasma must be transferred into one labeled 
opaque polypropylene tube to avoid carry-over of erythrocytes. All samples must be stored 
in an upright position at −25 °C (freezer settings: intended temperature −25 °C; upper limit 
−20 °C). The exact time of withdrawal of the blood sample must be entered in the eCRF, 
as well as the status of the subject (fed or fasted), and the time of last previous study drug 
intake. Blood samples for PK analysis must be drawn prior to study drug intake on the day 
of the visit (Visits 2, 3, 4, 5, 6, 7). Additional PK samples are drawn hourly post-dose at 
Visit 2. One additional PK sample is drawn 3 h post-dose at Visit 5.  
To prevent degradation of ponesimod in the plasma samples, exposure to light should be 
minimized. After centrifugation, plasma samples should be kept in the dark. 
7.2.1.3 Labeling and shipment 
Details of the collection, labeling and shipment of the samples can be found in the 
laboratory manual provided to the investigator. The tubes and labels for the samples will 
be provided to the investigator and/or staff by the central laboratory. 


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7.2.1.4  Bioanalysis 
The concentration of ponesimod in plasma will be determined by a validated liquid 
chromatography-tandem 
mass 
spectrometry 
assay 
by 
Actelion, 
Preclinical 
Pharmacokinetics and Metabolism. The lower limit of quantification is 1 ng/mL. 
Concentrations will be calculated by interpolation from a calibration curve. Quality control 
samples will be analyzed throughout the study. Their measured concentrations will be used 
to determine between-run and overall precision and accuracy of the analyses. 
The samples will be destroyed upon signature of the Clinical Study Report. 
7.2.2 Pharmacodynamic assessments 
The PD marker is absolute lymphocyte counts, which will be measured as part of the 
hematology tests [see Section 7.3.11]. An additional PD sample will be collected at Visit 5, 
3 hours (+/−20 minutes) post-dose.  
7.3 
Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are 
described in Section 10. 
7.3.1 12-lead ECG 
A standard 12-lead ECG will be recorded at all scheduled study visits (except  
FU2 – Visit 10) with the subject in a fully rested supine position after the subject has been 
allowed to rest for a minimum of 5 minutes prior to the measurement.  
At Visit 2 (Day 1), Visit 11 (EX-1) and at visits for re-initiation of study drug where 
post-dose monitoring will be required, the 12-lead ECG monitoring will be performed 
under the responsibility of the cardiac safety assessor who will also evaluate and interpret 
these assessments. At all other visits, it will be performed either under the responsibility of 
the cardiac safety assessor or the investigator.  
The following variables will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), 
QTc (ms), and any ECG findings. QTC (ms) will be calculated according to Bazett’s and 
Fridericia’s formula (QTcB = QT/(RR) ½ and QTcF = QT/(RR) ⅓, respectively). 
Before study drug administration (pre-dose) at Visit 2 (Day 1) and Visit 11 (EX-1), the 
cardiac safety assessor must provide the ECG results and interpretation to the principal 
investigator and support her/him, if requested, to make a final decision on the subject’s 
eligibility according to the inclusion/exclusion criteria. At Visit 2 (Day 1) and Visit 11 
(EX-1), the pre-dose ECG must be performed prior to enrollment and the exclusion 
criterion of HR < 50 bpm checked. 


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During the Core and Extension Treatment Periods, ECGs must be performed at pre-dose. 
In case of need of concomitant treatment with a QT-prolonging drug with known risk of 
Torsades de Pointes, additional ECGs will be performed according to the guidance 
provided in Appendix 3. 
At Visit 2 (Day 1), Visit 11 (EX-1) and on the day of re-initiation of study drug [see Section 
5.1.8], ECGs must be performed at pre-dose and hourly thereafter for a minimum of 4 
hours and up to 12 h post-dose. Subjects may be discharged from the hospital if they meet 
the discharge criteria before 12 h post-dose but no sooner than 4 h post-dose [see Section 
5.1.7]. If the subject does not meet the defined discharge criteria at 12 hours post-dose, the 
cardiac safety assessor notifies the principal investigator and the subject is prematurely 
discontinued from ponesimod but will be kept in the hospital for observation, and 
additional ECG measurements will be performed until changes in ECG variables are no 
longer clinically relevant (i.e., discharge criteria are met [see Section 5.1.7]), or until 
medically indicated. 
At Visit 2 (Day 1), Visit 11 (EX-1), and on the day of re-initiation of study drug where 
post-dose monitoring is required, significant findings – which in view of the cardiac safety 
assessor meet the definition of an AE and are resolved at the time of discharge of the subject 
– must be recorded directly on an Adverse Event page of the eCRF. All other significant 
findings, on Day 1, EX-1 or on the day of re-initiation of study drug where post-dose 
monitoring is required, that are unresolved at the time of discharge of the subject or with 
an onset on any other day (which in her/his view meet the definition of an AE) must be 
reported to the principal investigator who will record these events on the Adverse Event 
page of the eCRF. (The investigator may perform the function of the cardiac safety assessor 
if qualified, as per Section 3.4.2.) 
At Visits 3, 4, 5, 6 and 7 (Weeks 4, 8, 12, 16 and 20) in the Core Treatment Period 
and Visits EX-2, EX-3, EX-4, EX-5, EX-6, EX-7, EX-8, EX-9, EX-10, EX-11, and 
EX-12 (Extension Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, and 84) in the Extension 
Treatment Period, 12-lead ECG measurements are collected pre-dose. In the event 
of a grade 2 QTc elevation, a repeat 12-lead ECG must be collected 3 hours 
post-dose. If QTcF > 500 ms, the subject is prematurely discontinued from the 
study as stated in Section 5.1.10.1. In addition, a PK sample must be collected within 
20 minutes after the 3 hour post-dose ECG. 
 
Digital 12-lead ECG devices will be provided to each site by the central ECG reader for 
the duration of the study. Digital ECG recording must be performed for all subjects 
according to the study protocol schedule. The data records will be sent to the evaluation 
center for central reading. 
Details will be provided in the ECG laboratory manual. 


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7.3.2 Blood pressure 
BP measurements include SBP and DBP. 
BP monitoring will be performed using the same type of device throughout the study on 
the same arm with the subject in a fully rested supine position after the subject has been 
allowed to rest for a minimum of 5 minutes prior to the measurement.  
At each pre-dose assessment, SBP and DBP will each be measured twice. The two obtained 
measurements (i.e., two SBP measurements and two DBP measurements) and the position 
and arm used are to be recorded in the eCRF. The means of the two obtained measurements 
will be calculated by the eCRF.  
Post-dose assessments at Visit 2 (Day 1), Visit 11 (EX-1) and at visits for re-initiation of 
study drug where post-dose monitoring is required will only be measured once at each time 
point. This single obtained SBP measurement is to be used for determining discharge 
criteria on Day 1 and Visit 11 and on day of re-initiation of study drug where post-dose 
monitoring is required. 
At Visit 2 (Day 1), Visit 11 (EX-1) and at visits for re-initiation of study drug where post-
dose monitoring is required, the assessment of vital signs will be performed under the 
responsibility of the cardiac safety assessor who will also evaluate and interpret these 
assessments. At all other visits, it will be performed either under the responsibility of the 
cardiac safety assessor or investigator.  
At Visit 2 (Day 1), Visit 11 (EX-1) and at visits for re-initiation of study drug where 
post-dose monitoring is required, significant findings – which in view of the cardiac safety 
assessor meet the definition of an AE and are resolved at the time of discharge of the subject 
– must be recorded directly on an Adverse Event page of the eCRF. All other significant 
findings, on Day 1, EX-1 or on the first day of re-initiation of study drug where post-dose 
monitoring is required, that are unresolved at the time of discharge of the subject or with 
an onset on any other day (which in her/his view meet the definition of an AE) must be 
recorded on the Adverse Event page of the eCRF. 
BP measurements will be performed at all study visits (except FU2 – Visit 10). At Visit 2 
(Day 1), Visit 11 (EX-1) and on days of re-initiation of study drug, where post-dose 
monitoring is required [see Section 5.1.8], SBP and DBP will be measured at pre-dose, and 
hourly thereafter for a minimum of 4 hours and up to 12 h post-dose. Subjects may be 
discharged from the hospital if they meet the discharge criteria before 12 h post-dose but 
no sooner than 4 h post-dose [see Section 5.1.7]. If the subject does not meet the defined 
discharge criteria at 12 hours post-dose, the subject will be prematurely discontinued from 
ponesimod but will be kept in the hospital for observation, and additional BP measurements 


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will be performed until changes are no longer clinically relevant (i.e., discharge criteria are 
met [see Section 5.1.7]), or until medically indicated. 
7.3.3 Spirometry 
Spirometry tests will be performed at visits indicated in Table 1. In addition, unscheduled 
spirometry will have to be conducted in the event of respiratory symptoms (e.g., dyspnea). 
Spirometry at Visit 1 can be performed at any time during the screening period. Spirometry 
at Visit 2 (Day 1) must be performed within 48 hours of the visit and prior to study drug 
intake. At Visits 3 and 4 (Week 4 and Week 8), spirometry may be performed up to 3 days 
prior to the visit date and must be performed prior to study drug intake. At Visit 5 (Week 
12), spirometry may be performed up to 7 days prior to the visit date and must be performed 
prior to study drug intake. At Visits 8 and 23 (EOT1 and EOT2), spirometry may be 
performed up to 7 days prior to the visit date and no later than 7 days after the 
discontinuation of study drug. At all other visits indicated in Table 1, spirometry may be 
performed 7 days prior to or after the visit date. All spirometry assessments must be 
performed in the morning, preferably between 06:00 and 10:00, at approximately the same 
time to avoid diurnal variation. 
Spirometry testing will consist primarily of assessing FEV1 and FVC. Further parameters 
may be explored and/or used for spirometry quality control measures.  
Spirometry tests will be conducted according to the ATS/ERS guidelines [Miller 2005a, 
Miller 2005b, Macintyre 2005]. The pulmonary function facility will ensure that the 
spirometer is functioning properly and is calibrated according to manufacturer instruction 
and ATS/ERS guidelines. A copy of the calibrations of the day of a test must be stored as 
source documents in the subject charts at each subject visit, and a log of calibration results 
must be maintained at the site.  
Spirometry testing will be performed by a PFT technician, respiratory therapist or expert, 
or an equally experienced person according to the ATS/ERS guidelines [Miller 2005a] 
(e.g., for US, registered pulmonary function technologist and/or registered respiratory 
therapist). To the extent logistically feasible, attempts should be made to have the same 
tester throughout the study for a subject, and this information will be recorded in the eCRF. 
Back-up testers (PFT technician, respiratory therapist, or expert or an equally qualified 
person according to the ATS/ERS guidelines [Miller 2005a]) may conduct spirometry if 
the primary tester is not available. All PFT technicians or other qualified persons 
participating in the studies will be trained on the specific requirements for the studies and 
have refreshment on ATS/ERS recommendations before study start and when compliance 
issues are identified.  


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Subjects must refrain from taking short-acting ß2 agonists (i.e., salbutamol) for 6 hours and 
long-acting ß2 agonists for 24 hours prior to spirometry testing. To perform the spirometry 
test, subjects will be rested for a minimum of 5 minutes prior to start. Sufficient forced 
expiratory maneuvers (up to a maximum of eight) will be performed to produce a minimum 
of three technically acceptable and repeatable traces (according to ATS/ERS guideline 
criteria. The best (largest) FEV1 and FVC values from the three acceptable and repeatable 
tests are to be selected by the PFT technician and recorded in the eCRF and will serve for 
the calculation of % of predicted values and used for the endpoint derivations. These values 
may come from separate maneuvers. The FEV1 and FVC measures obtained at Visit 2 (Day 
1) and selected as described above will be used as the study baseline. 
PFT values that trigger study drug discontinuation are described in Section 5.1.10.7. 
Clinically relevant findings meeting the definition of an AE (new AE, or worsening of 
previously existing condition) [see Section 10.1.1] must be recorded on an AE page of the 
eCRF. 
Predicted normal values for FVC and FEV1 will be used to determine exclusion criteria as 
well as withdrawal criteria [see Section 5.1.10.7]. Predicted normal values will be adjusted 
for subjects from ethnic groups other than white/Caucasian. The formulas for the 
calculation of the predicted normal values for FEV1 and FVC and the ethnic group 
adjustments used in this study are those of the European Community Coal and Steel 
[Quanjer 1993]. 
7.3.4 DLCO 
DLCO tests will be performed along with spirometry [Section 7.3.3]. DLCO tests will be 
assessed by the single breath testing technique. DLCO efforts, up to a maximum of five, 
will be performed to produce at least two technically acceptable and repeatable traces, 
according to ATS/ERS guideline criteria [Macintyre 2005]. There must be a minimal 
interval of at least 4 minutes between each effort performed.  
The average of at least two within session DLCO efforts that meet the acceptability criteria 
are to be reported as the value for this session in the eCRF. If only one acceptable effort is 
achieved, this value is to be reported for this session in the eCRF. If no acceptable effort is 
achieved, the effort with the highest inspiratory vital capacity is to be reported in the eCRF. 
Reported DLCO values will be entered in the eCRF, without any further adjustments. 
If clinically significant alterations in DLCO variables indicating a pulmonary condition that 
could result in increased risk for the subject are observed, he/she may be prematurely 
discontinued from ponesimod at the discretion of the investigator. Clinically relevant 
findings meeting the definition of an AE (new AE, or worsening of previously existing 
condition) [see Section 10.1.1] must be recorded on an AE page of the eCRF. 


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7.3.5 Chest X-ray 
A CXR will be performed at Visit 1 (screening), and assessed by the local radiologist in 
order to exclude any subject with findings suggestive of active or latent TB. Any CXR that 
had been performed within 90 days prior to screening can be used; if available, there is no 
need to repeat CXR at screening.  
7.3.6 Test for tuberculosis 
An interferon gamma release assay (QuantiFERON-TB-Gold®) will be performed at 
Visit 1 (screening) to screen for active or latent TB. The test will be analyzed and 
interpreted at the central laboratory [see Section 7.3.11] and electronically transferred to 
the sponsor.  
Only subjects with a negative test at screening and without CXR findings 
[see Section 7.3.5] at screening or within the previous 90 days suggestive of active or latent 
TB can be included in the study. If the test result is positive, subjects must not be included 
in the study, except if there is documentation that the subject has received adequate 
treatment for TB previously. If the test result is inconclusive (invalid, indeterminate, or 
borderline), the test may be repeated once and a negative result must be obtained prior to 
enrollment in order to include the subject. If the result of the repeated test is again 
inconclusive (invalid, indeterminate, or borderline), subjects must not be included in the 
study. 
Details on the performance of the test for TB will be provided in the specific central 
laboratory manual. 
7.3.7 Ophthalmological assessments 
Ophthalmological assessments will be performed by an ophthalmologist at visits indicated 
in Table 1. Testing at Visit 1 can be performed at any time during the screening period. 
Testing at Visits 8 and 23 (EOT1 and EOT2) may be performed up to 7 days prior to the 
visit date and no later than 7 days after the discontinuation of study drug. Testing at all 
other visits indicated in Table 1, may be performed 7 days prior to or after the visit date. 
In addition, unscheduled ophthalmological examination will be done in the event of visual 
symptoms.  
The safety ophthalmological assessment includes previous eye history and ophthalmic 
condition, any new or current ophthalmological symptoms, assessment of best corrected 
visual acuity (Early Treatment Diabetic Retinopathy Study charts), measurement of 
Goldmann applanation tonometry, slitlamp examination of the anterior segment, and 
dilated indirect funduscopy. While the visual acuity, and measurement of Goldmann 
applanation tonometry exams themselves may be performed by a delegate (e.g., certified 
technician, optometrician), the review and interpretation must be performed by the 
ophthalmologist. Conduct, review, and interpretation of all other ophthalmological exams 


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must be performed by the ophthalmologist. Fluorescence angiography (if applicable) may 
be performed by a delegate (e.g., certified technician, optometrician) but always in the 
presence of the ophthalmologist who will review and interpret the results.  
The purpose of the assessment prior to enrollment is to exclude subjects with macular 
edema or diabetic retinopathy from the study, and to document a baseline assessment. No 
data will be collected in the eCRF, but clinically relevant findings meeting the definition 
of an AE (new AE, or worsening of previously existing condition) [see Section 10.1.1] 
must be recorded on an AE page of the eCRF. 
7.3.8 Optical Coherence Tomography 
OCT will be assessed at visits indicated in Table 1. Testing at Visit 1 can be performed at 
any time during the screening period. Testing at Visits 8 and 23 (EOT1 and EOT2) may be 
performed up to 7 days prior to the visit date and no later than 7 days after the 
discontinuation of study drug. Testing at all other visits indicated in Table 1, may be 
performed 7 days prior to or after the visit date. In addition, unscheduled OCT examination 
will have to be assessed in the event of visual symptoms or findings suggestive of macular 
edema according to the ophthalmologist. While the OCT exam may be performed by a 
delegate (e.g., certified technician, optometrician), the review and interpretation must be 
performed by the ophthalmologist.  
The purpose of the assessment prior to enrollment is to exclude subjects with macular 
edema or diabetic retinopathy from the study, and to document a baseline assessment. The 
site will use the OCT device available locally and must ensure it is working properly. To 
the extent that is logistically feasible, the same OCT machine is to be used for each 
individual subject throughout the study.  
No data will be collected in the eCRF, but clinically relevant findings meeting the 
definition of an AE (new AE, or worsening of previously existing condition) 
[see Section 10.1.1] must be recorded on an AE page of the eCRF. 
The OSB will receive all information related to suspected cases of macular edema and will 
perform a central review of OCT results and subject data of suspected cases of macular 
edema. 
7.3.9 Weight and height 
Body weight will be measured at visits indicated in Table 1. Body height is only measured 
at Visit 1 (screening). Data will be collected in the eCRF. Measurements will be conducted 
with subjects wearing clothes but without shoes. 


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7.3.10 Physical examination 
Physical examination is performed at visits indicated in Table 1. Unscheduled physical 
examination may be performed at any time during the study (Visits U1, U2, …). 
Physical examination should be recorded by body system in the eCRF as normal or 
abnormal. If an abnormality is found, it should be specified on the corresponding eCRF 
page, describing the signs related to the abnormality (e.g., systolic murmur) not the 
diagnosis (e.g., mitral valve insufficiency). Clinically relevant findings meeting the 
definition of an AE (new AE, or worsening of previously existing condition), must be 
recorded on an AE page of the eCRF. 
7.3.11 Laboratory assessments 
7.3.11.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits. Central laboratory data will be 
automatically transferred from the central laboratory database to Actelion’s clinical 
database. 
Under specific circumstances (e.g., subject lives far away from the site and cannot return 
for a unscheduled visit during the first 24 weeks), laboratory samples could be drawn in a 
local laboratory close to where the subject lives and analyzed at the central laboratory. In 
such circumstances, the local laboratory must be provided with the central laboratory kits, 
which must be used for blood collection. The blood samples collected locally will be 
shipped by the local laboratory to the central laboratory for analysis. Local laboratories 
should be identified prior to enrollment, if possible. 
Local laboratory results will be collected in the following situations: 
• In case of missing central laboratory values, local laboratory values (if available) for 
the tests assessed per protocol are to be recorded in the eCRF (together with the 
corresponding normal ranges), especially local laboratory results related to the 
diagnostic work-up (i.e., detection, confirmation and/or monitoring) of decrease in 
lymphocyte, neutrophils, or white blood cell (WBC) count, ALT/AST elevations, 
serum creatinine increase, or decrease in calculated creatinine clearance. In the event 
that several local laboratory samples are taken on the same day or if the sample was 
tested several times, the ‘worst’ value (e.g., highest value for ALT/AST) should be 
reported in the eCRF. 
• In exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency) where a local laboratory is used for the collection 


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and analysis of blood samples, the local laboratory results (with the corresponding 
normal ranges) will be entered into the clinical database via dedicated eCRF pages.  
For these local laboratories, the investigator/delegate will provide Actelion with the name, 
professional degree and curriculum vitae of the laboratory director, a copy of the 
laboratory’s certification, and the normal ranges for each laboratory test that is evaluated 
in the study. These laboratory references must be updated whenever necessary. 
In case a central laboratory sample is lost, has deteriorated or cannot be analyzed for 
whatever reason, the investigator will collect an additional sample as soon as possible for 
repeat analysis if still clinically relevant. 
The central laboratory will provide all laboratory results by fax or normal mail to the site.  
All laboratory reports must be signed and dated by the principal investigator or delegate 
within 5 calendar days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings meeting the 
definition of an AE [see Section 10.1.1] must be reported as an AE or SAE as appropriate 
[see Section 10], and must be followed until the value returns to within the normal range 
or is stable, or until the change is no longer clinically relevant. Further laboratory analyses 
should be performed as indicated and according to the judgment of the investigator. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.3.11.2 Laboratory tests 
Blood samples will be drawn before the morning administration of study medication, at 
visits indicated in Table 1. Urinalysis will be assessed using dipsticks at visits indicated in 
Table 1.  
Hematology 
• Red blood cell count 
• Total and differential WBC counts (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, band forms) 
• Platelet count 
• Hb 
• Hematocrit 
Clinical chemistry 
• Glucose 
• ALT, AST, alkaline phosphatase, TBL, lactate dehydrogenase 


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• Creatinine 
• Calculated creatinine clearance (Cockroft-Gault) 
• INR 
• Urea 
• Uric acid 
• Total cholesterol 
• Triglycerides 
• Sodium, potassium, chloride, calcium 
• Total protein, albumin 
• C-reactive protein 
Virus serology 
• Hepatitis B surface antigen, Hepatitis C antibodies, HIV1 and HIV2 antibodies at Visit 
1 (screening) 
Additional analyses in the event of infections 
• A serum sample will be taken at Visit 1 (screening) to be stored at the central laboratory 
for potential retrospective analyses of viral serology titers in the event of infections 
(e.g., suspected opportunistic infection) during the study. 
Test for TB 
• An interferon gamma release assay will be performed at Visit 1 (screening) to screen 
for active or latent TB [see Section 7.3.6]. 
Pregnancy test 
A serum pregnancy test for WOCBP will be performed at Visit 1 (screening) and if 
pregnancy is suspected during the study. A urine or a serum pregnancy test will be 
performed at Visit 2 (Day 1). Urine pregnancy tests will be performed at visits indicated in 
Table 1. Home urine pregnancy tests will be conducted by the subject at Weeks EX-28, 
EX-32, EX-40, EX-44, EX-52, EX-56, EX-64, EX-68, EX-76, EX-80, EX-88, and EX-92. 
The subject will telephone the site and convey the results of the home urine pregnancy test. 
The site must follow-up with the subject in case results are not received by the site within 
7 days of the planned home urine test date.  
In order for WOCBP to be enrolled in the study, they must have a confirmed negative 
serum pregnancy test at Visit 1 (screening) and a second confirmed negative urine or serum 
pregnancy test prior to enrollment at Visit 2 (Day 1). The two tests must be performed a 
minimum of 3 weeks or 10 days apart, respectively.  
Serum pregnancy testing results data will be automatically transferred from the central 
laboratory database to Actelion’s clinical database. Urine pregnancy testing results will be 


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recorded in the eCRF. In case of pregnancy, a Pregnancy Form must be completed [see 
Section 10.3]. 
Urinalysis 
• pH 
• Glucose 
• Proteins 
• Blood 
• Leukocytes 
• Bilirubin, urobilinogen 
Urine dipsticks provided by the central laboratory will be used to perform the urinalysis. 
The test should be performed and analyzed at the site. The results must be documented in 
the source documents / subject charts. No data will be collected in the eCRF. Clinically 
relevant findings meeting the definition of an AE (new AE, or worsening of previously 
existing condition) [see Section 10.1.1] will be recorded accordingly on an AE page of the 
eCRF. 
7.4 
Efficacy assessments 
7.4.1 Organ-specific assessments (Chronic GVHD Activity Assessment Form A) 
Organ-specific assessments will be performed at visits indicated in Table 1. These must be 
assessed by the investigator or a qualified delegate [see Section 3.4.1]. Baseline 
assessments are collected at Visit 2 (Day 1) before study drug is administered to the subject. 
Baseline or subsequent abnormalities not attributed to chronic GVHD will be recorded as 
AEs (if new since signing informed consent) but are not included as efficacy assessments. 
Organ-specific assessments are a part of the Chronic GVHD Activity Assessment eCRF. 
The Chronic GVHD Activity Assessment source document forms are in Appendix 7. 
7.4.1.1 Skin  
7.4.1.1.1 NIH Skin Score 
This 
NIH 
Skin 
Score 
is 
a 
4-point 
scale 
ranging 
from 
0–3 
[NIH Therapeutic Response 2014]. It considers body surface area (BSA) affected and the 
type of skin involvement (erythema, sclerotic and/or ulceration). It consists of the 
following four categories of increasing severity: 0 = no symptoms; 1 = ≤ 18% BSA and no 
sclerosis; 2 = 19–50% BSA and/or any moveable sclerosis; 3 = > 50% BSA and/or any 
non-moveable sclerosis, impaired mobility, or ulcers.  
The evaluator should determine the % BSA by the “Rule of 9s” [see Appendix 9]. This 
convention separates the skin surface area into multiples of 9, with the genitals 


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corresponding to 1%; the total is 100%. Each area is described below with the 
corresponding percentage. 
Anatomic structure 
BSA 
Anterior head 
4.5% 
Posterior head 
4.5% 
Anterior torso 
18% 
Posterior torso 
18% 
Anterior right leg 
9% 
Anterior left leg 
9% 
Posterior right leg 
9% 
Posterior left leg 
9% 
Anterior right arm 
4.5% 
Anterior left arm 
4.5% 
Posterior right arm 
4.5% 
Posterior left arm 
4.5% 
Genitals/perineum 
1% 
 
7.4.1.2 Mouth 
7.4.1.2.1 NIH Modified Oral Mucositis Score.  
The NIH Modified Mucosistis Score is a 13 point scale ranging from 0–12. It measures 
a) mucosal erythema (color intensity and percent of oral surface area); b) lichen-like 
(percent of oral surface area); and c) ulcerations (percent of oral surface area) 
[NIH Therapeutic Response 2014]. The 13-point scale is divided into four groups, roughly 
corresponding with: none, mild, moderate and severe. The categories are further defined in 
Form A in Appendix 7. 
7.4.1.3 Liver 
7.4.1.3.1 Liver tests: ALT, alkaline phosphatase, and TBL  
The liver tests used for the organ-specific assessments are ALT, alkaline phosphatase, and 
total serum bilirubin [Section 7.3.11].  
7.4.1.4 Lungs 
7.4.1.4.1 PFTs: FEV1 
The FEV1 is the basis of assessing response in lung. Collection of FEV1 is further detailed 
in Section 7.3.3. 


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7.4.1.4.2 Lung symptoms 
Lung symptoms data is collected to generate an NIH lung score, but this score does not 
form the basis of assessing response when FEV1 data is available. The NIH lung score is a 
4-point scale measuring increasing severity of breathing symptoms [Filipovich 2005, 
NIH Therapeutic Response 2014]. The investigator assesses symptoms ranging in a score 
from 0–3: 0 = no symptoms; 1 = mild symptoms (shortness of breath after climbing one 
flight of steps); 2 = moderate symptoms (shortness of breath after walking on flat ground); 
3 = severe symptoms (shortness of breath at rest; requiring oxygen). 
7.4.1.5 Eyes 
7.4.1.5.1 NIH Eye Score 
The NIH Eye Score is a 4-point scale measuring increasing severity of dryness 
[Filipovich 2005, NIH Therapeutic Response 2014]. The investigator assesses symptoms 
ranging in a score from 0–3: 0 = no symptoms; 1 = mild dry eye symptoms not affecting 
activities of daily living (ADL; requiring lubricant eye drops ≤ 3 × per day), 2 = moderate 
dry eye symptoms partially affecting ADL (requiring lubricant eye drops > 3 × per day or 
punctal plugs), without new vision impairment due to keratoconjunctivitis sicca (KCS); 
3 = severe dry eye symptoms significantly affecting ADL (special eyewear to relieve pain), 
or unable to work because of ocular symptoms, or loss of vision due to KCS. 
7.4.1.6 Joints and fascia 
7.4.1.6.1 NIH Joint and Fascia Score 
The NIH Joint and Fascia Sore is a 4-point scale measuring increasing severity of 
symptoms of the joints and fascia including those affecting range of motion, limb tightness 
and inflammation [Inamoto 2014a, NIH Therapeutic Response 2014]. The investigator 
assesses symptoms ranging in a score from 0–3: 0 = no symptoms; 1 = mild tightness of 
arms and legs, normal or mild decrease in range of motion (ROM) and not affecting ADL; 
2 = tightness of arms or legs or joint contractures, erythema thought to be due to fasciitis, 
moderate decrease ROM and mild-to-moderate limitation of ADL; 3 = contractures with 
significant decrease in ROM, and significant limitation of ADL (unable to tie shoes, button 
shirts, dress self, etc.) 
7.4.1.6.2 Photographic Range of Motion 
The P-ROM is a 25-point scale based on predicted range of motion. The scale consists of 
a series of photographic images capturing ROM separately at the shoulders, elbows, 
wrists/fingers, and ankles [Inamoto 2014a, NIH Therapeutic Response 2014]. The score is 
the sum of all four joints, with lower scores indicating a decreased ROM. Shoulders, 
elbows and wrists/fingers are scored on a scale from 1–7 with 1 = worst ROM and 
7 = normal ROM. Ankles are scored on a scale of 1–4 with 1 = worst ROM and 4 = normal 
ROM. 


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7.4.1.7 GI tract 
Assessment of the GI tract is separated into three categories: upper GI, lower GI and 
esophagus. 
7.4.1.7.1 NIH Upper GI Score 
The NIH Upper GI Score is a 4-point scale measuring increasing severity of the upper GI 
symptoms: 
early 
satiety, 
or 
anorexia, 
or 
nausea 
and 
vomiting 
[NIH Therapeutic Response 2014]. The investigator assesses symptoms ranging in a score 
from 0–3: 0 = no symptoms; 1 = mild, occasional symptoms, with little reduction in oral 
intake during the past week; 2 = moderate, intermittent symptoms, with some reduction in 
oral intake during the past week; 3 = more severe or persistent symptoms throughout the 
day, with marked reduction in oral intake, on almost every day of the past week. 
7.4.1.7.2 NIH Lower GI Score 
The NIH Lower GI Score is a 4 point scale measuring increasing severity of diarrhea 
[NIH Therapeutic Response 2014]. The investigator assesses symptoms ranging in a score 
from 0–3: 0 = no loose or liquid stools during the past week; 1 = occasional loose or liquid 
stools on some days during the past week; 2 = intermittent loose or liquid stools throughout 
the day, on almost every day of the past week, without requiring intervention to prevent or 
correct volume depletion; 3 = voluminous diarrhea on almost every day of the past week, 
requiring intervention to prevent or correct volume depletion. 
7.4.1.7.3 NIH Esophagus Score 
The NIH Esophagus Score is a 4-point scale measuring increasing severity of esophageal 
symptoms of dysphagia or odynophagia [NIH Therapeutic Response 2014]. The 
investigator assesses symptoms ranging in a score from 0–3: 0 = no esophageal symptoms; 
1 = occasional dysphagia or odynophagia with solid foods or pills during the past week; 
2 = intermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or 
soft foods, during the past week; 3 = dysphagia or odynophagia for almost all oral intake, 
on almost every day of the past week. 
7.4.2 Clinician global reported ratings (Chronic GVHD Activity Assessment 
Form A) 
7.4.2.1 Clinician Overall Severity Scale. 
The 
Clinician 
Overall 
Severity 
Score 
consists 
of 
an 
11-point 
scale 
[NIH Therapeutic Response 2014]. The investigator rates the severity of the subject’s 
chronic GVHD symptoms on a scale of 0–10 with a score of 0 = chronic GVHD symptoms 
are not at all severe and a score of 10 = the most severe chronic GVHD symptoms possible. 
The Clinician Overall Severity Score will be performed at visits indicated in Table 1. This 
must be assessed by the investigator or a qualified delegate. Baseline assessments are 


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collected at Visit 2 (Day 1) before study drug is administered to the subject. The Clinician 
Overall Severity Score is part of the Chronic GVHD Activity Assessment eCRF. The 
Chronic GVHD Activity Assessment source document forms are in Appendix 7.  
7.4.2.2 Clinician None-Mild-Moderate-Severe Scale 
The Clinician None-Mild-Moderate-Severe Scale is a 4-point scale measuring increasing 
severity of chronic GVHD symptoms [NIH Therapeutic Response 2014]. The investigator 
assesses symptoms ranging in a score from 0–3: 0 = none; 1 = mild; 2 = moderate; 3 = 
severe. 
The Clinician None-Mild-Moderate-Severe Scale will be performed at visits indicated in 
Table 1. This must be assessed by the investigator or a qualified delegate. Baseline 
assessments are collected at Visit 2 (Day 1) before study drug is administered to the subject. 
The Clinician None-Mild-Moderate-Severe Scale is part of the Chronic GVHD Activity 
Assessment eCRF. The Chronic GVHD Activity Assessment source document forms are 
in Appendix 7.  
7.4.2.3 Clinician 7-Point Change Scale 
The Clinician 7-Point Change Scale is a 7-point scale measuring chronic GVHD changes 
over time [NIH Therapeutic Response 2014]. The investigator scores changes in subjects’ 
overall chronic GVHD symptoms since the last visit on a scale of 7: +3 = very much better; 
+2 = moderately better; +1 = a little better; 0 = about the same; −1 = a little worse; −2 = 
moderately worse; −3 = very much worse. Assessments will occur during Visits 5 and 8. 
At Visits 5 and 8, the investigator must assess the change in the subject’s chronic GVHD 
symptoms since the last visit (Visits 4 and 7, respectively). 
The Clinician 7-Point Change Scale will be performed at visits indicated in Table 1 except 
for Visit 2 (Day 1). This must be assessed by the investigator or a qualified delegate. No 
baseline assessments are collected for this parameter. The Clinician 7-Point Change Scale 
is part of the Chronic GVHD Activity Assessment eCRF. The Chronic GVHD Activity 
Assessment source document forms are in Appendix 7. 
7.5 
Quality of Life assessments 
7.5.1 Lee Symptom Scale  
The Lee Symptom Scale (LSS) is a Quality of Life questionnaire used to assess the burden 
of chronic GVHD symptoms) [Lee 2002]. It measures many organ-specific symptoms as 
well as symptoms of fatigue and psychological disorders. Subjects will complete the 
questionnaire at visits indicated in Table 1. 
The LSS instructs the subject to review a list of symptoms and report any that have been 
bothering him/her in the past month and to what extent. It includes 30 items sorted under 


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the following categories: skin; eyes and mouth; breathing; eating and digestion; muscles 
and joints; energy; and mental and emotional. The degree of burden is measured on a 
5-point scale from 0–4 (0 – not at all, 1 – slightly, 2 – moderately, 3 – quite a bit, and 
4 – extremely). 
It is recommended that the LSS is completed prior to any clinical assessments. Subjects 
should complete the LSS while waiting for their appointment before any interaction with 
health care providers to avoid any potential bias in their responses. 
A sample of the LSS is provided as Appendix 8. Subjects will complete the questionnaire 
on a validated paper form that will be collected and transcribed in the eCRF. 
The LSS does not require a license agreement. 
7.5.2 Patient-reported chronic GVHD symptoms (Chronic GVHD Activity 
Assessment Form B) 
7.5.2.1 Skin itching 
Subjects will complete an itching symptoms scale at visits indicated in Table 1. The scale 
requests the subjects to recall their worst itching symptoms in the past 7 days and score it 
on a scale of 0–10 with 0 = not present and 10 = as bad as you can imagine. The 
subject-reported skin-itching scale is part of the Chronic GVHD Activity Assessment 
eCRF. The Chronic GVHD Activity Assessment source document forms are in 
Appendix 7. 
7.5.2.2 Skin and/or joint tightening 
Subjects will complete a skin and/or joint tightening symptoms scale at visits indicated in 
Table 1. The scale requests the subjects to recall their worst skin and/or joint tightening 
symptoms in the past 7 days and score it on a scale of 0–10 with 0 = not present and 10 = as 
bad as you can imagine. The subject-reported skin-itching scale is part of the Chronic 
GVHD Activity Assessment eCRF. The Chronic GVHD Activity Assessment source 
document forms are in Appendix 7. 
7.5.2.3 Mouth sensitivity  
Subjects will complete a mouth sensitivity scale at visits indicated in Table 1. The scale 
requests the subjects to recall their worst mouth sensitivity symptoms in the past 7 days 
and score it on a scale of 0–10 with 0 = Not present and 10 = As bad as you can imagine. 
The subject-reported mouth-sensitivity scale is part of the Chronic GVHD Activity 
Assessment eCRF. The Chronic GVHD Activity Assessment source document forms are 
in Appendix 7. 


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7.5.2.4 Genital discomfort 
Subjects will complete a genital discomfort scale at visits indicated in Table 1. The scale 
requests the subjects to recall their worst genital discomfort symptoms in the past 7 days 
and score it on a scale of 0–10 with 0 = not present and 10 = as bad as you can imagine. 
The subject-reported genital-discomfort scale is part of the Chronic GVHD Activity 
Assessment eCRF. The Chronic GVHD Activity Assessment source document forms are 
in Appendix 7. 
7.5.2.5 Eyes 
Subjects will complete an eyes symptom scale at visits indicated in Table 1. Subjects are 
asked to provide the main complaint with regard to their eyes and the associated severity 
on an 11-point scale ranging from 0–10 with 0 = not at all severe and 10 = most severe. 
The subject-reported eyes-symptoms scale is part of the Chronic GVHD Activity 
Assessment eCRF. The Chronic GVHD Activity Assessment source document forms are 
in Appendix 7. 
7.5.3 Patient-reported global ratings (Chronic GVHD Activity Assessment Form 
B) 
7.5.3.1 Patient-Reported Overall Severity Scale 
The subject will complete the Patient-Reported Overall Severity Scale at visits indicated 
in Table 1. Subjects are asked to score how severe their chronic GVHD symptoms are on 
a scale of 0–10 with 0 = chronic GVHD symptoms not at all severe and 10 = most severe 
chronic GVHD symptoms possible. The Patient-Reported Overall Severity Scale is part of 
the Chronic GVHD Activity Assessment eCRF. The Chronic GVHD Activity Assessment 
source document forms are in Appendix 7. 
7.5.3.2 Patient-Reported Mild-Moderate-Severe Scale 
The subject will complete the Patient-Reported Mild-Moderate-Severe Scale at visits 
indicated in Table 1. Subjects are asked to report if they think their overall chronic GVHD 
is mild, moderate or severe. The Patient-Reported Mild-Moderate-Severe Scale is part of 
the Chronic GVHD Activity Assessment eCRF. The Chronic GVHD Activity Assessment 
source document forms are in Appendix 7. 
7.5.3.3 Patient-Reported 7-Point Change Scale 
The subject will complete the Patient-Reported 7-Point Change Scale at visits indicated in 
Table 1. Subjects are asked to compare their current chronic GVHD symptoms to one 
month prior on a scale of 7: +3 = very much better; +2 = moderately better; +1 = a little 
better; 0 = about the same; −1 = a little worse; −2 = moderately worse; −3 = very much 
worse. The Patient-Reported 7-Point Change Scale is part of the Chronic GVHD Activity 


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Assessment eCRF. The Chronic GVHD Activity Assessment source document forms are 
in Appendix 7. 
7.6 
Exploratory biomarker assessments  
7.6.1 Blood lymphocyte subsets 
S1P1 modulators such as ponesimod reduce total lymphocyte counts (T and 
B lymphocytes) in healthy subjects as a defined PD effect. T- and B-cells consist of 
different subsets having distinct functions in chronic GVHD disease manifestation and 
progression. Analysis of specific blood lymphocyte subsets provides a detailed 
understanding of the ponesimod effect on B and T lymphocyte subsets in a chronic GVHD 
patient population. 
7.6.1.1 Sampling time 
Blood samples for lymphocyte subsets will be taken from every subject at visits indicated 
in Table 1. 
7.6.1.2 Sampling procedure 
Up to 5 mL of blood is collected. 
7.6.1.3 Labeling and shipment 
Details of the collection, labeling and shipment of the samples can be found in the 
laboratory manual provided to the investigator. The tubes and labels for the samples will 
be provided to the investigator and/or staff by the sponsor or the central laboratory. 
7.6.1.4 Bioanalysis 
Blood samples will be analyzed by the sponsor following the principles of GCLP. The 
assays are validated for the purpose of exploration. B- and T-cell subsets are defined by a 
combination of cell surface markers and are analyzed in four separate panels (panel 1–4). 
The specified list of surface markers is not exhaustive. 
• Panel 1: CD19, CD20, IgD, CD27, CD38, CD45, CXCR3, CD138 
• Panel 2: CD3, CD4, CD8, CD45RA, CD25, CD45, CD127, CCR7 
• Panel 3: CD3, CD4, CD8, CCR6, CXCR3, CXCR5, CD45, CRTH2 
• Panel 4: CD45, CD19, CD10, CD21, CD 27, IgD 
7.6.2 Plasma biomarkers 
A recent report on biomarkers for chronic GVHD prepared by the NIH Biomarker Working 
Group identified several candidate biomarkers for the purpose of diagnosis, prognosis/risk 
stratification and prediction of treatment effect [NIH Biomarkers]. Biomarkers with 


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sufficient evidence (cohesive findings in > 2 reports) will be investigated in plasma samples 
using assays validated for the purpose of exploration. 
7.6.2.1 Sampling time 
Plasma samples will be taken from every subject at visits indicated in Table 1. 
7.6.2.2 Sampling procedure 
5 mL of blood is collected in vacutainer tubes containing EDTA as anti-coagulant.  
7.6.2.3 Labeling and shipment 
Details of the collection, labeling and shipment of the samples can be found in the 
laboratory manual provided to the investigator. The tubes and labels for the samples will 
be provided to the investigator and/or staff by the central laboratory. 
7.6.2.4 Bioanalysis 
Plasma samples will be analyzed by the central laboratory. The assays will be validated for 
the purpose of exploration. 
7.6.3 Exploratory biomarker samples 
New scientific evidence on biomarkers related to chronic GVHD or S1P1 modulators may 
trigger new analysis.  
Research samples allow investigation of questions related to: 
A. Change of biomarker level over 24 weeks in a chronic GVHD patient population 
B. Baseline biomarker level in a chronic GVHD patient population 
C. Effect of ponesimod on biomarker level in a chronic GVHD patient population 
Research samples are collected under the core ICF and can be stored by the sponsor for the 
duration specified in the core ICF. 
7.6.3.1 Sampling time 
Blood samples will be taken at visits indicated in Table 1. 
7.6.3.2 Sampling procedure 
5 mL of blood is collected in vacutainer tubes containing EDTA as anticoagulant.  
7.6.3.3 Labeling and shipment 
Details of the collection, labeling and shipment of the samples can be found in the 
laboratory manual provided to the investigator. The tubes and labels for the samples will 
be provided to the investigator and/or staff by the central laboratory. 


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7.7 
Total blood volume 
The total blood volume to be drawn per subject during the Core Treatment Period is 
described in Table 7. 
Table 7 
Total blood volume drawn per subject - Core Treatment Period and 
Follow-up Period 1  
Test 
Number 
of tests 
Volume 
per test 
Total volume per 
scheduled study 
visits 
Viral serology at screening 
1 
 5 mL 
5 mL 
Interferon gamma release assay for tuberculosis at 
screening 
1 
3 × 1 mL 
 3 mL 
Serum sample at baseline1 
1 
 5 mL 
 5 mL 
Hematology2 
12 
3 mL 
36 mL 
Blood chemistry3 
12 
7.5 mL 
90 mL 
Ponesimod pharmacokinetics4 
12 
3 mL 
36 mL 
Blood lymphocyte subsets 
3 
5 mL 
15 mL 
Plasma biomarkers 
3 
5 mL 
15 mL 
Exploratory biomarker samples 
3 
5 mL 
15 mL 
Total blood volume drawn at scheduled study visits: 220 mL 
1. To be stored at the central laboratory for potential retrospective analyses of viral serology titers in the event of 
infections. 
2. Additional samples may be needed in the event of absolute lymphocytes < 100 cells/μL and in case of a second 
serum pregnancy test prior to enrollment. 
3. Includes serum pregnancy or post-menopausal test at screening, if needed. 
4. Additional samples may be needed in the event of additional ECG measurements on Day 1 (Visit 2). 
 
The total blood volume to be drawn per subject during the Extension Treatment Period is 
described in Table 8. 
Table 8 
Total blood volume drawn per subject - Extension Treatment Period 
and Follow-up Period 2  
Test 
Number 
of tests 
Volume 
per test 
Total volume per 
scheduled study 
visits 
Hematology1 
14 
3 mL 
42 mL 
Blood chemistry 
14 
7.5 mL 
105 mL 
Total blood volume drawn at scheduled study visits: 147 mL 
1. Additional samples may be needed in the event of total lymphocytes < 100 cells/μL. 
 
8 
SCHEDULE OF VISITS AND ASSESSMENTS 
A tabulated summary of all visits and assessments described in the following sections is 
provided in Table 1. The schedule of visit dates should be established at the time of 


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screening. To the extent possible, subjects will be expected to adhere to the established 
visit schedule. 
The time point for every visit is defined taking as a reference Day 1 (Visit 2), which is the 
day of enrollment.  
When scheduling the different assessments for a subject visit, the following should be taken 
into account: 
• The subject must come to the clinic before the morning administration of study drug, 
when applicable.  
• At Visit 2 (Day 1), Visit 11 (EX-1) and on the days of re-initiation of study drug (if 
applicable), the assessments during the visits will be divided into two parts: before (pre-
dose) and after (post-dose) the administration of ponesimod, which will be taken at the 
site on the day of visits. 
• At other visits, ECGs, SBP/DBP, PFTs, blood drawings for hematology and blood 
chemistry, along with all other assessments, are to be performed pre-dose.  
• Pre-dose PK samplings are to be done at Visits 2 (Day 1), 3 (Week 4), 4 (Week 8), 
5 (Week 12), 6 (Week 16) and 7 (Week 20). Additional samples are drawn post-dose 
at Visits 2 (Day 1) and 5 (Week 12). At Visit 2, post-dose sampling must be drawn 
hourly at approximately the same time as post-dose ECGs are performed (as per 
Section 7.2.1.1). At Visit 5, the sample is collected 3 hours post-dose. A PK sample is 
also collected at EOT1, Visit 8 (Week 24); no study drug is taken at this visit. 
• Resting time: 
o When the subject is to go to another department within the hospital for a specific 
test, sufficient time should be allowed for the subject to rest prior to the 
examination. 
o Sufficient time between blood drawing and cardiac assessments (i.e., ECGs and/or 
BP measurement) is to be allowed.  
• Preferably, questionnaires will be completed by the subject in the morning prior to any 
other protocol assessment and prior to any other discussion with the investigator. 
Subjects will provide responses to the questionnaires while waiting for their 
appointment. Questionnaires should be completed prior to any discussion with the 
investigator in the following order: 
o Patient-reported chronic GVHD symptoms and patient-reported overall ratings 
(Chronic GVHD Activity Assessments Patient self-report Form B, [Appendix 7]) 
o LSS  
To ensure compliance, at each visit the study personnel must remind WOCBP to use the 
MOC defined for this study. The reminders must be documented in the eCRF. 


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It is permitted to re-screen subjects once if the reason for non-eligibility was transient (e.g., 
abnormal laboratory test, insufficient wash-out period of a forbidden medication), provided 
that documented authorization has been received from Actelion. All pre-enrollment 
assessments should then be repeated at the time of re-screening (with the exception of 
CXR). 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., re-initiation of study drug, AE, central laboratory re-
test, etc.), appropriate assessments may be required or may be performed based on the 
judgment of the investigator and must be recorded in the eCRF. After an unscheduled visit, 
the regular scheduled study visits must continue according to the planned visit and 
assessment schedule. 
8.1 
Screening period 
The screening period must take place within 30 days prior to enrollment and include the 
Visit 1 (screening) and the pre-dose assessments of Visit 2 (Day 1).  
The start of screening occurs on the day the first screening assessment was performed (i.e., 
signature of informed consent). 
8.1.1 Visit 1 (screening) 
Visit 1 will be performed from 30 days to 1 day prior to enrollment. The Visit 1 date is 
defined as the date of the first assessment performed for the study (i.e., informed consent 
signature). During this visit, subject informed consent will be obtained, and assessments 
required for the determination of subject eligibility will be performed. These assessments 
may generally be performed on separate days within the screening period.  
Visit 1 includes: 
• After discussing the study with the investigator and after agreeing to study participation 
by signing the ICF, subjects will be assigned a subject number by the interactive 
response technology (IRT) provider. For any subject, it is the responsibility of the 
investigator to obtain written informed consent (subject’s signature) prior to 
performing any protocol-mandated assessment. However, assessments performed as 
part of the routine care of the subject may be used to assess eligibility. The subject 
number will identify the subject throughout the study. In case of re-screening [see 
Section 8], the subject number assigned during the first screening procedure will be 
retained. 
• Review of chronic GVHD diagnosis and assess stage and score per 2014 NIH 
consensus criteria [Appendix 2] 
• Recording of demographics, medical history, smoking status, and disease 
characteristics 


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• Recording of previous and concomitant medications [see Section 5.2] 
• SBP/DBP 
• Body weight and height 
• Physical examination  
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry, serum pregnancy test for WOCBP and exploratory 
biomarker assessments (blood lymphocyte subsets, plasma biomarkers, exploratory 
biomarker samples) 
• TB test 
• Viral serology 
• Urinalysis 
• 12-lead ECG  
• CXR (any CXR performed within 90 days prior to screening can be used). In case of 
rescreening, CXR does not need to be repeated. 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable. 
The investigator must check inclusion/exclusion criteria. The subject must meet all 
eligibility criteria to be enrolled into the study. Eligibility will be assessed again at Visit 2 
before the subject is enrolled and receives study drug. The reasons for screening failure are 
documented in the eCRF (screening information is collected for all screen failure subjects). 
8.1.2 Visit 2 Enrollment Day 1 (pre-dose) 
The assessments during this visit will be divided into two parts: before (pre-dose) and after 
(post-dose) the administration of ponesimod. During this visit, the inclusion and exclusion 
criteria will be confirmed and baseline assessments will be performed and recorded.  
For WOCBP, the urine or serum pregnancy test at Visit 2 must be performed at least 
21 days or 7 days, respectively, after the serum pregnancy test performed at Visit 1.  
All Visit 2 pre-dose assessments are mandatory and must be performed within the allowed 
time window (described in Section 8.1.2.1). These same assessments may concurrently 
also serve as the Visit 1 screening assessment, if the screening assessment was not 
previously performed. 
8.1.2.1 Visit 2 – Day 1 – pre-dose assessments 
The investigator must check all inclusion/exclusion criteria. Pre-dose assessments include: 


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Assessments performed within 48 hours prior to study drug administration (pre-dose) 
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• Body weight 
• Chronic GVHD Activity Assessments – physician-assessed [Appendix 7 – Form A] 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report 
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Hematology and blood chemistry 
• Urine or serum pregnancy test for WOCBP (must be at least 21 days and at least 7 days 
after Visit 1 serum pregnancy, respectively)  
Assessments performed on the morning of study drug administration (pre-dose) 
• PK/PD samples 
• Recording of change in previous and concomitant medications since Visit 1 
[see Section 5.2] 
• SBP/DBP (under the responsibility of the cardiac safety assessor) 
• 12-lead ECG (under the responsibility of the cardiac safety assessor) 
• Recording of MOC (for WOCBP only) 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable. 
8.2 
Core Treatment Period 
The Core Treatment Period consists of Visits 2 (first study drug administration) to 
8 (Enrollment – Day 1, Week 4, and every 4 weeks thereafter until EOT1 / Week 24).  
8.2.1 Visit 2 – Enrollment Day 1 (post-dose) 
Visit 2 corresponds to the start of the treatment period (Day 1 of the study). The ECGs 
(pre- and post-dose), BP (pre- and post-dose), and first dose administration must be 
performed on the same day and define the date of the visit. This date should preferably 
correspond to the date of enrollment in the IRT system.  
8.2.1.1 Visit 2 - Day 1 - Enrollment and post-dose assessment 
If eligible, the subject should be enrolled in the study, and take the first dose of study drug. 
The subject must be monitored for up to 12 h post-dose. Starting at 4 hours post-dose, the 
cardiac safety assessor must check whether the subject fulfills the hospital discharge 


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criteria [see Section 5.1.7]. Subjects may be discharged from the hospital if they meet the 
discharge criteria before 12 h post-dose but no sooner than 4 h post-dose [see Section 
5.1.7]. 
Visit 2 enrollment and post-dose assessment includes: 
• After confirmation of eligibility (i.e., verification of all entry criteria) by the 
investigator: 
o Enrollment via IRT to obtain study treatment kit number 
o Dispensing of study treatment 
• SBP/DBP hourly for up to 12 h post-dose with a minimum of 4 h post-dose (under the 
responsibility of the cardiac safety assessor) 
• 12-lead ECG hourly for up to 12 h post-dose with a minimum of 4 h post-dose (under 
the responsibility of the cardiac safety assessor) 
• PK sampling hourly for up to 12 h post-dose with a minimum of 4 samples taken. 
• Recording of AEs and SAEs. (Note: On Day 1, significant findings, which in the view 
of the cardiac safety assessor meet the definition of an AE and are resolved at the time 
of discharge of the subject, must be reported to the principal investigator and recorded 
directly on the Adverse Event page of the eCRF.) 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart and the eCRF. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  
Subjects will need to gradually up-titrate from 2 mg to 5 mg during Days 1 to 7. As there 
is no site visit planned until Week 4, subjects will be instructed on how to perform the 
gradual up-titration during Visit 2.  
The subject will be instructed to contact the site if he/she has any questions or problems. 
8.2.2 Visit 3 – Week 4  
The visit window for this visit is ± 3 days. The date of drug dispensing, preferably 
corresponding to the date of registration of the visit in the IRT system, defines the date of 
the visit. Hematology, blood chemistry, urinalysis, spirometry, DLCO and pregnancy tests 
may be performed up to 3 days prior to this visit date. The visits include: 
• Recording of changes in concomitant medications 
• Assessing the MOC and recording in the eCRF (for WOCBP only) 
• SBP/DBP (pre-dose)  


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• 12-lead ECG pre-dose  
• Hematology, blood chemistry (pre-dose, local and central labs) 
• PK sampling (pre-dose) 
• PD sampling (pre-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP  
• Spirometry (pre-dose; under the responsibility of the pulmonologist) 
• DLCO (pre-dose; under the responsibility of the pulmonologist) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any blister wallets 
o not take study treatment on the day of study visit prior to coming to the site. 
8.2.3 Visit 4 – Week 8  
The visit window for this visit is ± 3 days. The date of drug dispensing, preferably 
corresponding to the date of registration of the visit in the IRT system, defines the date of 
the visit. Hematology, blood chemistry, urinalysis, spirometry, DLCO and pregnancy tests 
may be performed up to 3 days prior to this visit date. The visits include: 
• Recording of changes in concomitant medications 
• Assessing the MOC and recording in the eCRF (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Hematology, blood chemistry (pre-dose, local and central labs) 
• PK sampling (pre-dose) 
• PD sample (pre-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP 
• Spirometry (pre-dose; under the responsibility of the pulmonologist) 
• DLCO (pre-dose; under the responsibility of the pulmonologist) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 


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• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any blister wallets 
o not take study treatment on the day of study visit prior to coming to the site 
8.2.4 Visit 5 – Week 12  
The visit window for this visit is ± 7 days. The date of drug dispensing, preferably 
corresponding to the date of registration of the visit in the IRT system defines the date of 
the visit. Spirometry, DLCO, OCT, ophthalmological examination, hematology, blood 
chemistry, urinalysis, spirometry, DLCO and pregnancy tests may be performed up to 7 
days prior to or after this visit date. The visits include: 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
- 
Patient 
self-report 
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Recording of changes in concomitant medications 
• Assessing the MOC and recording in the eCRF (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Physical examination  
• Spirometry (pre-dose; under the responsibility of the pulmonologist) 
• DLCO (pre-dose; under the responsibility of the pulmonologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry (pre-dose) 
• PK sampling (pre-dose and 3 hours post-dose) 
• PD sampling (pre-dose and 3 hours post-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP 
• Chronic GVHD Activity Assessments – physician-assessed [Appendix 7 – Form A] 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 


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• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any bottles or blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  
8.2.5 Visits 6 and 7 - Weeks 16 and 20  
The visit window for these visits is ± 7 days. The date of drug dispensing, preferably 
corresponding to the date of registration of the visit in the IRT system defines the date of 
the visit. Hematology, blood chemistry, urinalysis and pregnancy tests may be performed 
up to 7 days prior to or after this visit date. The visits include:  
• Recording of changes in concomitant medications 
• Assessing and recording of MOC (for WOCBP) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Hematology, blood chemistry (pre-dose)  
• PK sampling (pre-dose) 
• PD sampling (pre-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any bottles or blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  
8.2.6 Visit 8 – EOT1 Visit  
The EOT1 visit will take place at Week 24 (± 7 days) or earlier in case of premature 
discontinuation of study drug. In all cases, the EOT1 visit must take place 1 to 3 days after 
the last dose of study drug. It is strongly preferred that the EOT1 visit takes place 1 day 
after the last dose of study drug. Spirometry, DLCO, hematology, blood chemistry, 
urinalysis and pregnancy tests should be performed 1 to 3 days after the last dose of study 
drug and do not need to be performed on the same day as the EOT1 visit. OCT and the 


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ophthalmological examination may be performed up to 7 days after the last dose of study 
drug. 
The visit includes: 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report  
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Chronic GVHD Activity Assessments - physician assessed [Appendix 7 – Form A] 
• Recording of changes in concomitant medications 
• Assessing and recording of MOC (for WOCBP only) 
• SBP/DBP 
• 12-lead ECG  
• Body weight 
• Physical examination  
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry, PK/PD and exploratory biomarker assessments (blood 
lymphocyte subsets, plasma biomarkers, exploratory biomarker samples) 
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit.  
8.3 
Core Safety Follow-up Period / Follow-up Period 1 
The Follow-up Period 1 consists of the 30-day (+7 day window) post-core treatment safety 
follow-up visit (FU1) and the 90-day (+7 day window) post-core treatment safety follow-
up visit (FU2).  
The EOS visit occurs: 
• At visit FU1 if a subject discontinues study drug prematurely during the Core 
Treatment Period.  


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• At FU2 if the subject does not prematurely discontinue study drug during the Core 
Treatment Period.  
For subjects who completed the 24 week Core Treatment Period: if such a subject enters 
the Extension Treatment Period prior to or on the same day of a scheduled FU1 and/or FU2 
visit, then the respective FU1 and/or FU2 visits are cancelled. If these visits are cancelled 
then EOS occurs only after the subject completes the Extension Safety Follow-up Period 
[Section 8.4.5]. 
8.3.1 Visit 9 - 30-day post-Core Treatment Safety Follow-up visit 1 (FU1) 
The FU1 visit includes: 
• Administer Chronic GVHD Activity Assessment – Patient self-report [Appendix 7  
– Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Chronic GVHD Activity Assessments - physician assessed [Appendix 7 – Form A] 
• Recording of changes in concomitant medications 
• SBP/DBP 
• 12-lead ECG  
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• Hematology, blood chemistry, PD and exploratory biomarker assessments (blood 
lymphocyte subsets, plasma biomarkers, exploratory biomarker samples) 
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Schedule an appointment for next visit and instruct subject to: 
8.3.2 Visit 10 - 90-day post-treatment Safety Follow-up visit 2 (FU2) 
The FU2 visit includes: 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report  
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Chronic GVHD Activity Assessments - physician assessed [Appendix 7 – Form A] 
• Recording of changes in concomitant medications 
• Hematology, blood chemistry  


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• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
8.4 
Extension Treatment Period 
Subjects eligible for the retreatment extension may restart ponesimod at the earliest 7 days 
after Visit 8 (EOT1). Restarting ponesimod requires an up-titration to the maximum 
tolerated dose the subject received during the Core Treatment Period (same dose as at 
EOT1). At the first retreatment extension visit, the subject must be monitored for up to 12 
h post-dose. Starting at 4 h post-dose, the cardiac safety assessor must check whether the 
subject fulfills the cardiac monitoring discharge criteria [see Section 5.1.7]. Subjects may 
be discharged from the cardiac monitoring setting if they meet the discharge criteria before 
12 h post-dose but no sooner than 4 h post-dose [see Section 5.1.7]. 
8.4.1 Visit 11 (EX-1)  
Assessments performed within 48 hours prior to study drug administration (pre-dose) 
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• Body weight 
• Physical examination 
• Chronic GVHD Activity Assessments – physician-assessed [Appendix 7 – Form A] 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report  
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Hematology and blood chemistry 
Assessments performed on the morning of study drug administration (pre-dose) 
• PD samples 
• Recording of change in previous and concomitant medications since FU visit of the 
Core Treatment Period (FU1 or FU2) 
• Urine pregnancy test for WOCBP (if applicable) 
• SBP/DBP (under the responsibility of the cardiac safety assessor) 
• 12-lead ECG (under the responsibility of the cardiac safety assessor) 
• Recording of MOC (for WOCBP only) 
• Recording of AEs/SAEs 
Dosing and assessments performed post-dose 


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• After confirmation of eligibility (i.e., verification of all entry criteria) by the 
investigator: 
o IRT to obtain study treatment kit number 
o Dispensing of study treatment 
• SBP/DBP hourly for up to 12 h post-dose with a minimum of 4 h post-dose (under the 
responsibility of the cardiac safety assessor) 
• 12-lead ECG hourly for up to 12 h post-dose with a minimum of 4 h post-dose (under 
the responsibility of the cardiac safety assessor) 
• Recording of AEs and SAEs. (Note: On Day EX-1, significant findings, which in the 
view of the cardiac safety assessor meet the definition of an AE and are resolved at the 
time of discharge of the subject, must be reported to the principal investigator and 
recorded directly on an Adverse Event page of the eCRF.) 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart and the eCRF. 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  
Subjects will need to gradually up-titrate to their previously tolerated dose within EX- Days 
1 to 14.  
The subject will be instructed to contact the site if he/she has any questions or problems. 
8.4.2 Visits 12, 13, 15, and 16 (EX-2, EX-3, EX-5, and EX-6), Extension Weeks 4, 8, 
16, and 20 
The visit window for these visits is +/– 7 days. 
• Recording of changes in concomitant medications 
• Assessing and recording of MOC (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose)  
• Hematology, blood chemistry  
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 


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o bring back any bottles or blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  
8.4.3 Visits 14, 17, 18, 19, 20, 21, and 22 (EX-4, EX-7, EX-8, EX-9, EX-10, EX-11, 
and EX-12), Extension Weeks 12, 24, 36, 48, 60, 72, and 84 
The visit window for these visits is +/– 7 days. 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report  
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Chronic GVHD Activity Assessments - physician assessed [Appendix 7 – Form A] 
• Recording of changes in concomitant medications 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose)  
• Assessing and recording of MOC (for WOCBP only) 
• Body weight 
• Physical examination  
• Spirometry (pre-dose; under the responsibility of the pulmonologist) 
• DLCO (pre-dose; under the responsibility of the pulmonologist) 
• OCT, visit EX-4 only (under the responsibility of the ophthalmologist) 
• Ophthalmological examination, visit EX-4 only (under the responsibility of the 
ophthalmologist) 
• Hematology, blood chemistry (pre-dose) 
• PD sampling (pre-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart 
• Schedule an appointment for next visit and instruct subject to: 
o bring back any bottles or blister wallets 
o not take study treatment on the day of study visit prior to coming to the site  


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8.4.4 Visit 23 (EX-13, EOT2) Extension Week 96  
The EOT2 visit will take place at Week 96 (± 7 days) or earlier in case of premature 
discontinuation of study drug. In all cases, the EOT2 visit must take place within 3 days 
after the last dose of study drug. It is strongly preferred that the EOT2 visit takes place 
1 day after the last dose of study drug. Spirometry, DLCO, hematology, blood chemistry, 
urinalysis and pregnancy tests should be performed within 3 days after the last dose of 
study drug and do not need to be performed on the same day as the EOT2 visit. OCT and 
the ophthalmological examination may be performed up to 7 days after the last dose of 
study drug. 
The visit includes: 
• Administer 
Chronic 
GVHD 
Activity 
Assessment 
– 
Patient 
self-report  
[Appendix 7 – Form B] 
• Administer LSS (subject completes the questionnaire after patient self-report but prior 
to any clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment) 
• Chronic GVHD Activity Assessments - physician assessed [Appendix 7 – Form A] 
• Recording of changes in concomitant medications 
• SBP/DBP 
• 12-lead ECG  
• Assessing and recording of MOC (for WOCBP only) 
• Body weight 
• Physical examination  
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry  
• PD sampling  
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call  
• Remind WOCBP to use the MOC defined for this study. The reminders must be 
documented in the hospital chart 
• Schedule an appointment for next visit and instruct subject to: 


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8.4.5 Extension Safety Follow-up Period (Follow-up Period 2) 
Subjects enrolled in the Extension Treatment Period will be followed for 30 days after the 
last dose of study drug. The safety follow-up 3 visit (FU3) occurs 30 days (+7 day window) 
after the last dose of study drug. This is the EOS visit. 
The FU3 visit includes: 
• Recording of changes in concomitant medications 
• Assessing and recording of MOC (for WOCBP only) 
• SBP/DBP 
• 12-lead ECG 
• Spirometry (under the responsibility of the pulmonologist) 
• DLCO (under the responsibility of the pulmonologist) 
• Hematology, blood chemistry 
• PD sampling  
• Urinalysis  
• Urine pregnancy test for WOCBP (if applicable) 
• Recording of AEs and SAEs 
8.5 
Unscheduled visits 
An unscheduled site visit may be performed at any time during the study (between 
scheduled visits), as necessary, based on the investigator’s discretion. These visits include 
(but are not limited to) those performed due to safety (e.g., occurrence of an AE, laboratory 
abnormalities), administration of study drug (e.g., re-initiation of study drug requiring up-
titration, return of unused study medication, need to initiate treatment with a QT-
prolonging drug), and/or other health-related issues. 
The date of the visit and the reason for such visits as well as any data related to study 
assessments performed at unscheduled visits will be recorded in the eCRF. 
8.5.1 Visits for re-initiation of study drug 
As described in detail in Section 5.1.8, subjects may need to be monitored at the study site 
when re-initiating study drug following a study drug treatment interruption. 
The following assessments/procedures need to be done during the re-initiation visit: 
• Recording of changes in concomitant medications 
• Assessing and recording of MOC (for WOCBP only) 
• Hematology, blood chemistry (pre-dose)  
• SBP/DBP (pre-dose) 


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• SBP/DBP hourly for up to 12 h post-dose (under the responsibility of the cardiac safety 
assessor) with a minimum of 4 h post-dose. 
• 12-lead ECG (pre-dose) 
• 12-lead ECG hourly for up to 12 h post-dose (under the responsibility of the cardiac 
safety assessor) with a minimum of 4 h post-dose.  
• Urine pregnancy test for WOCBP (if applicable) 
• IRT call and study drug dispensing 
• The discharge criteria will be applied as described for Day 1. Subjects may be 
discharged from the hospital if they meet the discharge criteria before 12 h post-dose 
but no sooner than 4 h post-dose [see Section 5.1.7] 
• Recording of AEs and SAEs. 
The date of visit and any data related to study assessments performed during this visit (12-
lead ECGs, SBP/DBP) will be reported on the specific eCRF pages for unscheduled visit 
for re-initiation requiring up-titration of study drug.  
These visits for the cardiac monitoring of the subjects when re-initiating study drug are 
additional unscheduled visits. The regular scheduled study visits must be resumed 
according to the original visit and assessment schedule. If the visit occurs at the same time 
as a regular visit, all non-redundant regular visit assessments have to be performed as well. 
8.5.2 Unscheduled visits for reasons other than re-initiation of study drug 
Unscheduled visits may be performed at any time during the study for reasons other than 
re-initiation of study drug. Depending on the reason for the unscheduled visit (e.g., loss of 
efficacy, AE, etc.), appropriate assessments may be performed based on the judgment of 
the investigator and must be recorded in the eCRF. After an unscheduled visit, the regular 
scheduled study visits must continue according to the planned visit and assessment 
schedule. 
Unscheduled visit assessments may include: 
• Assessment of concomitant medications 
• Assessment of MOC (for WOCBP only) 
• PFTs 
• SBP/DBP (pre-dose) 
• 12-lead ECGs (e.g., in case of need of concomitant treatment with a QT prolonging 
drug with known risk of Torsades de Pointes [see Appendix 3], pre-dose).  
• Ophthalmological examination 
• OCT (e.g., presence of visual symptoms suggestive of macular edema) 
• Spirometry (under the responsibility of the pulmonologist) 


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• DLCO (under the responsibility of the pulmonologist) 
• Physical examination 
• Measurement of body weight 
• Complete laboratory tests including: hematology, blood chemistry, urinalysis, or serum 
pregnancy test (for WOCBP only) 
• Assessment of AEs and SAEs 
• Return of study drug blisters and unused medication and dispensing of new blisters, if 
appropriate. 
Additional unscheduled spirometry will have to be conducted in the event of respiratory 
symptoms (e.g., dyspnea) during the course of the study. Administration of inhaled 
short-acting ß2 agonists (e.g., albuterol/salbutamol) for symptom relief may be performed 
at the discretion of the investigator. Administration of short-acting ß2 agonists will be 
collected in the eCRF. 
If any of the laboratory parameters listed in Section 7.3.11.2 need to be analyzed, this must 
be done at the central laboratory, except in case of emergency; if it has been done at a local 
laboratory, results must be recorded in the eCRF [see Section 7.3.11]). 
9 
STUDY COMPLETION AND POST-STUDY 
TREATMENT/MEDICAL CARE 
9.1 
Study completion 
For an individual subject, EOS is reached when treatment and post-treatment safety follow-
up periods have been completed.  
The reason(s) for discontinuing the study along with, if applicable, who made the decision 
(subject, investigator or Actelion) must be recorded in the eCRF.  
EOS on a study level occurs at the time all subjects have completed their EOS visits, as 
described above. 
9.2 
Premature withdrawal from study 
Subjects may voluntarily withdraw from the study for any reason at any time. Subjects are 
considered withdrawn if they state an intention to withdraw further participation in all 
components of the study, die or are lost to follow-up for any other reason. The investigator 
may withdraw a subject from the study (without regard to the subject’s consent) if, on 
balance, they believe that continued participation in the study would be contrary to the best 
interests of the subject. Withdrawal from the study may also result from a decision by 
Actelion for any reason, including premature termination or suspension of the study [see 
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Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual fail. The site must take preventive measures to avoid a 
subject being lost to follow-up (e.g., document different ways of contact such as telephone 
number, home address, e-mail address, person to be contacted in case the subject cannot 
be reached). If the subject cannot be reached, the site must make a reasonable effort to 
contact the subject, document all attempts and enter the loss of follow-up information into 
the eCRF. The following methods must be used: at least three telephone calls must be 
placed to the last available telephone number and one registered letter must be sent by post 
to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., site staff visit to the subject’s home), 
respecting the subject’s right to privacy. If the subject is still unreachable after all contact 
attempts listed above, he/she will be considered to be lost to follow-up.  
If premature withdrawal occurs for any reason, the reason for premature withdrawal from 
the study, along with who made the decision (subject, investigator or Actelion) must be 
recorded in the eCRF. 
If, for whatever reason (except death or loss-to-follow-up), a subject was withdrawn from 
the study, the investigator should make efforts to conduct a last visit/contact to assess the 
safety and well-being of the subject, collect unused study drug and discuss follow-up 
medical care. The investigator must provide follow-up medical care for all subjects who 
are prematurely withdrawn from the study, or must refer them for appropriate ongoing care, 
as described in Section 9.4. 
9.3 
Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If a study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IRBs/IECs and health authorities, as appropriate, and provide the reasons 
for the suspension or termination.  
If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 9.2 for subjects prematurely 
withdrawn from the study. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
subjects’ interests. 
In addition, if the investigator suspends or terminates a study without prior agreement from 
Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and provide 
both with a detailed written explanation of the termination or suspension. 


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If the IRB/IEC suspends or terminates its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 
9.4 
Medical care of subjects after study completion / withdrawal from 
study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s)/medical care is 
necessary and available according to local regulations.  
10 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom or disease that occurs in a subject during the course 
of the study (beginning with signing of the ICF), whether or not considered by the 
investigator as related to study treatment.  
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 30 days2 after study treatment discontinuation) 
whether or not considered by the investigator as related to study treatment. 
AEs include: 
• 
Exacerbation of a pre-existing disease. 
• 
Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• 
Disease or medical condition detected or diagnosed during the course of the study 
even though it may have been present prior to the start of the study. 
• 
Continuous persistent disease or symptoms present at study start that worsen 
following the start of the study. 
• 
Abnormal assessments, e.g., change on physical examination or ECG findings if 
they represent a clinically significant finding that was not present at study start or 
worsened during the course of the study. 
• 
Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the 
                                                 
 
 
2 Should cover at least 5 elimination half-lives, if more than 30 days. 


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course of the study or led to dose reduction, interruption or premature 
discontinuation of study treatment. 
Overdose, misuse and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study drug log of the eCRF. 
10.1.2 Intensity of adverse events 
The severity of AEs will be classified according to the common terminology criteria for 
adverse events (CTCAE) version 4.03 (June 2010) [NCI 2010]. Grades 1 through 5 refer 
to the severity of the AE, which are based on general guidelines described below. Not all 
grades are appropriate for each AE. Therefore, the CTCAE may list some AEs with less 
than five options for grade selection. 
If the intensity/seriousness of an AE worsens during the course of the study, a new AE 
eCRF page must be completed. The onset date of this new AE corresponds to the date of 
worsening. If the AE lessens in intensity/seriousness, no change in the severity is required. 
The five grades of severity are defined as follows: 
 Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. The event may be noticeable to the subject. It does not influence 
daily activities, and usually does not require intervention. 
 Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living that refer to preparing meals, shopping for groceries 
or clothes, using the telephone, managing money etc. 
 Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living that refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medication, and not bedridden. 
 Grade 4 
Life-threatening consequences; urgent intervention indicated. 
 Grade 5 
Death related to AE. 
An AE of grade 1–3 may or may not be serious [see Section 10.1.1]. These grading terms 
are used to describe the severity of a specific event. Medical judgment should be used on 


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a case-by-case basis. Any AE reported with a toxicity level of grade 4 or grade 5 indicates 
a level of seriousness that must be reported as an SAE [refer to Section 10.1.2 for 
definitions of SAEs]. 
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations. 
10.1.3 Relationship to study treatment  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment and reported as either related or 
unrelated. The determination of the likelihood that the study drug caused the AE will be 
provided by an investigator who is a qualified physician. 
10.1.4 Adverse events associated to study design or protocol-mandated procedures 
An AE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of the underlying disease. 
10.1.5 Reporting of adverse events 
10.1.5.1 Subjects prematurely discontinued from the Core Treatment Period 
All AEs occurring after study start (i.e., signing of informed consent) and up to 30 days 
after study treatment discontinuation must be recorded on specific AE pages of the eCRF. 
10.1.5.2 Subjects not prematurely discontinued from the Core Treatment Period and 
not entering the Extension Treatment Period  
All AEs occurring after study start (i.e., signing of informed consent) and up to 90 days 
after study treatment discontinuation must be recorded on specific AE pages of the eCRF. 
10.1.5.3 All Subjects entering the Extension Treatment Period  
All AEs occurring on or after study start (i.e., signing of informed consent) and up to 
30 days after study treatment discontinuation must be recorded on specific AE pages of the 
eCRF. 
10.1.6 Follow-up of adverse events 
AEs still ongoing more than 30 days after study treatment discontinuation must be followed 
up until they are no longer considered clinically relevant. 


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10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• 
Fatal. 
• 
Life-threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• 
Requiring inpatient hospitalization, or prolongation of existing hospitalization. 
• 
Resulting in persistent or significant disability or incapacity. 
• 
Congenital anomaly or birth defect. 
• 
Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered 
to 
be 
SAEs 
when 
– 
based 
upon 
appropriate 
medical 
judgment 
– they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definitions above.  
The following reasons for hospitalization are exempted from being reported:  
• 
Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• 
Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that 
did not worsen, e.g., hospitalization for coronary angiography in a subject with 
stable angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (for example if 
a complication prolongs hospitalization). 
10.2.1.2 Serious adverse events associated with the study design or protocol-mandated 
procedures  
An SAE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of the underlying disease or a 
complication of an invasive procedure that is specifically required by the protocol. 


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10.2.2 Reporting of serious adverse events  
10.2.2.1 During screening period  
All SAEs that occur after study start (i.e., signing of informed consent) must be reported 
(whether considered associated or not associated with study design or study-mandated 
procedures).  
These SAEs must be reported on an SAE form and also in the eCRF.  
10.2.2.2 During Core Treatment Period and Extension Treatment Period 
All SAEs, regardless of investigator-attributed causal relationship, must be reported. 
These SAEs must be reported on an SAE form and also on the AE pages in the eCRF. 
10.2.2.3 During the follow-up period for subjects prematurely discontinued from the 
Core Treatment Period 
All SAEs, regardless of investigator-attributed causal relationship, which occur during the 
follow-up period up to 30 days after study treatment discontinuation must be reported on 
AE pages in the eCRF and on an SAE form. 
10.2.2.4 During follow-up period for subjects not prematurely discontinued from the 
Core Treatment Period and not entering the Extension Treatment Period 
All SAEs, regardless of investigator-attributed causal relationship, which occur during the 
follow-up period up to 90 days after study treatment discontinuation must be reported on 
AE pages in the eCRF and on an SAE form. 
10.2.2.5 During follow-up period for all subjects entering the Extension Treatment 
Period 
All SAEs, regardless of investigator-attributed causal relationship, which occur during the 
follow-up period up to 30 days after study treatment discontinuation must be reported on 
AE pages in the eCRF and on an SAE form. 
10.2.3 Follow-up of serious adverse events  
SAEs still ongoing at the EOS visit must be followed up until resolution or stabilization, 
or until the event outcome is provided, e.g., death.  
10.2.4 After the follow-up period  
New SAEs occurring after the follow-up period must be reported to the Actelion drug 
safety department within 24 hours of the investigator’s knowledge of the event, only if 
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10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment.  
The SAE forms must be faxed to the Actelion drug safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English and 
must assess the causal relationship of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The Actelion drug safety department may contact the investigator 
to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The reference safety document to assess expectedness of a suspect serious adverse reaction 
and reported by the sponsor to health authorities, ECs/IRBs and investigators is the 
reference safety information section of the Investigator’s Brochure [Ponesimod IB].  
The SAEs listed below are commonly seen with the underlying disease and are therefore 
expected to occur in this subject population. These SAEs will be treated as 
“disease-related” and expected (unless fatal) and will therefore not require expedited 
reporting to health authorities, IRBs/IECs, and investigators. However, these events will 
be monitored during the study by the sponsor and by the Study Monitoring Committee: 
• 
Relapses of the underlying leukemia and complications. 
10.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.  
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during the 
study including during the 30 days following study treatment discontinuation must be 
reported within 24 hours of the investigator’s knowledge of the event.  


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Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion drug safety department (see contact details provided on the Actelion Pregnancy 
form), and on an AE page in the eCRF. 
Male contraception 
Nonclinical studies have shown no evidence of an effect on male reproductive organs 
during the administration of ponesimod. It is considered very unlikely that a significant 
dose of ponesimod would be delivered to the female by seminal transfer and the potential 
risk of harm to a human fetus is considered to be very small, based on the high safety 
margins of 1730 to 1920 for estimated exposure to ponesimod potentially achieved in 
human females via seminal fluid transfer. Therefore, there is no specific recommendation 
for male contraception. (Note: For allowed concomitant therapies during this trial that 
require male contraception, the respective method of contraception must be applied.) 
10.3.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to the 
Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
drug discontinuation must be reported on separate AE pages in the eCRF. Any SAE 
occurring during pregnancy must be reported on an SAE form as described in 
Section 10.3.1. 
10.4 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
project-specific labs/examinations as required) is monitored and reviewed on a continuous 
basis by the Actelion clinical team (in charge of ensuring subjects’ safety as well as data 
quality) by periodically monitoring clinical studies’ activities from protocol conception to 
database closure. In addition, an SMC is monitoring safety data [see Section 3.5]. 


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11 
STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated contract research 
organizations supervised by Actelion. 
The Statistical Analysis Plan (SAP) will be approved prior to database lock for the final 
analyses. The SAP provides the full details of all analyses, data displays, and algorithms to 
be used for data derivations. 
All data will be listed, and endpoints will be summarized by appropriate descriptive 
statistics (tables or figures), typically including: 
• 
Number of non-missing observations, number of missing observations, mean, standard 
deviation (STD), median, Q1, Q3, minimum and maximum for continuous endpoints; 
• 
Number of non-missing observations, number of missing observations and frequency 
with percentage per category (percentages based on the number of non-missing 
observations) for categorical endpoints; 
• 
Number of subjects at risk, cumulative number of events, cumulative number of 
censored observations and Kaplan-Meier estimates of the survival function for 
time-to-event endpoints. 
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
A percentage (relative) change from baseline is defined as the absolute change from 
baseline divided by the baseline value (if the baseline value not equal 0) multiplied by 100. 
11.1 Analysis sets 
11.1.1 Screened analysis set 
This analysis set includes all subjects who were screened and received a subject number. 
11.1.2 Full analysis set 
The Full analysis set (FAS) includes all subjects who received at least one dose of study 
medication. 
11.1.3 Per-protocol set 
The Per-protocol set (PPS) is defined as subjects from the FAS without any major protocol 
deviations. The most important protocol deviations include: 
• Subject failing to reach the Week 24 assessment, i.e., by discontinuing treatment early 
or for any other reason than lack of efficacy or death 
• Subject withdrawing consent before the Week 24 assessment 


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• Subjects not adhering to the treatment regimen (mandatory concomitant medication, 
up-titration, study drug) 
• Subject receiving prohibited concomitant therapy 
• Start of any other IS systemic therapies during the course of the trial  
Additional details of the definition of the PPS will be described in the SAP. 
11.1.4 Safety set 
The Safety set (SAF) is defined like the FAS. 
11.1.5 PD analysis set 
The PD analysis set (PDS) includes all subjects who received at least 4 weeks of study 
treatment and have an absolute lymphocyte count measurement at baseline and at least one 
measurement between the Week 4 visit and Week 12 visit. 
11.1.6 PK analysis set 
The PK analysis set (PKS) includes all subjects from the SAF, who provided at least one 
blood sample. 
11.1.7 Extension set  
The extension set (ES) includes all subjects enrolled in the Extension Treatment Period 
who received at least one dose of ponesimod in the Extension Treatment Period. 
11.1.8 Usage of the analysis sets 
The primary analysis is based on the PD variable and will be performed on the PDS (main 
analysis) and on the FAS as well. Sensitivity analyses of the primary analysis will be 
performed based on the PDS and FAS. 
All Safety variables will be analyzed using the SAF.  
Exploratory efficacy variables will be analyzed using both FAS and PPS, as applicable. 
Details will be provided in the SAP. 
Quality of Life endpoints will be analyzed based on the FAS. 
PK evaluations will be analyzed using the PKS, and PD evaluations (other than primary 
PD variable) will be analyzed based on the PDS. 
All safety and efficacy endpoints in the Extension Treatment Period will be analyzed on 
the ES. 


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11.2 Variables 
11.2.1 Primary PD variable 
The change in absolute lymphocyte count from baseline to Week 4, Week 8 and Week 12 
in the Core Treatment Period is defined as:  
• 
 = Absolute lymphocyte count for dose d – absolute lymphocyte count at baseline  
The change in absolute lymphocyte counts ( ) is assessed at Week 4 for the 5 mg dose, at 
Week 8 for 10 mg and at Week 12 for 20 mg in the Core Treatment Period. 
11.2.2 Safety variables 
The following safety endpoints/variables will be analyzed. The SAP will summarize these 
analyses in more detail. Safety endpoints will be analyzed from first study drug intake up 
to 30 days (inclusive) after last study drug intake. 
Overall safety endpoints 
• Treatment-emergent AEs, SAEs, and AEs of special interest  
• AEs leading to premature discontinuation of study drug 
• Deaths 
Absolute lymphocyte count 
• Treatment-emergent absolute lymphocyte count < 0.2 × 109/L (< 200 cells/mm3) 
Cardiac rate and rhythm safety endpoints 
• Treatment-emergent morphological ECG abnormalities  
• Change in 12-lead ECG variables (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to 
selected post-dose assessments (1h, 2h, 3h, 4h) on Day 1 and on day(s) of re-initiation 
of study drug 
• Notable abnormalities for selected 12-lead ECG variables (HR, PR, QT, QTc) at 3 h 
post-dose assessment on Day 1 and pre-dose on Weeks 4, 8, 12, and 24 (notable 
abnormalities definition in Appendix 6) 
• Cardiac safety events will include:  
o Treatment-emergent QTc > 450 ms (male), > 470 ms (female), > 500 ms 
(male), and > 520 ms (female) 
o Treatment-emergent QTc increase from baseline > 30 ms, > 60 ms 
o Other treatment-emergent abnormalities observed by 12-lead ECG 
o Treatment-emergent (serious) cardiac AEs of special interest. 


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Pulmonary function safety endpoints 
• Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values 
• Treatment-emergent decrease of percent of predicted FEV1 or FVC > 20% from 
baseline values 
• Change in FEV1 and FVC from baseline, absolute and % of absolute change to all visits 
up to FU1 
• Among subjects with a decrease of > 200 mL and > 12% in FEV1 or FVC, respectively, 
from baseline to EOT1, reversibility defined as a decrease of < 200 mL and < 12% in 
FEV1 or FVC, respectively, from baseline to last available follow-up 
• Change from baseline to FU1 vs change from baseline to EOT1, in FEV1 or FVC 
(absolute and % of predicted) 
• Change in lung diffusion capacity as assessed by DLCO expressed in absolute change 
and % of predicted value from baseline to all time points up to FU1 
• Change from baseline to FU1 vs change from baseline to EOT1 in DLCO (absolute and 
% of predicted) 
• (Serious) pulmonary AEs of special interest  
• Withdrawal due to pulmonary reasons/AE 
Other safety endpoints 
• Treatment-emergent notable BP abnormalities [definition in Appendix 6]. 
• Treatment-emergent notable laboratory abnormalities [definition in Appendix 6]. 
11.2.3 Exploratory efficacy variables 
The exploratory endpoints are defined as follows: 
• Achievement of a partial or complete overall response at 24 weeks post enrollment 
(per NIH Consensus Development Project response criteria) 
Definitions for the efficacy endpoint are based on the draft 2014 NIH Consensus 
Guidelines [see Appendix 7]. 
Baseline or subsequent organ abnormalities that are not due to chronic GVHD are not 
evaluable for response (at the organ level). 
Complete overall response definition: 
A complete response is defined as resolution of all reversible manifestations due to chronic 
GVHD in the following organs at the Week 24 assessment, resulting in: 
• Skin: NIH Skin Score of 0 after previous involvement 
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• Liver: normal ALT, alkaline phosphatase, and TBL after previous elevation of one or 
more 
• Upper GI: NIH Upper GI Score of 0 after previous involvement 
• Lower GI: NIH Lower GI Score of 0 after previous involvement 
• Esophagus: NIH Esophagus Score of 0 after previous involvement 
• Lungs: normal FEV1 absolute value after previous involvement (normalization to FEV1 
≥ 80% predicted is considered a complete response) 
• Eyes: NIH Eye Score of 0 after previous involvement 
• Joint/fascia: Both NIH Joint and Fascia Score of 0 and photographic range of motion 
(P-ROM) score of 25 after previous involvement by at least one measure 
• Global: Clinician Overall Severity Score of 0 
Partial overall response definition:  
A partial overall response is defined as improvement in a measure for at least one organ 
without progression in measures for any other organ. The proposed general guideline for 
defining partial response in a specific organ requires a change in score from baseline as 
follows: 
• Skin: decrease in NIH Skin Score by at least 1 point 
• Mouth: decrease in Modified Oral Mucositis Score by at least 2 points 
• Liver: decrease by 50% in ALT, alkaline phosphatase, or TBL 
• Upper GI: decrease in NIH Upper GI Score by at least 1 point 
• Lower GI: decrease in NIH Lower GI Score by at least 1 point 
• Esophagus: decrease in NIH Esophagus Score by at least 1 point 
• Lungs: increase by at least 10% predicted absolute value of FEV1, as long as initial 
FEV1 < 70% predicted  
• Eyes: decrease in NIH Eye Score by at least 1 point 
• Joint/fascia: decrease in NIH Joint and Fascia Score by 1 or more points or increase in 
P-ROM score by 1 or more points for any site 
• Global: Clinician Overall Severity Score decreases by 2 or more points on a  
0–10 scale 
The proposed general guideline for defining progression in a specific organ requires a 
change in score from baseline as follows: 
• Skin: increase in NIH Skin Score by at least 1 point, except from 0 to 1 
• Mouth: increase in Modified Oral Mucositis Score by at least 2 points 


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• Liver: increase by ≥ 2 × ULN for ALT, alkaline phosphatase or TBL 
• Upper GI: increase in NIH Upper GI Score by at least 1 point, except from 0 to 1 
• Lower GI: increase in NIH Lower GI Score by at least 1 point, except from 0 to 1 
• Esophagus: increase in NIH Esophagus Score by at least 1 point, except from 0 to 1 
• Lungs: decrease by at least 10% absolute value of FEV1, as long as final FEV1 < 70% 
predicted 
• Eyes: increase in NIH Eye Score by at least 1 point, except from 0 to 1 
• Joint/fascia: increase in NIH Joint and Fascia Score by 1 or more points or decrease in 
P-ROM score by 1 or more points for any site 
• Global: Clinician Overall Severity Score increases by 2 or more points on a  
0–10 scale 
The endpoint is reached if the subject is considered a partial or complete responder at Week 
24. The remaining subjects will be considered as non-responders, this includes subjects 
with stable disease and subjects with mixed response (defined as complete or partial 
response in at least one organ accompanied by progression in another organ). Patients who 
discontinue the study prior to the Week 24 assessment are considered non-responders. 
• Need for rescue therapy for chronic GVHD 
o Rescue therapy is the addition of any new systemic or topical IS therapy or 
exceeding baseline dose for any non-steroid IS or exceeding glucocorticoid 
dose equivalent to prednisone > 1 mg/kg/day 
This exploratory endpoint is defined as a binary endpoint. Subjects will be considered as 
responders in case no rescue therapy is administered; subjects will be considered as 
non-responders in case subjects received a rescue therapy during the treatment phase for at 
least one day. Every effort will be made to collect the concomitant medications data with 
complete start dates in order to make sure the endpoint is derived correctly. Patients who 
discontinue the study prior to the Week 24 assessment are considered non-responders. 
• Partial or complete organ-specific response for the specific organ manifestation at 
Week 12 and Week 24 in subjects with a specific organ manifestation of chronic 
GVHD 
o Affected organs limited to 2014 NIH consensus criteria organs of skin, eyes, 
mouth, esophagus, upper GI, lower GI, liver, lungs, and joints and fascia 
This endpoint is a binary sub-endpoint of the first exploratory endpoint (see above), split 
by organ. The endpoint will be derived in the same way as described above but at an organ 
level. The endpoint will be evaluated independently at the Week 12 and Week 24 
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Only subjects with manifestations at baseline or subjects developing manifestations during 
the study at the corresponding organ will be included in the analyses of the sub-endpoints. 
Patients who discontinue the study prior to the Week 24 assessment are considered non-
responders. 
• Partial or complete overall response at Week 12 
This binary endpoint is defined like the first exploratory endpoint (see above) but at the 
Week 12 assessment.  
• Complete response at 24 weeks 
A responder of this binary endpoint is defined as reaching a complete response at the Week 
24 assessment. A non-responder is defined as reaching a partial or mixed response or no 
response (stable disease or progression) at the Week 24 assessment or dropping out of the 
study prior to the Week 24 assessment. 
• Partial or complete overall response at latest evaluable assessment during the core study 
(Week 12 and Week 24) 
• Average glucocorticoid daily dose over 24 weeks versus baseline dose 
The average dose is defined as the sum of all doses of glucocorticoid received, adjusted by 
the time in days. 
• Percent glucocorticoid dose at Week 24 versus baseline.  
This exploratory endpoint is defined as the percentage of the glucocorticoid dose received 
at the Week 24 assessment compared to the dose received at baseline. 
11.2.4 Other variables 
Quality of Life endpoints 
The Quality of Life endpoints are defined in Section 6.4. 
• Change from baseline to Week 12 and Week 24 in LSS for chronic GVHD 
[Appendix 8] 
• Change from baseline to Week 12 and Week 24 in each of the subject-reported chronic 
GVHD symptoms (skin, eyes, mouth and genitals [Appendix 7 – Form B]). 
• Change from baseline to Week 12 and Week 24 in each of the subject-reported global 
ratings (Mild-Moderate-Severe Scale, Overall Severity Scale and 7-Point Change Scale 
[Appendix 7 – Form B]). 


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PK evaluations 
• Ctrough concentrations of ponesimod at Day 1, and Weeks 4, 8, 12, 16, and 20 (all 
samples pre-dose), and Week 24 
• Ponesimod concentration 3 hours post-dose at Day 1 and Week 12 
PD evaluations 
• Peripheral absolute blood lymphocyte count change from baseline (pre-dose on Day 1) 
to Weeks 4, 8, 12, 16, 20, 24, and FU1, and change from pre-dose Week 12 to 3 hours 
post-dose Week 12. 
• Peripheral absolute lymphocyte count reversibility from EOT1 to FU1 all expressed in 
absolute change and percent change from baseline 
PK/PD relationship 
• The PK and selected efficacy and safety variables will be correlated with the PD 
(peripheral absolute lymphocyte count and magnitude of reduction of lymphocyte 
count). If deemed appropriate, the PK will also be correlated with selected safety 
variables. 
11.2.5 Variables in Extension Treatment Period 
Variables in the Extension Treatment Period will be defined in the same way as defined in 
the treatment and follow-up periods of the Core Treatment Period and will be fully 
described in the SAP. As the Extension Treatment Period exceeds the Core Treatment 
Period by 72 weeks the time points of analysis will be adapted appropriately for all relevant 
endpoints. The visit EX-1 (Visit 11) will be considered as the baseline visit in the Extension 
Treatment Period. 
11.2.6 Overall testing strategy of the PD variable 
The primary analysis of this study is based on the absolute lymphocyte counts at 
pre-specified time points. Hypotheses are setup to establish a within-subject dose response 
at baseline vs the Week 4 (5 mg), Week 8 (10 mg) and Week 12 (20 mg) assessments in 
the Core Treatment Period. 
11.2.7 Analysis of the primary PD variable(s) 
11.2.7.1 Hypotheses and statistical model 
The null hypothesis is that there is no dose response on the change from baseline in absolute 
lymphocyte counts ld in the intra-subject dose escalation within the first 12 weeks of 


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treatment, and the alternative hypothesis is the existence of any intra-subject dose response 
within the first 12 weeks of treatment:  
𝐻𝐻0: 𝑙𝑙𝑑𝑑≥ 0 for all doses d = 5, 10, 20 mg 
                                        vs 
𝐻𝐻1: 𝑙𝑙𝑑𝑑<  0 for at least 1 dose d = 5, 10, 20 mg 
11.2.7.2 Handling of missing data 
As the PDS includes all subjects who received at least 4 weeks of study treatment with at 
least one valid lymphocyte measurement on or after the Week 4 assessment, all available 
data at the visits of interest (Week 4, Week 8 and Week 12) will be included in the analysis. 
Thus, data of subjects with one, two or three post-baseline measurements at the predefined 
time points will contribute to the dose-response analysis. Every effort will be made to 
collect lymphocyte data, as complete as possible, for every subject at every visit. Last 
observation carried forward (LOCF) will be used as a sensitivity analysis as described 
below. 
11.2.7.3 Main analysis of the primary PD variable (primary analysis) 
To meet the objective of demonstrating existence of an intra-subject dose response on the 
absolute lymphocyte count reduction from baseline in subjects with GVHD, at least one 
null hypothesis must be rejected with a one-sided significance level of 5%. The type-1 error 
will be controlled via a hierarchical ordering of the tests: pairwise comparisons will be 
conducted in decreasing dose order. Within-subject t-tests will be performed at each dose 
level (assuming normally distributed data).  
In addition, an Emax model will be fitted for the baseline, Week 4, Week 8 and Week 12 
data. The data will be summarized with point-wise and model-based estimates, standard 
deviation and 95% CIs on the reduction in absolute lymphocyte counts from baseline at the 
examined dose levels. A plot of the estimated dose-response curve with 95% credibility 
interval limits will be presented along with the observed response at each dose. 
The primary analysis will be performed on the PD analysis set and conducted after the last 
patient has completed the Follow-Up 1 visit in the Core Treatment Period.  
11.2.7.4 Supportive/sensitivity analyses 
A sensitivity analysis of the primary analysis will be performed on the FAS (in case the 
FAS does not contain the same number of subjects as the PDS). 
Further t-tests will be performed across dose levels (5 mg vs 10 mg, 5 mg vs 20 mg and 10 
mg vs 20 mg). These tests, performed at a one-sided significance level of 5%, will be 


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considered as exploratory. These pairwise comparisons will be performed on the FAS and 
PDS. 
An LOCF approach (using the Week 4 visit or later) will be performed for subjects with a 
missing Week 8 or Week 12 assessment, based on the FAS. 
The dose-response modeling will be repeated using the Week 4, Week 8 and Week 24 
assessment (instead of the Week 12 assessment), based on the PDS. 
11.2.7.5 Subgroup analyses 
No subgroup analyses are planned due to small sample size. 
11.2.8 Analysis of the efficacy variables 
The analyses of all exploratory endpoints will be based on the PPS and FAS, if applicable. 
The following binary endpoints will be summarized descriptively as described in Section 
11: 
• Achievement of a partial or complete overall response at 24 weeks (per NIH Consensus 
Development Project response criteria) 
• Need for rescue therapy for chronic GVHD 
• Partial or complete organ-specific response for the specific organ manifestation at 
Week 12 and Week 24 in subjects with a specific organ manifestation of chronic 
GVHD 
• Partial or complete overall response at Week 12 
• Complete response at Week 24 
• Partial or complete overall response at latest evaluable assessment during the core study 
(Week 12 and Week 24) 
The remaining two exposure-related, continuous endpoints will be analyzed based on 
summary statistics as described in Section 11: 
• Average glucocorticoid daily dose over 24 weeks versus baseline dose 
• Percent glucocorticoid dose at Week 24 versus baseline 
11.2.9 Analysis of the efficacy variables during the Extension Treatment Period 
The analyses of all exploratory endpoints will be based on the ES. 
All efficacy variables will be summarized descriptively, by visit, based on the ES. If subject 
numbers drop below a certain threshold only listings will be provided. No statistical tests 
will be applied to any of these endpoints.  


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The endpoint “Achievement of a partial or complete overall response at 24 weeks (per NIH 
Consensus Development Project response criteria)” will be analyzed at Week 24 and Week 
96 in the Extension Treatment Period and selected other time points. 
The endpoint “Need for rescue therapy for chronic GVHD” will be analyzed throughout 
96 weeks of treatment or up to premature discontinuation. 
The endpoint “Partial or complete organ-specific response for the specific organ 
manifestation at Week 12 and Week 24 in subjects with a specific organ manifestation of 
chronic GVHD” will be assessed at Weeks 12, 24, and 96 in the Extension Treatment 
Period and selected other time points. 
The endpoint “Partial or complete overall response at Week 12” will also be analyzed at 
Week 12 in the Extension Treatment Period. 
The endpoint “Complete response at Week 24” will be assessed at Week 24 and Week 96 
in the Extension Treatment Period and selected other time points. 
The endpoint “Partial or complete overall response at latest evaluable assessment during 
the study” will be extended to the whole Extension Treatment Period. 
The exposure related endpoints will be analyzed based on summary statistics. Both 
endpoints “Percent glucocorticoid dose at Week 24 versus baseline” and “Average 
glucocorticoid daily dose over 24 weeks versus baseline dose” will be analyzed at the end 
of treatment visit (EOT2) in the Extension Treatment Period, and compared to the baseline 
visit of the Extension Treatment Period (Visit EX-1).  
If there are not enough subjects in the ES population, only listings will be provided. 
11.2.10Analysis of the safety variable(s) 
All safety analyses will be conducted on data up to 30 days (inclusive) after last study drug 
intake for the Core Treatment Period and for the Extension Treatment Period. All AEs will 
be coded using the latest version of MedDRA available at the time of database closure. 
11.2.10.1 Adverse Events 
11.2.10.1.1 Treatment-emergent AEs, SAEs, and AEs of special interest 
Treatment-emergent AEs and SAEs will be tabulated by system organ class (SOC) and 
preferred terms within each SOC: the number and percentage of subjects who experienced 
at least one (S)AE, at least one (S)AE within each SOC and at least one S(AE) within each 
preferred term will be displayed. (S)AEs will also be summarized by decreasing frequency 
of preferred term. (S)AEs will also be tabulated by maximum intensity. 
AEs of special interest will be summarized in the same way as stated above. 


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Treatment-emergent AEs and SAEs and AEs of special interest will be analyzed for the 
Extension Treatment Period as described above. 
11.2.10.1.2 AEs leading to premature discontinuation of study drug 
(S)AEs leading to premature discontinuation of study drug will be summarized in a similar 
manner as described above. 
(S)AEs leading to premature discontinuation of study drug will be summarized for the 
Extension Treatment Period as described above. 
11.2.10.1.3 Deaths 
Fatal SAEs occurring any time after the start of treatment will be summarized in a similar 
manner as described above. Fatal SAEs will also be summarized for the Extension 
Treatment Period. 
11.2.10.2 Absolute lymphocyte count 
Data of subjects with treatment-emergent absolute lymphocyte count < 0.2 × 109/L (< 200 
cells/mm3) will be summarized descriptively for the Core Treatment Period and for the 
Extension Treatment Period. 
11.2.10.3 Cardiac Safety 
11.2.10.3.1 Treatment-emergent morphological ECG abnormalities (as defined by the 
ECG provider) 
Treatment-emergent morphological ECG abnormalities will be summarized descriptively 
for the Core Treatment Period and for the Extension Treatment Period. 
11.2.10.3.2 12-lead ECG assessments 
Descriptive summary statistics, by time and visit, will be provided for observed treatment-
emergent values and absolute changes from baseline in numeric 12-lead ECG values (HR, 
PR, QRS, QT, QTcB and QTcF). Data will be summarized from pre-dose to the post-dose 
assessments at 1 h, 2 h, 3 h and 4 h on Day 1. 12-lead ECG data will also be summarized 
for the Extension Treatment Period. 
11.2.10.3.3 Notable abnormalities for selected 12-lead ECG variables 
Notable abnormalities for selected 12-lead ECG variables (HR, PR, QT, QTcF) will be 
summarized for all data at the 3-hour post dose assessments on Day 1 and pre-dose at 
Weeks 4, 8, 12, and 24. Notable abnormalities will also be summarized for the Extension 
Treatment Period. 
11.2.10.3.4 Cardiac safety events 
Cardiac safety events will include:  


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• Treatment-emergent QTc > 450 ms (male), > 470 ms (female), > 500 ms (male), and 
> 520 ms (female) 
• Treatment-emergent QTc increase from baseline > 30 ms, > 60 ms 
• Other treatment-emergent abnormalities observed by 12-lead ECG 
• Treatment-emergent (serious) cardiac AEs of special interest. 
Cardiac safety events will be summarized descriptively for the Core Treatment Period and 
for the Extension Treatment Period. 
11.2.10.4 Pulmonary safety 
11.2.10.4.1 PFT 
Descriptive summary statistics by visit will be provided for observed treatment-emergent 
values and changes from baseline by visit in FEV1, FVC and FEV1/FVC ratio (all expressed 
in absolute change, % change and % change of percent predicted value).  
The number and proportions of treatment-emergent decreases of FEV1 or FVC and percent 
predicted FEV1 or FVC > 20% from baseline up to Week 24 will be summarized. 
Reversibility of pulmonary parameters will be analyzed at the last available follow-up visit. 
The analysis will summarize subjects still showing a decrease of > 200 mL in FEV1 and 
FVC or a change in FEV1 and FVC of > 12% from baseline at the follow-up visit among 
subjects with a decrease of > 200 mL or > 12% in FEV1 or FVC from baseline to EOT1.  
The mean (and 95% CIs) change from baseline to FU1 and from baseline to EOT1 in FEV1 
or FVC (absolute and % predicted) will be summarized and plotted. A scatter plot will 
display the change from baseline to EOT1 versus the change from baseline to FU1 on an 
individual subject level. 
PFT data will be analyzed in a similar manner during the Extension Treatment Period. 
11.2.10.4.2 Lung diffusion capacity (DLCO) 
Descriptive summary statistics and changes from baseline by visit will be provided for 
observed treatment-emergent values and changes from baseline (expressed in absolute 
change and % of predicted value) in DLCO. In addition the DLCO change from baseline to 
FU1 versus change from baseline to EOT1, expressed in absolute change and percent of 
predicted values change, will be summarized. DLCO data will be analyzed in a similar 
manner during the Extension Treatment Period. 
11.2.10.4.3 Pulmonary safety events 
Pulmonary safety events will include:  
• Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values 


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• (Serious) pulmonary AEs of special interest  
• Withdrawal due to pulmonary reasons/AE 
Pulmonary safety events will be summarized descriptively for the Core Treatment Period 
and for the Extension Treatment Period. 
11.2.10.5 Vital signs 
Descriptive summary statistics by visit will be provided for observed treatment-emergent 
values and absolute changes from baseline in HR, BP and body weight. 
Treatment-emergent notable BP abnormalities will also be summarized. Vital signs data 
will be analyzed for the Core Treatment Period and for the Extension Treatment Period. 
11.2.10.6 Laboratory  
11.2.10.6.1 Laboratory tests 
For the Core Treatment Period, descriptive summary statistics by visit will be provided for 
observed treatment-emergent values and absolute and percent changes from baseline for 
laboratory tests (hematology, blood chemistry, urinalysis). Data will be displayed in SI 
units whenever possible and graphical approaches will be applied.  
Laboratory data will be analyzed in a similar manner for the Extension Treatment Period. 
11.2.10.6.2 Laboratory safety events 
Laboratory safety events will include:  
• Treatment-emergent laboratory test abnormalities based on normal ranges of the 
central laboratory, project-specific ranges and CTCAE [CTCAE 2010]  
• Treatment-emergent laboratory test abnormalities based on FDA Guidance for Drug 
Induced Liver Injury [FDA 2009] (for ALT/AST/TBIL) 
• Absolute lymphocyte count reversibility after EOT, expressed in absolute change and 
percent change from baseline. 
Laboratory safety events will be summarized descriptively for the Core Treatment Period 
and for the Extension Treatment Period. 
11.2.10.7 Ocular safety 
Ocular safety events will include: 
• Treatment-emergent ocular AEs of specific interest 
Ocular safety events will also be summarized for the Extension Treatment Period. 


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11.2.11Analysis of (other) variable(s) 
11.2.11.1 Quality of Life endpoints 
Quality of life endpoints will be summarized for the Core Treatment Period and for the 
Extension Treatment Period. 
11.2.11.1.1 Lee Symptom Scale for chronic GVHD 
Absolute values and changes from baseline of the LSS for chronic GVHD will be 
summarized descriptively in the PPS and FAS by visit. 
11.2.11.1.2 Patient-reported chronic GVHD symptoms scale and patient-reported global 
ratings scale 
Absolute values and changes from baseline of both scales will be summarized descriptively 
in the PPS and FAS by visit. 
11.2.11.2 PK analysis 
Ctrough (pre-dose) plasma concentrations of ponesimod on Day 1 and Weeks 4, 8, 12, 16, 
20 (all samples pre-dose), and Week 24, and plasma concentrations of ponesimod at 3 h 
post-dose at Day 1 and Week 12, will be analyzed by descriptive statistics, including 
arithmetic mean, standard deviation, minimum, maximum, and median. 
11.2.11.3 PD analysis 
For the Core Treatment Period, peripheral absolute lymphocyte counts at each visit 
assessment and changes from baseline will be analyzed by descriptive statistics, including 
arithmetic mean, standard deviation, minimum, maximum, and median. 
Peripheral absolute lymphocyte count reversibility from EOT1 to FU1 will be summarized 
and plotted. 
PD analyses will be repeated in the Extension Treatment Period. 
11.2.11.4 PK/PD relationship 
Selected efficacy and safety variables will be correlated with the PD (peripheral absolute 
lymphocyte count and magnitude of reduction of lymphocyte count). If deemed 
appropriate, the PK will also be correlated with selected safety variables. 
11.3 Interim analyses 
There is no interim analysis planned for this study. 


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11.4 Sample size 
The sample size of this single-arm intra-subject dose-escalation study is based on 
simulations, comparing lymphocyte data at baseline to Week 4 data of the estimated 5 mg 
dose, using t-tests. 
11.4.1 Sample size for primary endpoint 
Based on these simulations, 30 subjects will be recruited in order to establish an 
intra-subject dose response and to collect sufficient safety data. The simulations were 
performed, comparing the change of absolute lymphocyte counts at Week 4 (5 mg dose; 
mean: 0.85 × 109/L; STD 0.40) vs baseline (mean: 1.2 × 109/L; STD 0.60), applying t-tests 
with a one-sided alpha-level of 0.05. Based on those assumptions a power of around 85% 
is reached. As absolute lymphocyte counts are expected to be closest to baseline data for 
the 5 mg dose, the sample size of 30 subjects is expected to be sufficient for the 10 mg and 
20 mg doses, as well. Even in case of a 25% dropout rate, assuming 23 subjects reaching 
the Week 12 assessment, there should be enough subjects in the study to establish a dose 
response (Power of approximately 75% at 5 mg dose). 
Since no studies of subjects receiving ponesimod have been conducted in chronic GVHD, 
historical data of the Actelion MS and psoriasis programs have been used to determine the 
sample size. As chronic GVHD subjects are known to have reduced lymphocyte counts, 
assumptions were adjusted appropriately. Dose-response modeling techniques were 
applied to support the sample size estimation [details in Section 11.4.2]. 
11.4.2 Sample size assumptions 
Dose-response modeling 
Dose-response modeling was performed, applying MCP-Mod techniques [Bretz 2005] on 
the historical lymphocyte data from MS studies (AC-058B201 core and AC-058B202 
extension study; doses studied were placebo, 10 mg, 20 mg, and 40 mg), in order to 
establish a dose response at the chronic GVHD study-specific visits (Week 4, Week 8 and 
Week 12) and to estimate a mean lymphocyte value for the 5 mg dose that is administered 
up to Week 4 in the chronic GVHD study. Data of the MS program seemed to be the most 
appropriate choice for the sample size calculations, as data, doses and length of studies 
reflect the chronic GVHD study setup. The MCP-Mod estimate of the 5 mg dose was 
included in the sample size simulations of the PD endpoint (details below), adjusted for 
lower lymphocyte levels of subjects with chronic GVHD. 
Four doses (10 mg, 20 mg, 40 mg and placebo) were included in the dose-response model, 
based on all available baseline placebo data of the AC-058B201 study, Week 8 data of the 
10 mg dose (AC-058B201/B202) and Week 12 data of the 20 and 40 mg doses (AC-
058B201/B202), selecting data according to the dose-escalation and assessment schedule 
of the chronic GVHD study. A candidate set of models was tested (including linear, Emax, 


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sigmoid Emax and logistic dose-response curve), and a highly significant dose response was 
established for the candidate models mentioned above (trend-test value of T > 30, p< 
0.0001), with the Emax and sigmoid Emax being the optimal models, depending on the choice 
of the input parameters. The derived mean lymphocyte estimates for the 5 mg dose were 
around 1.4 × 109/L (estimates similar for different linear Emax and sigmoid Emax models and 
for different data selections, including AC-058B201 core phase data and pooled AC-
058B201/B202 data). Mean absolute lymphocyte counts for other doses were estimated 
from historical data (mean absolute lymphocyte count of 10 mg at Week 8: 1.0 × 109/L 
[STD: 0.39]; 20 mg at Week 12: 0.65 × 109/L [STD: 0.28]; baseline: 2.0 × 109/L [STD: 
0.69] at the specific time points). 
Assuming chronic GVHD subjects enter the study with a reduced absolute lymphocyte 
count of at least 40%, mean estimates were adjusted proportionally, i.e., a mean baseline 
absolute lymphocyte count of 1.2 × 109/L (STD 0.6), a count of 0.85 × 109/L (STD 0.4) for 
the 5 mg dose, a count of 0.6 × 109/L (STD 0.35) for the 10 mg dose and a count of 
0.4 × 109/L (STD 0.25) for the 20 mg dose. 
Pairwise comparisons of dose levels 
Simulations were carried out using the assumptions described above, in order to assess the 
power of t-tests of the absolute lymphocyte counts of the 5 mg dose versus baseline, based 
on a lymphocyte reduction of 40% compared to MS data (including drop out analysis): 
Analysis 
No. 
Patients 
Alpha 
(1-sided) 
Lymph. 
Reduction 
compared 
to MS data 
Mean 
Lymph. 
Count 
Placebo 
Mean 
Lymph. 
Count 
Pon. 5 mg 
STD 
Power 
Primary 
Sample Size 
30 
0.05 
40% 
1.20 
0.85 0.6/0.4 
85% 
Drop-Out 
Sample Size 
23 
0.05 
40% 
1.20 
0.85 0.6/0.4 
75% 
Assuming an absolute lymphocyte count reduction of 40% (mean of 1.2 × 109/L (STD 0.6) 
at baseline and a mean of 0.85 × 109/L (STD 0.4) for the 5 mg dose), results in a sample of 
30 subjects, based on a 1-sided alpha level of 5% and a Power of approximately 85%. If 
up to 25% of the subjects drop out during the Core Treatment Period, the Power reduces to 
75%. 
Further simulations showed that with 30 subjects included in the study, all doses could be 
clearly distinguished from each other (minimal power of > approximately 84% from 
comparison of 5 mg versus 10 mg at one-sided alpha of 5%, based on an absolute 
lymphocyte count reduction of 40% as compared to MS data and STD of 0.6/0.4). 


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11.4.3 Sample size re-estimation 
Not applicable. 
12 
DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible to ensure the accuracy, completeness, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived 
from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site staff will be trained 
to enter and edit the data via a secure network, with secure access features (username, 
password and identification – an electronic password system). A complete electronic audit 
trail will be maintained. The investigator/delegate will approve the data (i.e., confirm the 
accuracy of the data recorded) using an electronic signature (ref. to 21 CFR Part 11). 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be 
recorded in the eCRF.  
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents submitted to Actelion, subjects must be identified only by number and 
never by name or initials, hospital numbers or any other identifier. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
enrollment number, the subject’s name, date of birth and address or any other locally 
accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be 
sent to Actelion and must be kept in strict confidence by the investigator/delegate. 
12.3 Database management and quality control 
eCRFs will be used for all subjects. The investigator will have access to the site eCRF data 
until the database is locked. Thereafter, they will have read-only access. The eCRF must 
be kept current to reflect subject status at any time point during the course of the study.  
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 


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on an ongoing basis to look for unexpected patterns in data and study monitoring. If 
discrepant data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the eCRF. All electronic queries 
visible in the system either require a data correction (when applicable) and a response from 
the investigator/delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator/delegate must, on request, supply Actelion with 
any required background data from the study documentation or clinical records. This is 
particularly important when errors in data transcription are suspected. In the case of health 
authority queries, it is also necessary to have access to the complete study records, provided 
that subject confidentiality is protected. 
This process will continue until database closure. 
Study drug accountability and compliance, laboratory samples, PK samples, and ECGs will 
be processed centrally through their respective central laboratory/provider, and the results 
will be sent electronically to Actelion. If local laboratory date is obtained as may be 
required per-protocol in certain instances, it must be entered in the eCRF by the site.  
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate standard operating procedure (SOP). After database closure, the investigator 
will receive the eCRF of the subjects from his/her site (including all data changes made) 
on electronic media or as a paper copy. 
13 
PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH-GCP guidelines, the principles of the “Declaration of Helsinki” and with the laws 
and regulations of the country in which the research is conducted.  
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the subject 
(such as Subject Information Leaflet used to obtain informed consent) to an Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC). Approval from the 
committee must be obtained before starting the study, and must be documented in a dated 
letter to the investigator, clearly identifying the study, the documents reviewed, and the 
date of approval.  
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IRB/IEC in accordance with local procedures and 
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A list of members participating in the IRB/IEC meetings must be provided, including the 
names, qualifications and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation. If a study staff member was 
present during a meeting, it must be clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. The investigator/delegate must explain to subjects that they are 
completely free to refuse to enter the study, or to withdraw from it at any time for any 
reason. 
The ICF will be provided in the country local language(s). 
Site staff authorized to participate to the consent process and/or to obtain consent from the 
subject and/or legal representative will be listed on an Actelion Delegation of Authority 
form. A study physician must always be involved in the consent process.  
The subject and/or legal representative must sign, personally date and time (if appropriate) 
the ICF before any study-related procedures (i.e., any procedures required by the protocol) 
begin. The ICF must also be signed, personally dated and timed (if appropriate) by the 
authorized site staff listed on Actelion Delegation of Authority form. 
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation.  
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional person 
present during the consent process (e.g., subject family member), copy of the signed ICF 
given to the subject / legal representative. 
In the case that the site would like to recruit a subject who would be considered as 
vulnerable (e.g., subject cannot read or write, does not speak or understand the ICF 
language), additional measures must be implemented in order to ensure subject rights are 
respected and the consent obtained is legally valid. Actelion, the regulatory authorities (if 
applicable) and the IRB/IEC must be informed prior to the recruitment. The consent 
process (e.g., involvement of an impartial witness) must be fully described, submitted to, 
and approved by the IRB/IEC, according to procedures and before subjects are recruited.  


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13.4 Compensation to subjects and investigators 
Actelion provides insurance in order to indemnify (with both legal and financial coverage) 
the investigator/site against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when the 
change involves only logistical or administrative aspects (e.g., change in telephone 
number), or in case it would be necessary to eliminate an immediate hazard to the subject.  
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. IRB/IEC and regulatory authorities must be 
informed, according to their requirements, but no later than 15 calendar days after the 
event. 
13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to the IRB/IEC and regulatory authorities, 
according to their requirements. 
13.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring and available when needed. 
These records are to be classified into two different categories of documents: investigator’s 
file, and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (e.g., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the investigational site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Actelion to store these documents outside the site so that they 
can be retrieved in case of a regulatory inspection. No study document should be destroyed 


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without prior written approval from Actelion. Should the investigator wish to assign the 
study records to another party or move them to another location, Actelion must be notified 
in advance.  
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the monitor has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the monitor. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original subject’s data. The 
printouts will be considered as the official clinical study records.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The monitor does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Actelion’s instructions. If it were not possible for the 
monitor to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. The printouts should be filed 
either with the subject medical records or with the subject’s eCRF. 
13.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required essential 
study documents are approved by Actelion. The study treatment will be shipped to the site 
upon approval of the required essential documents.  
The principal investigator must ensure that all site personnel involved in the study will be 
present during the SIV and will dedicate enough time to it. Site Information Technology 
support should also be available during the initiation visit.  
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the principal investigator and filed in the investigator site file (ISF). 
During the study, the monitor will contact and visit the investigational site regularly and, 
on request, must be permitted to have access to trial facilities and all source documents 


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needed to verify adherence to the protocol and the completeness, consistency and accuracy 
of the data being entered in the eCRFs and other protocol-related documents. Actelion 
monitoring standards require full verification that informed consent has been provided, and 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety and tolerability endpoints. Additional checks of 
the consistency of the source data with the eCRFs will be performed according to the study-
specific monitoring plan. The frequency of the monitoring visits will be based on subject 
recruitment rate and critical data collection times. 
The investigator/sub-investigator must ensure that the eCRF is completed after a subject’s 
visit to the site and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the monitor. The required site personnel must be available during monitoring visits and 
allow adequate time to meet with the monitor to discuss study related issues.  
The investigator agrees to cooperate with the monitor(s) to ensure that any issues detected 
in the course of these monitoring visits are resolved. If the subject is hospitalized or dies in 
a hospital other than the study site, the investigator is responsible for contacting that 
hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site and when there are no more active 
subjects and after all study data have been accepted by medical review and all follow-up 
issues have been resolved. In case a site does not enroll any subjects, the close-out visit 
may be performed prior to study database closure at the discretion of Actelion. 
13.9 Investigator site file 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per 
ICH-GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP as well as instructions from Actelion. If the site needs to transfer the 
ISF to another location and/or if site facility can no longer store the ISF, the principal 
investigator must inform Actelion immediately.  


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If the principal investigator will change, or if the site will relocate, the monitor must be 
notified as soon as possible.  
13.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence 
to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating this audit, 
the investigator will be contacted by Actelion to arrange a time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health authorities and/or IRB/IEC may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion).  
Should an inspection be requested by a health authority and/or IRB/IEC, the investigator 
must inform Actelion immediately, (usually via the monitor) that such a request has been 
made.  
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
13.12 Reporting of study results and publication  
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the coordinating investigator (or principal investigator for single-center 
studies). 
The coordinating investigator and the Steering Committee, if any, will have the opportunity 
to review the analysis of the data and to discuss the interpretation of the study results with 
Actelion prior to publication. 
Actelion will post results from its clinical studies on Actelion’s Clinical Trial Register, and 
on external/national registries, as required by law. 
Actelion’s Policy on Disclosure of Clinical Research Information can be found at:  
http://www.actelion.com/documents/corporate/policies_charters/policy_clinical-research-
information.pdf 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before publication in a peer-reviewed journal. 


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Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• Substantial contributions to: the conception or design of the study, or the acquisition, 
analysis or interpretation of data; and 
• Drafting of the publication or critical review for important intellectual content; and  
• Providing final approval of the version to be published; and 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  
The list of authors of any publication of study results may include representatives of 
Actelion, and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent rights. 
Neither the institution nor the investigator should permit publication during such a review 
period. 
Actelion’s Policy on Scientific Publications can be found at: 
http://www.actelion.com/documents/corporate/policies_charters/policy_scientific-
publications.pdf 


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14 
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http://ncifrederick.cancer.gov/events/GvHD/Biomarker.pdf 
[NIH Design of Clinical Trials 2014] 
National 
Institutes 
of 
Health 
Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: VI. Design of Clinical Trials Working Group Report; available at: 
http://ncifrederick.cancer.gov/events/GvHD/ClinicalTrialsWorkingGroupReport.pd
f, accessed 16 December 2014. 
[NIH Therapeutic Response 2014] 2014 NIH chronic GVHD Consensus Conference, 
Response Criteria Working Group documents, in press, personal communication by 
Dr Steven Pavletic. 
[Nishimori 2013] Nishimori, H., Y. Maeda and M. Tanimoto. Chronic Graft-Versus-Host 
Disease: Disease Biology and Novel Therapeutic Strategies. Acta Med Okayama. 
2013;67(1):1-8. 
[Pai 2014] Pai CS, Chen M, Mirsoian A, et al. Treatment of chronic graft-versus-host 
disease with bortezomib. Blood. 2014;124:1677-88. 
[Pasquini 2013] Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem 
cell 
transplantation: 
CIBMTR 
Summary 
Slides, 
2013. 
Available 
at: 
http://www.cibmtr.org, accessed 16 December 2014. 


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[Pavletic 2006] Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in 
chronic graft-versus-host disease: National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: IV. Response Criteria Working Group report. Biol Blood Marrow 
Transplant 2006; 12:252-66. 
[Piali 2011] Piali, L, et al., The selective sphingosine 1-phosphate receptor 1 agonist 
ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol 
Exp Ther, 2011; 337(2):p.547-56. 
[Pinschewer 2000] Pinschewer DD, Ochsenbein AF, Odermatt B, et al. FTY720 
immunosuppression impairs effector T cell peripheral homing without affecting 
induction, expansion, and memory. J Immunol 2000;164:5761–70. 
[Ponesimod IB] Ponesimod S1P1 receptor agonist. Investigator’s Brochure, Version 10 
Amendment 1, July 2015. 
[Quanjer 1993] Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault 
JC. Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal. 
Official Statement of the European Respiratory Society. Eur Respir J Suppl  
1993;16:5–40. 
[Schwab 2007] Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from 
lymphoid organs. Nat Immunol 2007;8:1295–301. 
[Song 2006] Song, J, et al., Inhibition of donor-derived T cells trafficking into target organs 
by FTY720 during acute graft-versus-host disease in small bowel transplantation. 
Clin Exp Immunol, 2006; 146(1):85-92. 
[Stewart 2004] Stewart B, Storer B, Storek J, et al. Duration of immunosuppressive 
treatment for chronic graft-versus-host-disease. Blood 2004; 104:3501-3506. 
[Storek 2008] Reconstitution of the immune system after hematopoietic stem cell 
transplantation in humans. Semin Immunopathol. 2008 Dec;30(4):425-37.  
[Teshima 2009] Teshima T, Nagafuji K, Henzan H, et al. Rituximab for the treatment of 
corticoisteroid-refractory chronic graft-versus-host disease. Int J Hematol 
2009;90:253-60. 
[Vaclavkova 2014] Vaclavkova A, Chimenti S, Arenberger P, et al. Oral ponesimod in 
patients 
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placebo-controlled Phase 2 trial. Lancet. 2014;384:2036–45. 


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[Vigorito 2009] Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIH 
consensus criteria for classification of late acute and chronic GVHD. Blood. 
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[Weisdorf 2007] Weisdorf D. GVHD - the nuts and bolts. Hematology Am Soc Hematol 
Educ Program 2007;62-67. 
[Wolff 2011a] Wolff D, Bertz H, Greinix H, et al. The treatment of chronic 
graft-versus-host disease. Dtsch Arztebl Int 2011;108:732-740. 
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Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic 
Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2011;17:1-17. 
[Woosley 2016] Woosley, RL, Romero, KA. QTdrugs List, 2016, AZCERT, Inc. 1822 
Innovation Park Dr., Oro Valley, AZ 85755 
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[Yamamoto 2014] Yamamoto W, Ogusa E, Matsumoto K, Maruta A, Ishigatsubo Y, 
Kanamori H. Lymphocyte recovery on day 100 after allogeneic hematopoietic stem 
cell transplant predicts non-relapse mortality in patients with acute leukemia or 
myelodysplastic syndrome. Leuk Lymphoma. 2014 May; 55(5):1113-8.  
[You 2013] You, S, et al., Therapeutic use of a selective S1P1 receptor modulator 
ponesimod in autoimmune diabetes. PLoS One, 2013. 8(10): p. e77296. 


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15 
APPENDICES 
Appendix 1 
Additional subject eligibility guidance 
The following guidance should be applied by investigators in assessing the eligibility for 
subjects for enrollment in this study, with respect to inclusion criteria 5b and 5c. 
 
Inclusion criterion 5b 
The investigator must determine subject to be glucocorticoid refractory, dependent, or 
intolerant at screening. 
Guidance 
Systemic glucocorticoids are established first-line therapy for chronic GVHD. This 
study will not include subjects who could benefit from standard use of glucocorticoids. 
Therefore, a glucocorticoid refractory, dependent, or intolerant status must exist for all 
eligible subjects. 
Currently, there are no uniformly accepted definitions for these states in chronic 
GVHD. 
The investigator should consider the following definitions in his or her assessment of 
the subject’s prior experience with glucocorticoids: 
Refractory to or dependent on glucocorticoids 
• Progression on prednisone-equivalent steroid dose at 1 mg/kg/day for 2 weeks 
• Stable disease on prednisone-equivalent steroid dose at ≥ 0.5 mg/kg/day for 4–8 
weeks 
• Inability to taper below prednisone-equivalent steroid dose of 0.5 mg/kg/day 
• Treatment with prednisone-equivalent steroid dose of > 0.25 mg/kg/day received 
for ≥ 12 weeks 
Sources: [Wolff 2011b, Pai 2014, Inamoto 2014b] 
 
Intolerant to glucocorticoids 
• 
Subjects have a glucocorticoid intolerance that required a dose reduction. 
Intolerance includes the development of severe side effects due to glucocorticoid 
use, such as poorly controlled hypertension or diabetes, active peptic ulcer disease, 
myopathy, psychiatric derangements, significant bone loss, or systemic fungal 
infection. 
 
 
 
 
 


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Inclusion criterion 5c 
Subjects have evidence of GVHD progression at enrollment despite ≥ 4 weeks current 
systemic IS therapy, OR are without evidence of GVHD improvement at enrollment 
despite ≥ 8 weeks current systemic IS therapy. Current systemic IS therapy must be 
same as in inclusion criterion 4. 
Guidance 
This study seeks to avoid enrolling subjects who are improving on their current 
systemic IS therapy or who have not received an adequate duration of therapy to 
demonstrate response.  
• Lack of response (progression or no improvement) to the current systemic IS 
therapy, determined at enrollment, will need to be documented in the eCRF. 
Investigators should consider the 2014 NIH response criteria checklist [see 
Appendix 7] when comparing chronic GVHD disease activity at enrollment versus 
previous chronic GVHD activity. Reason for lack of response has to be 
documented in the medical record and eCRF at the time of enrollment. Subjects 
with indications of overall partial or complete response are not eligible.  
• For the purposes of this study, current systemic IS therapy is systemic 
glucocorticoids AND/OR one of the following systemic agents: CsA, TAC, MMF, 
MPS, EVL, SRL, or MTX. These agents are present at enrollment and will be 
continued during the study. It is not required that these agents were initiated at the 
same time, or that dosing was always constant. It is required that the agents were 
given together over the minimum duration (4 or 8 weeks)* leading up to 
enrollment, and that there were no dose changes in the 14 days prior to enrollment. 
• Other agents (e.g., cyclophosphamide, rituximab) may have been initiated and 
stopped in the past; however, these are not considered to be part of the current 
systemic IS therapy, and specific washout periods prior to enrollment must be 
achieved to permit eligibility. These agents and washout periods are described in 
the exclusion criteria. 
Source 
*Duration and response requirements adapted from Martin 2009. 
 


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Appendix 2 Chronic GVHD Stage and Score forms 
 
All forms in Appendix 2 are NIH Consensus Development Criteria [Jagasia 2015]. 


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Appendix 2 Chronic GVHD Stage and Score forms (cont’d) 
Organ Scoring Chronic GVHD Form 
 


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Appendix 2  Chronic GVHD Stage and Score forms (cont’d) 
Organ Scoring Chronic GVHD Form (continued) 
  


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Appendix 2  Chronic GVHD Stage and Score forms (cont’d) 
Organ Scoring Chronic GVHD Form (continued) 
 


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Appendix 2 Chronic GVHD Stage and Score forms (cont’d) 
Genital Tract Chronic GVHD Assessment Scoring Form  
  


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Appendix 3 
Guidance for initiating or dose increasing QT-prolonging drugs with 
known risk of Torsades de Pointes 
QT-prolonging medications with known risk of Torsades de Pointes (e.g., azithromycin, 
citalopram, clarithromycin, erythromycin, escitalopram, moxifloxacin,…) should be 
administered with caution since ponesimod may potentially enhance their effect on QT 
interval. A list of QT-prolonging medications with known risk of Torsades de Pointes is 
published by AZCERT http://crediblemeds.org/ [Woosley 2016]. The investigator should 
also take into account other relevant risk factors such as hypokalaemia when considering 
treatment with a QT-prolonging drug. If treatment with such drugs is considered necessary, 
the principal investigator should always discuss with the cardiac safety assessor the 
appropriateness of combining such drugs with ponesimod and may interrupt or prematurely 
discontinue study drug. If the principal investigator determines in the best interest of the 
subject to concomitantly administer a QT-prolonging drug with known risk of Torsades de 
Pointes and ponesimod, the following recommendations must be adhered to:  
a) for a need to start treatment or to increase the dose of a QT-prolonging drug with known 
risk of Torsades de Pointes during up-titration, treatment with study drug must be 
interrupted.  
• Study drug can only be re-initiated [see Section 5.1.8] after the QT-prolonging drug 
has been stopped or once the QT-prolonging drug has reached the steady-state  
o Once the QT-prolonging drug has reached the steady-state and prior to 
re-initiation of study drug, the QTcF interval obtained pre-dose on the day of 
the planned re-initiation must be ≤ 450 ms for males or ≤ 470 ms for females; 
o Following re-initiation of study drug, at next visit (scheduled or unscheduled 
occurring after completion of the up-titration), perform ECG measurements 
pre-dose. 


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Appendix 3 Guidance for initiating or dose increasing QT-prolonging drugs with 
known risk of Torsades de Pointes (cont’d) 
b) for a need to start treatment or to increase the dose of a QT prolonging drug with known 
risk of Torsades de Pointes during the study, during any maintenance dosing of 5, 10 or 20 
mg ponesimod.  
• At visit (scheduled or unscheduled) prior to initiation or dose increase of QT prolonging 
drug with known risk of TsdP, perform ECGs measurements pre-dose.  
o If prior to initiation or dose increase of QT prolonging drug with known risk of 
TsdP, the QTcF interval is > 450 ms for males or > 470 ms for females, 
treatment with study drug must be interrupted. 
• At next visit (scheduled or unscheduled occurring once the QT prolonging drug has 
reached the steady-state (approximately after 5 half-lives of the QT prolonging drug)) 
following initiation or dose increase of QT prolonging drug with known risk of TsdP, 
perform ECGs measurements pre-dose. 
 


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Appendix 4 
Prohibited anti-arrhythmic or HR-lowering drugs 
The following anti-arrhythmic and HR-lowering drugs (systemic administration) are 
prohibited during the study [see Section 5.3.5, Forbidden concomitant therapies]: 
•         Adenosine 
•         Lidocaine 
•         Acetobulol 
•         Lorajmine 
•         Ajmaline 
•         Lorcainide 
•         Amiodarone 
•         Metoprolol 
•         Aprinidine 
•         Mexiletine 
•         Atenolol 
•         Morcizine 
•         Azimilide 
•         Nadolol 
•         Bepridil 
•         Phenytoin 
•         Betaxolol 
•         Pilocarpine 
•         Bisiprolol 
•         Prajmaline 
•         Bretylium 
•         Procainamide 
•         Bunaftine 
•         Propafenone 
•         Carvidiol 
•         Propranolol 
•         Cibenzoline 
•         Quinidine 
•         Disopyramide 
•         Sotalol 
•         Dofetilide 
•         Sparteine 
•         Dronedarone 
•         Tedisamil 
•         Encainide 
•         Timolol 
•         Esmolol 
•         Tocainide 
•         Flecainide 
•         Vernakalant 
•         Ibutilide 
 
•         Ivabradine 
 
 
If, in the judgment of the investigator, it is in the best interests of the subject to receive any 
of the drugs listed above, study drug must be premature discontinued. This list is not 
exhaustive, other anti-arrhythmic or HR-lowering drugs are also prohibited. In case of 
doubt, please discuss with sponsor the use of any potential anti-arrhythmic or HR-lowering 
drug. 


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Appendix 5 
Adverse events of special interest 
AEs of special interest include the anticipated risks of treatment with ponesimod or the 
known class effects and will address the following safety areas:  
• Effect on HR and rhythm related AEs (including adverse events related to hypotension) 
• Cardiovascular related AEs 
• Hypertension related AEs 
• Stroke related AEs 
• Seizure related AEs 
• Hepatobiliary disorders / liver enzyme abnormality related AEs 
• Pulmonary related AEs  
• Macular edema related AEs 
• Infection related AEs 
• Herpetic infections related AEs 
• Skin malignancy related AEs 
• Non-skin malignancy related AEs 
A list of AEs of special interest (MedDRA preferred terms) will be defined in the SAP. 
 


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Appendix 6 
Abnormalities for ECG, blood pressure and laboratory variables 
ECG and blood pressure abnormalities 
Notable abnormalities for ECG and blood pressure that are related to the potential effects 
of ponesimod will address the following variables: 
• Morphological ECG findings (defined as any abnormal finding not present prior to start 
of treatment). 
• HR outliers (bpm), based on ECG 
• PR interval (ms) 
• QT/QTc interval (ms), based on Bazett’s or Fridericia’s formula) 
• Blood pressure (mmHg) 
The definition of the abnormal values to be reported will be described in the SAP. 
Laboratory abnormalities 
Table 9 describes currently implemented thresholds for definition of project specific 
marked laboratory abnormalities and alerts for the different parameters analyzed in the 
ponesimod studies. These definitions are generally based on guidance from 
OTH-00005 - Definition of Marked Abnormalities in laboratory data. 
For parameters for which no definition of marked abnormalities was defined in 
[OTH-000005_v07_14 Oct 2014], threshold values have been defined according to the 
CTCAE v4.03 grading (generally: flagged “HH” or “LL” for ≥ grade 2 and “HHH” or 
“LLL” for grade 3 or 4) when available [CTCAE 2010]. Marked abnormalities resulting in 
a GVHD trial-specific alert are also identified in Table 9.  
Given the pharmacodynamic effects of ponesimod, specific definitions are given for 
lymphocytes and White Blood Cell count (WBC). Finally, clinical rationale (likelihood of 
risk or consequences) or consistency with fingolimod [Fingolimod], a compound in the 
same class of S1P receptor modulators was used for other parameters when appropriate.  
These project-specific definitions may be subject to change, and may be complemented by 
definitions provided by the central laboratory. In case of discrepancy between 
project-specific and central laboratory definitions, the definitions in Table 9 should be 
followed unless clearly justified. 


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Appendix 6 
Abnormalities for ECG, blood pressure and laboratory variables (cont’d) 
Table 9 
Definition of notable laboratory abnormalities for ponesimod 
Parameter 
LL 
LLL 
HH 
HHH 
Hemoglobin (g/L) 
< 100 
< 80 
Increase in > 20 g/L above 
ULN or above baseline (if 
baseline is above ULN) 
Increase in > 40 g/L above ULN or 
above baseline (if baseline is above 
ULN) 
MCH (pg/Cell) 
ND* 
ND 
ND 
ND 
MCV (fL) 
ND 
ND 
ND 
ND 
Hematocrit (L/L) 
< 0.28 (female) 
< 0.32 (male) 
< 0.20 
> 0.55 (female) 
> 0.60 (male) 
> 0.65 
Platelet count (109 /L) 
< 75  
< 50 
> 600 
> 999 
WBC count (109 /L) 
ND 
< 1.9 
> 20.0 
> 100.0 
Lymphocyte (109 /L) 
ND 
< 0.1 
< 0.2 TRIAL ALERT** 
> 4.0 
≥ 8.0 
Neutrophils (109 /L)  
< 1.5  
< 1.0 
< 0.5 TRIAL ALERT 
ND 
ND 
Eosinophils (109 /L)  
ND 
ND 
> 5.0  
ND 
Monocytes (109 /L) 
ND 
ND 
ND 
ND 
Basophils (109 /L) 
ND 
ND 
ND 
ND 
Polymorphonuclear 
leucocyte/Band cells (%) 
ND 
ND 
> 90% 
> 95% 
AST (U/L) 
ND 
ND 
≥ 3 × ULN 
≥ 3 × ULN TRIAL ALERT 
≥ 5 × ULN 
≥ 5 × ULN TRIAL ALERT 


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Parameter 
LL 
LLL 
HH 
HHH 
ALT (U/L) 
ND 
ND 
≥ 3 × ULN 
≥ 3 × ULN TRIAL ALERT 
≥ 5 × ULN 
≥ 5 × ULN TRIAL ALERT 
Total bilirubin (umol/L) 
ND 
ND 
> 1.5 × ULN TRIAL ALERT 
≥ 2 × ULN 
 
≥ 2 × ULN combined with ALT or 
AST ≥ 3 × ULN: TRIAL ALERT 
> 3 × ULN TRIAL ALERT 
≥ 5 × ULN 
Alkaline Phosphatase 
(U/L) 
ND 
ND 
> 2.5 × ULN 
> 5 × ULN 
INR 
ND 
ND 
≥ 1.5 × ULN OR ≥ 1.5 × 
baseline if on anticoagulation 
 
 
≥ 2.5 × ULN ≥ 2.5 × baseline if on 
anticoagulation 
 
≥ 1.5 × ULN combine with ALT or 
AST ≥ 3 × ULN: TRIAL ALERT 
Lactate dehydrogenase 
ND 
ND 
ND 
ND 
Creatinine (umol/L) 
ND 
ND 
> 1.5 × ULN or > 1.5 × baseline  > 3 ULN or > 3 × baseline 
Creatinine clearance 
(mL/min/1.73 m2) 
ND 
ND 
ND 
ND 
Urea (mmol/L) 
ND 
ND 
> 2.5 ULN 
> 5 ULN 
Albumin (g/L) 
< 30  
< 20 
ND 
ND 
Protein total (g/L) 
ND 
ND 
ND 
ND 
C-reactive protein 
(mg/L) 
ND 
ND 
ND 
ND 
Glucose (mmol/L) 
< 3.0 
< 2.2 
> 8.9 
> 13.9 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 


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Parameter 
LL 
LLL 
HH 
HHH 
Sodium (mmol/L) 
ND 
< 130 
> 150  
> 155  
Calcium (mmol/L) 
< 2.0  
< 1.75 
> 2.9 
> 3.1 
Chloride (mmol/L) 
ND 
ND 
ND 
ND 
Triglyceride (mmol/L) 
ND 
ND 
> 3.42 
> 11.4 
Cholesterol (mmol/L) 
ND 
ND 
> 7.75 
> 12.92 
 
 
 
 
 
*ND = Not defined; may be complemented by definitions provided by the central laboratory 
**ALERT = GVHD trial-specific alert that triggers specific actions in this protocol, including: retest, treatment interruption, and/or premature discontinuation.


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Appendix 7 Chronic GVHD Activity Assessment forms 
All forms in Appendix 7 are NIH Consensus Development Criteria [Lee 2015]. 
 
 


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Appendix 7 Chronic GVHD activity assessment forms (cont’d) 
 
 


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Appendix 7 Chronic GVHD activity assessment forms (cont’d) 
 


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Appendix 7 Chronic GVHD activity assessment forms (cont’d) 
 


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Appendix 8 Lee Symptom Scale 
 


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Appendix 9 
Rule of 9s