Clinical trial NCT04024813
Conditions: Primary Sclerosing Cholangitis
Keywords: PSC Cholangitis, Sclerosing Cholangitis Bile Duct Diseases Biliary Tract Diseases Digestive System Diseases
Sponsor: Gilead Sciences
Start date: 2019-11-12; Completion date: 2020-01-09
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the effect of seladelpar treatment compared to placebo on efficacy, safety, and tolerability in patients with primary sclerosing cholangitis (PSC).

Detailed description:

Arms: arm 1: Placebo for the remainder of the study arm 2: 5 mg seladelpar daily for the remainder of the study arm 3: 10 mg seladelpar for the remainder of the study arm 4: 25 mg seladelpar for the remainder of the study
Interventions: intervention 1: Seladelpar intervention 2: Placebo to match Seladelpar
Intervention descriptions: intervention 1: Capsule(s) administered orally once daily intervention 2: Capsule(s) administered orally once daily

Protocol documents:
Prot_SAP_001.pdf: 
CymaBay Therapeutics, Inc. 
Protocol CB8025-21845 
Protocol Version 2.0, 05-JUN-2019 
CONFIDENTIAL 
Page 1 of 86 
A PHASE 2, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, 
MULTIPLE CENTER STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
EFFICACY OF SELADELPAR ADMINISTERED FOR 24 WEEKS IN ADULT 
PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC)  
PROTOCOL NUMBER CB8025-21845 
for 
CymaBay Therapeutics, Inc. 
IND Number: 142198 
EudraCT Number: 2019-001760-30 
NCT: NCT04024813
Version 2.0 – 05 June 2019 
Confidentiality Statement: 
This document contains confidential information, which should not be disclosed, copied, referred to, 
released or published without written approval from CymaBay Therapeutics, Inc. Any supplemental 
information that may be added to this document is also confidential and proprietary to CymaBay 
Therapeutics, Inc. and must be kept in confidence in the same manner as the contents of this document. 
_b ' , 
CYMABAY 
Tl-IE RAPE UTI CS 


 
 
 
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STUDY IDENTIFICATION 
Sponsor: 
  
 
 
 
 
Sponsor’s Study Manager: 
 
 
 
 
 
 
 
Sponsor’s Study Director and 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD


 
 
 
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TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................11 
2. 
INTRODUCTION ......................................................................................................16 
2.1. 
PRIMARY SCLEROSING CHOLANGITIS (PSC) ..................................................16 
2.1.1. 
Disease Overview .......................................................................................................16 
2.1.2. 
Treatment of PSC .......................................................................................................17 
2.2. 
SELADELPAR ...........................................................................................................19 
2.2.1. 
Mechanism of Action .................................................................................................19 
2.2.2. 
Therapeutic Rationale for Seladelpar in PSC .............................................................19 
2.3. 
NONCLINICAL STUDIES........................................................................................20 
2.3.1. 
Nonclinical Safety Assessment ...................................................................................20 
2.4. 
CLINICAL STUDIES ................................................................................................21 
2.4.1. 
Phase 1 Study in Patients with Hepatic Impairment (CB8025-11732) ......................21 
2.4.2. 
Phase 1 Mass-Balance Study in Healthy Male and Female Participants 
(CB8025-11734) .........................................................................................................23 
2.4.3. 
Additional Sub-Population Data in the Phase 2 Low-Dose Study in Patients 
with PBC (CB8025-21629) ........................................................................................23 
2.4.3.1. 
Patients Treated for 52-Weeks ....................................................................................23 
2.4.3.2. 
Patients with Compensated Cirrhosis .........................................................................24 
2.5. 
STUDY OBJECTIVES ..............................................................................................24 
2.5.1. 
Primary Objective .......................................................................................................24 
2.5.2. 
Secondary Objectives .................................................................................................25 
 
 
3. 
STUDY DESIGN .......................................................................................................26 
3.1. 
STUDY OVERVIEW .................................................................................................26 
3.2. 
STUDY OUTCOMES MEASURES ..........................................................................27 
3.2.1. 
Primary Measures .......................................................................................................27 
3.2.2. 
Secondary Measures ...................................................................................................27 
 
 
3.3. 
RATIONALE FOR DOSE SELECTION OF SELADELPAR IN PSC 
PARTICIPANTS ........................................................................................................28 
3.4. 
RATIONALE FOR A PLACEBO CONTROL ARM ...............................................29 
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3.5. 
BENEFIT/RISK ASSESSMENT ...............................................................................30 
3.5.1. 
Potential Benefit .........................................................................................................30 
3.5.2. 
Potential Risk ..............................................................................................................30 
3.5.3. 
Procedural Risks .........................................................................................................31 
3.5.4. 
Summary .....................................................................................................................31 
4. 
PARTICIPANT SELECTION....................................................................................32 
4.1. 
INCLUSION CRITERIA ...........................................................................................32 
4.2. 
EXCLUSION CRITERIA ..........................................................................................33 
5. 
SCHEDULE OF STUDY PROCEDURES ................................................................35 
5.1. 
STUDY VISIT PROCEDURES .................................................................................38 
5.1.1. 
Day -56 to Day -1 Procedures (Screening Visits 1 and 2) ..........................................38 
5.1.2. 
Day 1 Procedures ........................................................................................................39 
5.1.3. 
Week 4 Procedures .....................................................................................................42 
5.1.4. 
Week 8 Procedures .....................................................................................................43 
5.1.5. 
Week 12 Procedures ...................................................................................................43 
5.1.6. 
Week 18 Procedures ...................................................................................................45 
5.1.7. 
Week 24 Procedures ...................................................................................................45 
5.1.8. 
Week 28 (EOS) Procedures ........................................................................................47 
5.1.9. 
Unscheduled (UNS) Visits .........................................................................................47 
5.2. 
CONCOMITANT AND PROHIBITED MEDICATIONS ........................................48 
5.2.1. 
Concomitant Medications ...........................................................................................48 
5.2.2. 
Prohibited Medications ...............................................................................................48 
5.3. 
CONCOMITANT PROCEDURES ............................................................................49 
5.4. 
DIET AND ACTIVITY CONTROL ..........................................................................49 
5.5. 
CLINICAL EVALUATIONS ....................................................................................49 
5.5.1. 
Medical History and Physical Examinations (PEs) ....................................................49 
5.5.2. 
Height and Weight ......................................................................................................50 
5.5.3. 
Vital Signs ..................................................................................................................50 
5.5.4. 
Electrocardiograms .....................................................................................................50 
5.5.5. 
Clinical Laboratory Assessments ...............................................................................50 
5.5.6. 
Pharmacokinetic Sample Collection and Processing ..................................................51 
5.5.7. 
Colonoscopy ...............................................................................................................52 


 
 
 
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5.5.8. 
Magnetic Resonance Cholangiopancreatography (MRCP) ........................................52 
5.5.9. 
Magnetic Resonance Imaging (MRI) with Contrast ...................................................52 
5.5.10. 
Liver Transient Elastography (TE) by FibroScan® ...................................................52 
5.5.11. 
PSC PRO ....................................................................................................................53 
5.5.12. 
5-D Pruritus Scale .......................................................................................................53 
5.5.13. 
Pruritus Numeric Rating Scale (NRS) ........................................................................53 
5.5.14. 
Mayo Partial IBD Score ..............................................................................................54 
5.5.15. 
Imaging Procedures and Laboratory Assessments Results Reporting .......................54 
6. 
CLINICAL SUPPLIES ...............................................................................................55 
6.1. 
INVESTIGATIONAL PRODUCT ............................................................................55 
6.2. 
STUDY DRUG ACCOUNTABILITY ......................................................................55 
6.3. 
STUDY DRUG STORAGE .......................................................................................55 
6.4. 
RANDOMIZATION AND STRATIFICATION .......................................................55 
6.5. 
DOSE REDUCTION AND TEMPORARY INTERRUPTION OF STUDY 
MEDICATION ...........................................................................................................55 
6.6. 
REMOVAL OF STUDY BLIND ...............................................................................56 
7. 
ADVERSE EVENTS..................................................................................................56 
7.1. 
DEFINITION OF ADVERSE EVENTS ....................................................................56 
7.2. 
DEFINITION OF SERIOUS ADVERSE EVENTS ..................................................56 
7.3. 
ASSESSMENT OF ADVERS EVENTS ...................................................................57 
7.3.1. 
Severity .......................................................................................................................57 
7.3.2. 
Outcome ......................................................................................................................57 
7.3.3. 
Relationship to Study Drug ........................................................................................58 
7.3.4. 
Action Taken with Study Medication .........................................................................58 
7.3.5. 
Recording, Reporting, and Follow-Up of Adverse Events .........................................58 
7.3.5.1. 
Non-Serious Adverse Events ......................................................................................58 
7.3.5.2. 
Serious Adverse Events ..............................................................................................59 
7.4. 
SAFETY MONITORING ..........................................................................................60 
7.4.1. 
Muscle Injury Safety Monitoring ...............................................................................62 
7.4.2. 
Renal Safety Monitoring .............................................................................................63 
7.4.3. 
Pancreatic Safety Monitoring .....................................................................................63 
7.5. 
PRECAUTIONS .........................................................................................................63 


 
 
 
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7.5.1. 
Pregnancy ...................................................................................................................63 
8. 
STUDY WITHDRAWAL OF INDIVIDUAL PARTICIPANTS ..............................64 
9. 
STUDY STOPPING CRITERIA ...............................................................................66 
10. 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS ....................66 
10.1. 
DATA MANAGEMENT ...........................................................................................66 
10.2. 
STATISTICAL ANALYSIS ......................................................................................66 
10.2.1. 
Sample Size ................................................................................................................66 
10.2.2. 
Interim Analysis (IA) ..................................................................................................67 
10.2.3. 
Analysis Sets ...............................................................................................................67 
10.2.3.1. 
Randomized Set ..........................................................................................................67 
10.2.3.2. 
Safety Set ....................................................................................................................67 
10.2.3.3. 
Full Analysis Set (FAS) ..............................................................................................67 
10.2.3.4. 
Per Protocol (PP) ........................................................................................................67 
10.2.3.5. 
Pharmacokinetic Set ...................................................................................................67 
10.2.4. 
Efficacy and Pharmacodynamics Analysis .................................................................68 
10.2.5. 
Safety and Tolerability Analysis ................................................................................68 
10.3. 
PHARMACOKINETIC ANALYSIS .........................................................................69 
11. 
ADMINISTRATIVE ASPECTS ................................................................................69 
11.1. 
PROTOCOL ADHERENCE ......................................................................................69 
11.2. 
STUDY MONITORING ............................................................................................69 
11.2.1. 
Source Documents ......................................................................................................70 
11.2.2. 
Case Report Forms .....................................................................................................70 
11.2.3. 
Protocol Deviations ....................................................................................................70 
11.3. 
AUDITS AND INSPECTIONS .................................................................................70 
11.4. 
ETHICS ......................................................................................................................70 
11.4.1. 
Ethics Review .............................................................................................................70 
11.4.2. 
Ethical Conduct ..........................................................................................................71 
11.4.3. 
Informed Consent .......................................................................................................71 
11.5. 
RECORDS ..................................................................................................................71 
11.6. 
QUALITY ASSURANCE ..........................................................................................72 
11.7. 
DISCLOSURE ............................................................................................................72 
11.8. 
DATA SAFETY MONITORING COMMITTEE (DSMC) .......................................72 


 
 
 
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11.9. 
FINANCING INSURANCE ......................................................................................73 
12. 
REFERENCES ...........................................................................................................76 
 
TABLE OF TABLES 
Number 
Title 
Page 
2.3.1-1 
Estimated Safety Exposure Margin of Seladelpar 
21 
2.4.1-1 
Summary (Mean ± Standard Deviation [SD] of PK Parameters for 
Seladelpar in Participants with Varying Degrees of Hepatic 
Impairment 
22 
2.4.3-1 
CB8025-21629: Alkaline Phosphatase – Mean Percent Change, AP 
< 1.67 × ULN and AP Normalization 
24 
5-1 
Schedule of Study Procedures 
36 
7.4.1-1 
DILI Criteria for Participants with Normal Baseline ALT and AST 
61 
7.4.1-2 
DILI Criteria for Participants with Abnormal Baseline ALT and 
AST 
61 
7.4.2-1 
Muscle Injury Safety Criteria for Study Drug Interruption or 
Stopping Rules 
62 
7.4.3-1 
Renal Safety Criteria for Study Drug Interruption or Stopping 
Rules 
63 
 
 
 
 
LIST OF FIGURES 
Figure 3.1-1 ....................................................................................................................................27 
 
 
 
 


 
 
 
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ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACG 
American College of Gastroenterology 
AE 
adverse event 
AIH 
autoimmune hepatitis 
AP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCA 
anti-neutrophil cytoplasmic antibody 
ANCOVA analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration–time curve 
BLM 
baseline measurement 
BUN 
blood urea nitrogen 
C4 
7-alpha-hydroxy-4-cholesten-3-one 
CK 
creatine kinase 
Cmax 
maximum drug concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
DSMC 
Data Safety Monitoring Committee 
DVM 
data validation manual 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee  
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
ERCP 
endoscopic retrograde cholangiopancreatography 
ET 
early treatment withdrawal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 


 
 
 
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HDL-C 
high-density lipoprotein cholesterol 
HI 
hepatic impairment 
HIV 
human immunodeficiency virus 
HoFH 
homozygous familial hypercholesterolemia 
hs-CRP 
high-sensitivity C-reactive protein 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG4 
immunoglobulin G4 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDL-C 
low-density lipoprotein cholesterol 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities  
MELD 
Model for End-Stage Liver Disease 
MMRM 
mixed-effect model repeated measures 
MRCP 
magnetic resonance cholangiopancreatography 
MRI 
magnetic resonance imaging 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect level 
NRS 
Numeric Rating Scale 
NSF 
nephrogenic systemic fibrosis 
OLE 
Open Label Extension 
p-ANCA 
perinuclear anti-neutrophil cytoplasmic antibody 
PBC 
Primary Biliary Cirrhosis 
PD 
Pharmacodynamic(s) 
PDK4 
pyruvate dehydrogenase kinase 4 
PE 
physical exam 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
per protocol 
PPARδ 
peroxisome proliferator-activated receptor-δ 
PRESTO 
Primary Sclerosing Cholangitis Risk Estimate Tool 


 
 
 
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PRO 
patient reported outcomes 
PRO-C3 
procollagen III N-terminal peptide 
PRO-C5 
C-terminal pro-peptide of type V collagen 
PSC 
primary sclerosing cholangitis 
PT 
prothrombin time 
PTC 
percutaneous transhepatic cholangiography 
QoL 
quality of life 
RBC 
red blood cell; erythrocyte 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCr 
serum creatinine 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected, unexpected serious adverse reaction 
t1/2 
half-life 
tmax 
time to reach maximum plasma concentration  
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
UNS 
unscheduled 
U.S.  
United States 
UK  
United Kingdom 
VAS 
visual analogue score 
WBC 
white blood cell 


 
 
 
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1. 
SYNOPSIS 
Title of Study: 
A Phase 2, Randomized, Double Blind, Placebo Controlled, Multiple Center Study to 
Evaluate the Safety, Tolerability, and Efficacy of Seladelpar Administered for 
24 Weeks in Adult Patients with Primary Sclerosing Cholangitis (PSC)  
Protocol Number: 
CB8025-21845 
Phase: 
2 
Investigational 
Product: 
Seladelpar 
Objectives: 
Primary Objective:  
• 
Evaluate the treatment effect of seladelpar on alkaline phosphatase (AP) in 
participants with PSC during the study period  
 
Secondary Objectives: 
• 
Assess the safety and tolerability of seladelpar in participants with PSC during 
the study period 
• 
Evaluate the effect of seladelpar on the following: 
o 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
bilirubin (total, direct), and gamma-glutamyl transpeptidase (GGT)  
o 
Total cholesterol, HDL-cholesterol (HDL-C), LDL-cholesterol 
(LDL-C), and triglycerides 
o 
7-alpha-hydroxy-4-cholesten-3-one (C4) and serum bile acids 
o 
High sensitivity C-reactive protein (hs-CRP) and fibrinogen 
o 
Enhanced liver fibrosis (ELF) Score (total and individual 
components) and procollagen III N-terminal peptide (PRO-C3) and 
C-terminal pro-peptide of type V collagen (PRO-C5) levels 
• 
Evaluate changes in pruritus, fatigue, and quality of life (QoL) 
• 
Assess changes in symptoms associated with Inflammatory Bowel Disease (IBD)  
• 
Evaluate the incidence, frequency and severity of PSC-related symptoms and 
adverse events (AEs) 
• 
Evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of seladelpar 
in participants with PSC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Methodology/ 
Study Design: 
This is a multiple-center evaluation of seladelpar in a randomized, double-blind, 
placebo-controlled, parallel-group study when administered for 24 weeks as a daily 
oral capsule in patients with PSC. Approximately, 100 participants will be 
randomized across approximately 60 sites worldwide. 
 
Patients to be studied will have confirmed PSC as defined as having any 2 of the 
following 3 diagnostic criteria: historical elevated AP, abnormal cholangiography or 
liver histology consistent with PSC. Participants will be required to have an AP > 1.5 
× upper limit of normal (ULN) and variability ≤ 40% for AP, ALT, AST and total 
bilirubin between two visits during Screening. Ursodeoxycholic acid (UDCA) 
therapy will be allowed at stable doses of < 20 mg/kg/day for at least 24 weeks.  
Patients with stable IBD are allowed, including those treated with a stable regimen of 
biologic, immunosuppressant, or systemic corticosteroid therapy. The presence or 
history of cirrhosis (compensated or decompensated), small duct PSC, overlapping 
autoimmune hepatitis (AIH), cholangiocarcinoma (diagnosed or suspected), acute 
cholangitis or recently placed bile duct stents or ballooning dilatation procedure will 
all be excluded from this study. Please refer to Section 4 of the protocol for the 
complete listing of the Inclusion and Exclusion Criteria. 
 
All patients with IBD will be required to have had a colonoscopy within the last 12 to 
18 months of consent with no evidence of dysplasia. All participants will undergo 
MRCP and MRI with contrast during Screening to assess bile duct strictures and the 
presence of cholangiocarcinoma. Transient elastography (TE) via FibroScan® will be 
performed to assess liver stiffness and to exclude cirrhotic patients during Screening.  
 
On Day 1, participants will be randomized into one of four treatment arms (seladelpar 
5 mg, seladelpar 10 mg, seladelpar 25 mg, or placebo) in a 1:1:1:1 ratio. Participants 
will be stratified at randomization, according to UDCA use (Yes/No) and by 
averaged Screening total bilirubin values (≤ ULN vs > ULN but ≤ 2 × ULN) to 
ensure even distribution across the are treatment groups.  
 
Participants will return to the clinic at Weeks 2, 4, 8, 12, 18, and 24 for on-treatment 
assessments and procedures. Participants will receive study-drug bottles on Day 1 
and at Weeks 4, 8, and 12. Dose reductions will be permitted based on specific safety 
parameters and with approval by the Sponsor Medical Monitor. MRCP and MRI with 
contrast will be performed at Week 24 to assess changes in bile duct strictures and 
volume. FibroScan® will be performed at Weeks 12 and 24 to assess changes in liver 
stiffness. Standardized patient reported outcomes (PRO) assessments for pruritus and 
other PSC symptoms, quality of life (QoL), and IBD-related symptoms will be 
performed at Day 1 and key visits during and after study drug treatment. Week 24 
will be the End of Treatment (EOT) clinic visit. All participants eligible and willing 
can be enrolled into a separate 12 month open-label extension (OLE) study starting at 
Week 24.  Participants who do not enroll in the OLE study participant will return to 
the clinic at Week 28 for an End of Study (EOS) follow-up visit. 
 
An interim analysis (IA) will be conducted when approximately 10 participants per 
treatment arm have completed the Week 12 visit. The overall safety and efficacy of 
seladelpar in PSC will be assessed at the IA, in addition to dose selection for the 
long-term OLE. Full 24-hour PK profiles will be collected in a subset of participants 
(at least 6 participants per treatment arm) at Day 1 and Week 12. A full listing of the 
study procedures and assessments by visit are listed in Section 5 of the protocol. 


 
 
 
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Study Design 
Schema: 
 
 
 
 
Participants: 
Approximately 100 participants randomized. 
Randomization 
1:1:1:1 
Participants will be stratified according to UDCA use (Yes/No) and averaged 
Screening total bilirubin values (≤ ULN vs > ULN but ≤ 2 × ULN) to ensure even 
distribution across the four treatment arms. 
Study Sites 
Approximately 60 sites in Australia, Europe, Israel, and North America 
Test Product(s): 
Seladelpar or placebo will be supplied as a single capsule intended to deliver 5 mg, 
10 mg, 25 mg or placebo administered orally, once daily. 
Study drug should be administered in the fasted state, approximately 2 hours before 
or after a meal. 
Duration of 
Treatment: 
Total study duration is up to 36 weeks.  
Screening: Up to 8 weeks 
Treatment Period: 24 weeks 
 
 
Criteria for 
Evaluation - Safety: 
 
Safety and tolerability will be assessed by monitoring AEs and concomitant 
medications. Additional assessments will include conducting physical examinations 
(PEs), 12-lead electrocardiograms (ECGs), measuring vital signs, and collecting 
clinical laboratory assessments. Specific safety monitoring algorithms for liver, 
muscle, renal and pancreatic injury have been incorporated into the study. 
Criteria for 
Evaluation - 
Pharmacokinetics:  
PK will be analyzed to determine the single dose and repeat dose steady-state 
exposure. The results in PSC participants will be compared to both healthy volunteers 
and other seladelpar-treated study populations. Measured PK parameters will include 
maximum observed plasma concentration (Cmax), time to reach maximum plasma 
concentration (tmax), area under the concentration-time curve from time 0 to last 
measurement (AUClast), terminal elimination phase half-life (t½) for seladelpar and 
the major metabolites (M1, M2, and M3).
 
 
 
 Urine will also be collected over the 24-hour periods to assess 
the renal clearance of seladelpar and primary metabolites. 
CCI
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SCREENING 
• • • 
D -56 
D1 
W2 
W4 
ON-TREATMENT STUDY PERIOD 
Seladelpar 10 mg PO QD 
(n=25) 
Seladelpar 25 mg PO QD 
(n=25) 
W8 
W12 
• 
W18 
W24 
(EOT) 
4 Wk Post-Treatment 
Safety Follow-up Visit 
OR 
12-Month Open-Label 
Extension 


 
 
 
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Criteria for 
Evaluation - Efficacy 
and 
Pharmacodynamics: 
Primary Efficacy 
• 
Relative (%) change in AP from Baseline to Week 24. 
 
Secondary Efficacy and Pharmacodynamics 
• 
Relative (%) change in AP at Week 12  
• 
Absolute change in AP from Baseline to Week 12 and Week 24 
• 
Proportion of participants achieving AP response parameters at Week 12 and 
Week 24 
• 
The absolute and percentage changes from Baseline at Week 24 of the following 
PD parameters: 
• 
ALT, AST, bilirubin (total and direct), and GGT 
• 
Total cholesterol, HDL-C, LDL-C, and triglycerides 
• 
C4 and serum bile acids 
• 
hs-CRP and fibrinogen 
• 
ELF Score (total and individual components), PRO-C3 levels and PRO-
C5 
• 
Changes in pruritus via the numeric rating scale (NRS), in addition to fatigue and 
quality of life as determined by PSC PROs and QoL tools during the study 
period 
• 
Incidence and severity of PSC-related symptoms during the study period 
• 
Incidence and severity of IBD-associated intestinal symptoms during the study 
period 
• 
Hepatic disease progression 
• 
Relationship of drug exposure and changes in efficacy, safety/tolerability and PD 
parameters after 24 weeks of treatment 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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Statistical Methods: 
The primary efficacy analysis will consist of comparing each seladelpar treatment 
arm against the placebo arm using Analysis of Covariance (ANCOVA) model. The 
model will have the relative change in AP from Baseline to Week 24 as the 
dependent variable, treatment arm, UDCA stratification group (Yes/No) and total 
bilirubin stratification group (≤ ULN vs > ULN but ≤ 2 × ULN) as factors, and 
baseline AP as a covariate. A sensitivity analysis for the primary efficacy endpoint 
will be performed using a mixed model for repeated measures (MMRM) approach. 
The secondary endpoints will be analyzed descriptively. The confidence intervals of 
treatment differences will be provided. The safety and tolerability endpoints will be 
summarized descriptively.  
At the planned IA, the evidence regarding the safety and efficacy of seladelpar in 
PSC participants will be assessed, in order to evaluate the appropriateness of 
continuing the study and inform dose selection for the OLE study. 
Sample Size 
Determination: 
A sample size of 25 participants randomized per treatment arm was chosen in order 
to gather sufficient proof-of-concept treatment response and safety data on seladelpar 
in this population. The sample size yields 20 completing participants per treatment 
arm, assuming 20% dropout rate, from randomization to Week 24. A sample size of 
20 in each arm will have at least 90% power to detect a difference in means of 25% 
in relative (%) change of AP from baseline, assuming that the common standard 
deviation is 20%, using a two-sample t-test with a 0.0166 two-sided significance 
level, where the significance level of 0.0166 is the multiplicity-adjusted level using 
Bonferroni approach. 
 
 
 


 
 
 
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2. 
INTRODUCTION 
2.1. 
PRIMARY SCLEROSING CHOLANGITIS (PSC) 
2.1.1. 
Disease Overview 
PSC is a chronic cholestatic liver disease that is characterized by diffuse inflammation and 
fibrosis of the bile ducts (Karlsen 2017). The intra and/or extrahepatic bile ducts can be affected 
with ongoing ductal destruction leading to cholestasis, advanced fibrosis, and cirrhosis. Disease 
progression will eventually lead to liver failure with its consequent complications such as portal 
hypertension and increased risk of malignancy, including hepatocellular carcinoma (HCC) and 
cholangiocarcinoma (Karlsen 2017). PSC is frequently associated with IBD, particularly 
ulcerative colitis, with an estimated prevalence of 70% of IBD in PSC patients, depending on 
screening programs and nationality (Mertz 2019). 
The disease typically has slow progression and its course may be variable from one patient to 
another (Lazaridis 2016). Males are affected twice as often as females and are usually diagnosed 
with the disease in their fourth decade of life (Molodecky 2011). Patients are often diagnosed 
incidentally, and nearly 50% are asymptomatic at the time of diagnosis (Lazaridis 2016).  
Despite being asymptomatic, patients with PSC have a shorter average time of survival 
compared with matched controls from the general population.  
Various review articles that consider the epidemiology of PSC on a global basis note a high 
degree of variability in prevalence and incidence figures (1 per 10,000 and 0.4-2.0 per 10,000, 
respectively) with the greatest incidence and prevalence in Scandinavia, the UK, and the United 
States (U.S.) (Karlsen 2017). Several studies have suggested an increasing trend in PSC 
incidence and prevalence rates. However, these apparent increases are more likely due to 
increasing awareness of the disease, greater understanding of the coincidence with IBD, and 
improved diagnostics revealing more patients at the asymptomatic stage of disease. 
The etiology of PSC remains unclear although it is likely caused by multiple factors. These 
include autoimmunity, portal bacteremia, absorption of toxins, ischemic injury, viral infections, 
toxic bile acids, and a genetic predisposition (Karlsen 2017). The pathogenesis of PSC involves 
the exposure of genetically predisposed individuals to an environmental antigen that 
subsequently elicits an aberrant immune response, leading to development of the disease. 
The diagnosis of PSC is challenging as most patients are asymptomatic or display nonspecific 
symptoms (Lazaridis 2016). Diagnosis is typically achieved after a complication such as 
cholangitis or when hepatic dysfunction occurs. The severity and symptoms can vary between 
individuals who suffer from PSC as it is made up of more than one disease subtype, which 
include classic PSC, small-duct PSC, and immunoglobulin G4 (IgG4) PSC. A diagnosis of PSC 
is made in patients with unexplained elevated serum AP and GGT and when MRCP or 
endoscopic retrograde cholangiopancreatography (ERCP) show characteristic bile duct changes 
with multifocal strictures and segmental dilatations, and when causes of secondary sclerosing 
cholangitis and other cholestatic disorders are excluded (Lazaridis 2016). At present, there is no 


 
 
 
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specific diagnostic serologic test for PSC. A marked increase in serum autoantibody levels can 
occur in patients with PSC, including anti-neutrophil cytoplasmic antibodies (ANCAs), 
anticardiolipin antibodies, and antinuclear antibodies (Sebode 2018). Patients who present with 
clinical, biochemical, and histological features compatible with PSC but have normal 
cholangiograms are classified as having small-duct PSC. Patients presenting with IBD and 
increased liver test values are generally suspected of having concurrent PSC. However, these 
abnormal values do not reflect the severity of the underlying disease.   
Currently, liver biopsies are rarely performed to diagnose PSC. However, changes observed from 
liver biopsies in PSC patients are generally nonspecific, although periductal concentric fibrosis 
(“onion skinning”) is a typical finding and may support the diagnosis of PSC (Lindor 2015). A 
liver biopsy is generally only performed in patients with a normal cholangiography assessment 
and suspected of having small-duct PSC, overlapping autoimmune hepatitis or suspected of 
being cirrhotic.  
PSC has been described to progress through four stages: 
• Stage 1:  Lymphocyte infiltrates and bile duct epithelial cell degeneration in the portal 
triads 
• Stage 2:  Inflammatory infiltrates and early fibrogenesis in the periportal parenchyma 
with piecemeal necrosis and enlarged bile ducts with minimal ductopenia 
• Stage 3:  Portal-to-portal bridging fibrosis with severe degeneration of the ducts and 
ductopenia 
• Stage 4:  End-stage liver disease with cirrhosis 
The most frequent clinical symptoms in PSC are fatigue and pruritus, with other less common 
symptoms such as abdominal discomfort, jaundice, and weight loss (Lindor 2015). Other 
symptoms may include vitamin deficiencies and bone disease and, in advanced liver disease, 
portal hypertension, coagulopathy, and liver failure (Fricker 2019). Secondary complications of 
PSC include bacterial cholangitis, gall stones, and malignancies (cholangiocarcinoma and HCC) 
(Lazaridis 2016).   
2.1.2. 
Treatment of PSC 
Currently, the primary therapy for PSC is endoscopic and/or radiologic dilatation or stenting of 
bile duct strictures targeted at reducing cholestasis and halting progression of strictures and other 
elements of the disease (Lindor 2015). Orthotopic liver transplantation remains the only 
clinically proven treatment for patients with PSC-related end stage liver disease. Patients 
receiving a transplant have improved survival rates, with 5-year survival rates of up to 70% 
(Khan 2012). However, PSC recurs in the donor liver in approximately 20%–25% of patients at 
5 years. Additionally, patients with PSC have a 5–35% lifetime risk of developing 
cholangiocarcinoma (Khan 2012). Liver transplantation for the treatment of cholangiocarcinoma 
remains experimental due to significantly lower patient survival due to recurrent disease 
(Zamora-Valdes 2018).   


 
 
 
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Although there is no established or approved pharmacologic therapy for PSC, UDCA has been 
studied in multiple prospective clinical studies and is considered the only pharmacologic 
treatment option with a significant biochemical response. However, the data supporting a 
beneficial effect on clinical endpoints and long-term outcomes remains conflicting.  Several 
prospective, randomized controlled trials have evaluated different doses of UDCA ranging from 
10–15 mg/kg/day to 17–23 mg/kg/day and most recently up to 28–30 mg/kg/day (Saffioti 2017). 
Currently, neither the American Association for the Study of Liver Diseases (AASLD) nor the 
European Association for the Study of the Liver’s (EASL) Clinical Guidelines make a 
recommendation for general use of UDCA in PSC (Beuers 2009; Chapman 2010). However, 
recent American College of Gastroenterology (ACG) guidelines have put a limitation on doses 
above 27 mg/kg/day with a suggestion that intermediate doses may offer an improved 
biochemical response associated with improved outcomes (Lindor 2015). AP is the traditional 
marker of cholestasis and biochemical response to UDCA in PSC and recent studies have 
demonstrated it as predictive of disease progression and outcomes of treated and untreated 
patients. PSC patients with very high serum AP levels treated with UDCA usually fail to 
adequately respond, whereas those with lower serum AP activity generally have a favorable 
response and excellent long-term prognosis (Stanich 2011). Guidance from clinical experts has 
suggested a trial of 24 weeks of UDCA and to continue treatment if the AP is reduced by 40% 
from baseline or < 1.5 × ULN and no significant tolerability or safety issues are observed 
(Tabibian 2014).  
A number of immunosuppressive (prednisolone, budesonide, azathioprine, cyclosporine, 
methotrexate, mycophenolate, tacrolimus), anti-inflammatory (pentoxifylline, etanercept, other 
anti-TNF monoclonal antibodies) and anti-fibrotic (colchicine, penicillamine, pirfenidone) agents 
approved for other indications have been evaluated as primary or adjunctive treatments for PSC 
(Saffioti 2017). None of these agents have demonstrated a significant clinical benefit. Small pilot 
studies are currently studying the role of antibiotics in PSC, with liver enzyme reductions seen 
after treatment with metronidazole or oral vancomycin. However, alterations of the gut 
microbiome have largely been evaluated in small uncontrolled studies and is still considered 
experimental. 
Several recent Phase 2 clinical studies have evaluated novel targets for the treatment for PSC 
with varying levels of treatment response. Nor-ursodeoxycholic acid, obeticholic acid and 
cilofexor have been studied for 12–24 weeks, demonstrating only a modest reduction in AP and 
other markers of hepatic injury (Fickert 2017; Kowdley 2017; Trauner 2019). The monoclonal 
antibodies, vedolizumab and simtuzumab, which specifically target key mechanisms 
hypothesized to be associated with PSC, have also been studied showing minimal or no 
treatment effect (Christensen 2018; Muir 2019). Most recently, the fibroblast growth factor 19 
analogue, NGM282, demonstrated significant reductions in bile acid synthesis, liver 
transaminases, and fibrosis markers but no improvement in AP (Hirschfield 2018). None of these 
agents have demonstrated an impact on hepatic or biliary histology. 
Therefore, a significant unmet medical need still exists for novel agents for the treatment of PSC 
in order to prevent disease progression and subsequent complications. 


 
 
 
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2.2. 
SELADELPAR 
2.2.1. 
Mechanism of Action 
Seladelpar is an oral, once daily, potent and highly selective agonist of PPARδ (Bays 2011). The 
PPARδ receptor is expressed in hepatocytes (Iwaisako 2012), where it controls genes involved in 
bile acid homoeostasis. Seladelpar down regulates the expression of CYP7A1 which encodes 
cholesterol 7α-hydroxylase, the enzyme that hydroxylates cholesterol in the first step in bile acid 
synthesis (Jones 2017). The PPARδ receptor is also expressed in cholangiocytes, Kupffer cells, 
and hepatic stellate cells, all of which have implications for potential activity in PSC (Xia 2012, 
Iwaisako 2012). Cholangiocytes use the PPARδ receptor to regulate transporters involved in the 
absorption and secretion of bile components (Xia 2012). Activation of the PPARδ receptor also 
results in anti-inflammatory effects in macrophages and Kupffer cells in the liver 
(Mukundan 2009; Odegaard 2008). Seladelpar also decreases established fibrosis and stellate cell 
activity as well as reducing macrophage infiltration in 2 separate nonalcoholic steatohepatitis 
(NASH) mouse models. (Haczeyni 2017, Choi 2018). In summary, these pre-clinical data 
provide a foundation for the potential biologic activity of seladelpar in PSC based on the 
demonstrated impact on bile acid synthesis, cholangiocyte function, inflammation and 
fibrogenesis. 
2.2.2. 
Therapeutic Rationale for Seladelpar in PSC 
The preliminary clinical evidence supporting the development of seladelpar in PSC include 
2 clinical Phase 2 studies in primary biliary cirrhosis (PBC) participants; CB8025-21528 (high 
dose study) and CB8025-21629 (ongoing low dose study).  
CB8205-21528 was a double-blind, randomized, 12-week placebo-controlled, dose ranging 
(50 mg/day or 200 mg/day) Phase 2 study in PBC participants who were inadequate responders 
to UDCA (Jones 2017). Seladelpar exhibited rapid, pronounced AP decreases with no significant 
differences between 50 mg and 200 mg (mean reduction of 53% vs. 63%) compared with a mean 
reduction of 2% in the placebo group. Other biochemical markers of cholestasis, including GGT 
and total bilirubin, were also decreased with seladelpar versus no significant changes with 
placebo. Bile acid synthesis, as measured by the biomarker C4, was suppressed by 55% and 77% 
at doses of 50 mg and 200 mg, respectively. However, three cases of reversible Grade 3 ALT 
elevations, balanced with the significant treatment response, resulted in the stopping of this trial 
and initiating a study evaluating daily doses of 2 mg, 5 mg, and 10 mg of seladelpar 
(CB8025-21629). 
CB8025-21629 is an ongoing open-label, randomized dose ranging Phase 2 study in PBC 
participants who either have had an inadequate response to UDCA or are intolerant to UDCA. 
The aim of this study is to further evaluate the safety and efficacy of seladelpar at lower doses. 
An IA was performed using available data as of January 2018. The safety and efficacy of 
seladelpar treatment was evaluated for subsets of participants completing 12 weeks and 26 weeks 
of seladelpar treatment. Analysis of the first subset comprised those completing 12 weeks of 
treatment on fixed daily doses of 2 mg, 5 mg and 10 mg. After 12 weeks, patients on 2 mg 
increased to 5 mg and those on 5 mg could escalate to 10 mg if their AP treatment goal was not 
achieved. At the time of this analysis, 71 patients were exposed to at least one dose of seladelpar, 


 
 
 
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of whom 53 received 12 weeks of treatment and 42 received 26 weeks of treatment. The 5 mg 
and 10 mg doses show consistent, meaningful, and reproducible decreases in AP levels. At 12 
weeks, changes in AP were -21%, -33%, and -45% in the 2 mg (N=6), 5 mg (N=25), and 10 mg 
(N=22) mg groups, respectively. At 26 weeks, the decrease in AP was equivalent across dosing 
regimens with -43%, -45%, and -43%, in the 5 mg (N=13), 5 mg to 10 mg (N=6), and 10 mg 
(N=19) groups, respectively, and with an overall proportion of participant with AP normalization 
of 29%. The increases in transaminases observed with seladelpar 50 mg and 200 mg doses have 
not been observed with 2 mg, 5 mg and 10 mg seladelpar doses. Median ALT levels decreased 
over 12 weeks at each of the dosing levels, with no evidence to date of the previous safety signal. 
Seladelpar did not increase pruritus. Baseline median pruritus visual analogue scale (VAS) was 
10 and 40 in the 5 mg and 10 mg group, respectively, and patients in the 10 mg group 
experienced consistent decreases during follow up (-24% at Week 26). Seladelpar was generally 
safe and well tolerated and there was no transaminase elevation safety signal. There were six 
serious adverse events (SAEs); none were deemed related to seladelpar. In summary, these 
results provide evidence that seladelpar doses of 5 mg adjusted to 10 mg and 10 mg demonstrate 
potent and durable anti-cholestatic effects over 26 weeks.  
Based on the identified pharmacologic activities in vitro, in animals and in humans as well as the 
favorable safety and tolerability profiles at doses less than 50 mg per day, seladelpar represents a 
potentially important therapeutic option for the treatment of PSC. 
2.3. 
NONCLINICAL STUDIES 
Please see the Investigator’s Brochure (IB) for details on the nonclinical studies conducted with 
seladelpar. 
2.3.1. 
Nonclinical Safety Assessment 
The proposed seladelpar daily doses to be studied in the Phase 2 PSC study are 5 mg, 10 mg, and 
25 mg for 24 weeks. These doses and duration of exposure are supported by the repeat dose 
toxicity studies of 26 weeks in Sprague-Dawley rats and 52 weeks in cynomolgus monkeys. The 
exposure in PSC patients is expected to be similar to those observed in PBC patients. Based on 
this, there are adequate safety margins based on area under the concentration–time curve (AUC) 
in both sexes in all species, except for male monkeys, for the 5 mg, 10 mg, and 25 mg doses 
proposed for this study. Further details of these chronic toxicology studies in both species are 
described in the IB. 
 
 


 
 
 
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Table 2.3.1-1:  
Estimated Safety Exposure Margin of Seladelpar 
Species 
Rat (26-week) 
Monkey (52-week) 
  
M 
F 
M 
F 
NOAEL (mg/kg/day) 
15 
80 
1 
5 
AUC (ng*h/mL) 
26,900 
77,300 
2,450 
12,000 
Margin (AUC) PBC – 10 mg 
23X 
66X 
2.1X 
10X 
Margin (AUC) PSC – 25 mg 
9.2X 
26X 
0.8X 
4.1X 
Margin (AUC) NASH – 50 mg 
9.9X 
28X 
0.9X 
4.4X 
Abbreviations: AUC=area under the plasma concentration versus time curve; NASH=nonalcoholic 
steatohepatitis; NOAEL=no-observed-adverse-effect-level.  
2.4. 
CLINICAL STUDIES 
The completed studies to date in the seladelpar clinical development program include seven 
Phase 1 studies and three Phase 2 studies. One Phase 1 study studied seladelpar PK, safety, 
tolerability, and bioavailability in participants with varying hepatic impairment (HI) in addition 
to healthy participants (CB8025-11732). All other Phase 1 studies assessed seladelpar PK, 
bioavailability, drug-drug interactions, effect on the QT internal, safety, and tolerability in 
healthy volunteers. The three Phase 2 studies have evaluated seladelpar in three different disease 
populations: (1) mixed dyslipidemia participants (M8025-20711), (2) homozygous familial 
hypercholesterolemia (HoFH) participants (CB8025-21427), and (3) PBC participants 
(CB8025-21528). 
Ongoing clinical studies include a Phase 1 mass balance study in healthy participants 
(CB8025-11734), a Phase 2 low dose study in PBC participants (CB8025-21629), a Phase 2 
study in NASH participants (CB8025-21730), a Phase 3 efficacy study in PBC participants 
(CB8025-31735), and a Phase 2/3 long term study (CB8025-31731) to allow continued access to 
seladelpar for eligible and willing PBC participants completing participation in prior seladelpar 
PBC studies (CB8025-21629 and CB8025-31735). 
These studies are supportive of the clinical development of seladelpar in patients with PSC.  
Please refer to the IB for additional detailed information on these studies. Additional clinical data 
not included in the IB is summarized in the following sections. 
2.4.1. 
Phase 1 Study in Patients with Hepatic Impairment (CB8025-11732) 
CB8025-11732 is a completed Phase 1, open-label, multicenter study to evaluate the PK, safety, 
and tolerability of a single oral dose of 10 mg seladelpar in participants with varying degrees of 
hepatic function. Participants were defined as having normal hepatic function (ALT, AST and 
total bilirubin within ULN) or characterized as having HI, classified as mild, moderate, or severe 
based on Child-Pugh score. A total of 32 participants were enrolled (8 per cohort), with all 
participants receiving a single dose of 10 mg seladelpar according to the protocol. All 
participants completed the study, except for 1 participant in the moderate HI group (Cohort 3) 
who withdrew from the study due to a family emergency. In summary, a single dose of 
seladelpar 10 mg was rapidly absorbed with a median Tmax of 0.5 to 2.0 hours across the cohorts. 
After reaching Cmax, seladelpar plasma levels steadily declined with mean t1/2 ranging from 6.19 


 
 
 
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to 7.21 hours across the cohorts. Seladelpar exposure (AUC0-t or AUC0-inf values) and exposure 
to M2 (the most abundant metabolite) more than doubled in participants with moderate or severe 
HI compared to participants with normal hepatic function. A summary of the key PK parameters 
is presented in Table 2.4.1-1. 
Table 2.4.1-1: Summary (Mean ± Standard Deviation [SD]) of PK Parameters for 
Seladelpar in Participants with Varying Degrees of Hepatic Impairment 
PK Parameter 
Normal 
(Cohort 1) 
Mild 
(Cohort 2) 
Moderate 
(Cohort 3) 
Severe  
(Cohort 4) 
Cmax (ng/mL) 
71.9 ± 28.0 
101 ± 58.7 
398 ± 199 
379 ± 180 
Tmax (hr) 
2.0 (0.50, 4.0) 
1.5 (0.50, 4.0) 
1.0 (0.50, 1.5) 
0.50 (0.50, 4.0) 
AUC0-t (hr*ng/mL) 
668 ± 217 
785 ± 423 
1763 ± 606 
1570 ± 886 
AUC0-inf (hr*ng/mL) 
705 ± 227 
815 ± 432 
1807 ± 612 
1616 ± 879 
t1/2 (hr) 
6.66 ± 1.57 
6.20 ± 1.75 
6.19 ± 1.37 
7.21 ± 1.58 
CL/F (L/hr) 
15.4 ± 4.45 
14.3 ± 4.92 
6.34 ± 3.00 
7.78 ± 3.52 
Vz/F (L) 
141 ± 29.0  
120 ± 36.5 
54.6 ± 21.2 
78.7 ± 30.6 
The appearance of seladelpar metabolites M1, M2, and M3 in plasma was similar to the parent 
compound and was followed by steady elimination. The overall mean t1/2 for the three 
metabolites ranged from 7.81 to 11.0 hours with no apparent effect of the degree of HI. Exposure 
to M2 increased with HI severity, with the most apparent difference in the moderate and severe 
cohorts. A greater than 2-fold increase in M2 AUC0-t values was observed in participants with 
moderate and severe impairment compared to normal participants. Changes in exposure to M1 
and M3 were less pronounced in participants with different degrees of HI as compared to healthy 
participants with normal hepatic function. Single doses of 10 mg seladelpar were well-tolerated 
by both healthy participants and those with differing degrees of HI. Twenty-five percent of 
participants reported at least one TEAE during study participation and no individual events were 
reported in more than one participant in any cohort. Three TEAEs in 3 participants in the mild HI 
group (diarrhea, gastroesophageal reflux disease, and arthralgia) were considered related to study 
treatment by the Investigator. All TEAEs were non-serious and mild in severity, except for 1 
severe SAE of esophageal varices hemorrhage in a participant in the severe HI group who had a 
history of intermittent bleeding from esophageal varices. This SAE began 4 days after the single 
dose of study drug was administered, did not result in study discontinuation, and was considered 
unlikely related to study treatment by the Investigator. There were no deaths or TEAEs that led 
to withdrawal during the study. No clinically important mean changes in vital signs, physical 
examination findings, or laboratory values were observed. 
In summary, these results support that the exposures of seladelpar and its major metabolites are 
comparable between healthy participants and participants with mild HI, including patients with 
compensated cirrhosis. The safety and tolerability of a single dose of seladelpar was acceptable 
across all degrees of HI. 


 
 
 
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2.4.2. 
Phase 1 Mass-Balance Study in Healthy Male and Female Participants 
(CB8025-11734) 
CB8025-11734 is an ongoing Phase 1, open-label, non-randomized study to determine the 
absorption, metabolism, and excretion of [14C]-seladelpar and to characterize and determine the 
metabolites present in plasma, urine, and feces in healthy male and female participants following 
a single oral administration of seladelpar. Preliminary pharmacokinetic and urinary excretion 
data of radiolabeled parent compound and primary metabolites are available. 
In this study, four males and four healthy female participants each received a single 10 mg dose 
of [14C] – seladelpar (approximately 100 µCi). Maximum overall mean concentrations of 
drug-derived radioactivity in blood and plasma were observed 4 hours post-dose for females and 
males with overall mean values of 144 µCi (females:178; males 109) and 252 µCi (females 299; 
males: 205) ng/equivalents/g, respectively) 
The overall mean recovery of radioactivity in urine and feces was 92.9% (female: 94.1%; male: 
91.8%) over the 216-hour study with recovery in individual participants that ranged from 78.0 to 
96.7%. An overall mean of 73.4% (female: 75.1%; male: 71.8%) of the dose was recovered in 
urine and 19.5% (female: 19.0%; male: 20.0%) of the dose was recovered in feces through the 
last collection interval. Most of the administered radioactivity was recovered in the first 72 hours 
post-dose (85.6%). 
Less than 1% of the administered dose is excreted unchanged in urine. M3 accounted for most of 
urinary excretion, followed by M1, then M2 (% excreted: M3 > M1 > M2 > seladelpar 
suggesting that seladelpar is extensively metabolized. In summary, these data support that both 
biliary and renal excretion contribute significantly to the overall clearance of seladelpar and the 
identified metabolites. 
2.4.3. 
Additional Sub-Population Data in the Phase 2 Low-Dose Study in Patients with 
PBC (CB8025-21629) 
2.4.3.1. 
Patients Treated for 52-Weeks 
CB8025-21629 is an on-going Phase 2 multi-center study of adult PBC patients who have an 
inadequate response to or intolerance of UDCA. The study protocol was initially designed as an 
open-label, randomized, uncontrolled, 8-week dose ranging parallel group (5, 10, and 25 mg) 
design with an open-label extension for up to 26 weeks of treatment. Upon a planned interim 
data review performed in July 2017, the study was modified to 1) add a 2 mg dose to better 
inform the dose range and assess a minimally effective dose; 2) limit the highest dose tested to 
10 mg; 3) extend the duration to 52 weeks; and 4) increase the number of participants in the 5 
and 10 mg dose arms from 12 to 49 participants each. As of 23 July 2018, a total of 34 
participants who were initially assigned either 5 mg (n=17) or 10 mg (n=17) dose groups have 
completed 52 weeks. The 5 mg dose group includes participants who may have titrated to 10 mg 
(5/10 mg). The 2 mg dose group is not represented in the 52-Week Cohort due to the small 
number of participants reaching this timepoint as of the date of the data cut. Table 2.4.3-1 
summarizes the changes in AP in the patients completing 52 weeks as compared to the 12-week 
response rates. 


 
 
 
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Table 2.4.3-1: CB8025-21629: Alkaline Phosphatase – Mean Percent Change, AP < 1.67 × 
ULN and AP Normalization 
 
 
12-Week Cohort 
52-Week Cohort 
5 mg  
(N=32) 
10 mg  
(N=32) 
5/10mg  
(N= 17) 
10 mg  
(N=17) 
Mean % Change in AP  
-37.09 
-42.70 
-46.91 
-45.88 
AP < 1.67 x ULN 
21 (65.6%) 
26 (81.3%) 
11 (64.7%) 
13 (76.5%) 
AP Normalized 
4 (12.5%) 
10 (31.3%) 
4 (23.5%) 
5 (29.4%) 
Lower doses of seladelpar were generally safe and well-tolerated, with most AEs being mild in 
severity, and no reported deaths. There was no evidence that seladelpar was associated with 
transaminase elevations or that it induced or worsened pruritus. At the time of the data cutoff 
presented in this protocol, a total of 11 participants experienced 11 SAEs during the study (6 
SAEs in the 5/10 mg group and 5 SAEs in the 10 mg group). All the SAEs were considered 
unrelated or unlikely/remotely related to seladelpar treatment. The most common AEs were 
pruritus (unrelated to study drug), followed by fatigue, diarrhea, and nausea. Pruritus and fatigue 
are expected AEs as they are the most frequent symptoms of PBC (Kaplan 2005). In summary, 
these data support a continued durable treatment effect with favorable safety and tolerability for 
up to 52 weeks. 
2.4.3.2. 
Patients with Compensated Cirrhosis 
Of the 119 participants enrolled into the study, 25 were diagnosed as having compensated 
cirrhosis (5/10 mg, n=14 and 10 mg, n=11) based on liver biopsy, imaging tests, and/or liver 
elastography. As of 23 July 2018, 15 of 25 participants received seladelpar for 3 months, 13 of 
26 for 6 months, and 8 of 26 for 1 year (Mayo 2019). 
Mean decreases in AP (%) were -25% and -39% at 3 months, -24% and -41% at 6 months, 
and -36% and -43% at 1 year in the 5/10 mg and 10 mg groups, respectively. After 1 year, all 
patients in 5/10 mg and 3 of 5 patients in 10 mg had AP < 1.67 × ULN; the median decreases in 
ALT (%) were -31% and -50%, and the median absolute changes in pruritus VAS were 0 and -25 
in 5/10 mg and 10 mg groups, respectively. Three patients with cirrhosis experienced an SAE, all 
unrelated to seladelpar. Total bilirubin, platelets, albumin, and international normalized ratio 
(INR) remained stable and no liver decompensation events were observed. These preliminary 
data demonstrate that seladelpar treatment is safe and well-tolerated and the demonstrated anti-
cholestatic and anti-inflammatory effects support the use of seladelpar in PBC patients with 
compensated cirrhosis. 
2.5. 
STUDY OBJECTIVES 
2.5.1. 
Primary Objective 
• Evaluate the treatment effect of seladelpar on relative (%) change in AP in 
participants with PSC during the study period 


 
 
 
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2.5.2. 
Secondary Objectives 
• Assess the safety and tolerability of seladelpar in participants with PSC during the 
study period 
• Evaluate the effect of seladelpar on the absolute and/or relative (%) changes of the 
following: 
o ALT, AP, AST, bilirubin (total, direct), and GGT  
o Total cholesterol, HDL-C, LDL-C, and triglycerides 
o C4 and serum bile acids 
o hs-CRP and fibrinogen 
o ELF Score (total and individual components), PRO-C3 and PRO-C5 levels 
• Evaluate changes in pruritus, fatigue, and QoL 
• Assess changes in symptoms associated with IBD during the study period 
• Evaluate the changes in PSC-related symptoms and AEs  
• Evaluate the PK and PD of seladelpar in participants with PSC 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
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3. 
STUDY DESIGN 
3.1. 
STUDY OVERVIEW 
This is a multiple center evaluation of seladelpar in a randomized, double blind, placebo 
controlled, parallel group study when administered for 24 weeks as a daily oral capsule in 
patients with PSC. Approximately 100 participants will be randomized across approximately 
60 sites worldwide. 
Patients to be studied will have confirmed PSC as defined as having any two of the three 
following criteria: historical elevated AP, abnormal cholangiography or liver histology consistent 
with PSC. Participants will be required to have an AP > 1.5 × ULN at Screening. UDCA therapy 
will be allowed at stable doses of < 20 mg/kg/day for at least 24 weeks. Patients with stable IBD 
are allowed, including those treated with a stable regimen of biologic, immunosuppressant, or 
systemic corticosteroid therapy. The history or presence of cirrhosis (compensated or 
decompensated), small-duct PSC, overlapping AIH, cholangiocarcinoma (diagnosed or 
suspected), acute cholangitis or recently placed bile duct stents or ballooning dilatation 
procedure will all be excluded from this study. Please refer to Section 4  of the protocol for the 
complete listing of the Inclusion and Exclusion Criteria. 
All patients with IBD will be required to have had a colonoscopy with no evidence of dysplasia 
within 12-18 months of consent (as defined by local country guidelines) or during the Screening 
period. MRCP and MRI with contrast will be performed during Screening to assess bile duct 
strictures and cholangiocarcinoma. FibroScan® will be performed during Screening to assess 
liver stiffness and to rule out cirrhosis.  
On Day 1, participants will be randomized into one of four treatment arms (seladelpar 5 mg, 
seladelpar 10 mg, seladelpar 25 mg, or placebo) in a 1:1:1:1 ratio. Participants will be stratified 
at randomization, according to UDCA use (Yes/No) and by averaged Screening total bilirubin 
values  (≤ ULN vs > ULN but ≤ 2 × ULN) to ensure even distribution across the four treatment 
arms.  
Participants will return to the clinic at Weeks 2, 4, 8, 12, 18, and 24 for on-treatment assessments 
and procedures. Participants will receive study-drug bottles on Day 1 and at Weeks 4, 8 and 12. 
Dose reductions will be permitted based on specific safety parameters and with approval by the 
Sponsor’s Medical Monitor. MRCP and MRI with contrast will be performed at Week 24 to 
assess changes in bile duct strictures and volume. FibroScan® will be performed at Weeks 12 
and 24 to assess changes in liver stiffness. PRO assessments for pruritus and other PSC 
symptoms, QoL and IBD-related symptoms will be evaluated at Day 1 and key visits during and 
after study drug treatment. Week 24 will be the EOT clinic visit. All participants eligible and 
willing can be enrolled into a separate 12-month OLE study starting at Week 24. Participants 
who do not enroll in the OLE study will return to the clinic at Week 28 for an EOS follow-up 
visit.  
An  IA will be conducted when approximately 10 participants per treatment arm have completed 
the Week 12 visit. The overall safety and efficacy of seladelpar in PSC will be assessed at the IA, 
in addition to dose selection for the long-term OLE. Full 24-hour PK profiles will be collected in 


 
 
 
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a subset of participants (up to 6 per arm) at Day 1 and Week 12. A full listing of the study 
procedures and assessments by visit are listed in Section 5 of the protocol. 
Figure 3.1-1 
 
Study Design Schema 
 
 
3.2. 
STUDY OUTCOMES MEASURES 
3.2.1. 
Primary Measures 
• Treatment response defined as relative (%) change in AP from Baseline to Week 24 
3.2.2. 
Secondary Measures 
• Assessment of TEAEs (National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] Version 5.0, (Appendix A), as well as 
biochemistry, hematology and urinalysis results 
• Relative (%) change in AP at Week 12 
• Absolute change in AP at Week 12 and Week 24 
• Proportion of participants achieving the following AP response parameters at Week 
12 and Week 24: 
• Normalization defined as < ULN 
• < 1.3 × ULN 
• < 1.5 × ULN 
• > 20%, 30%, and 40% relative decrease from Baseline 
• Absolute and relative changes in ALT, AST, GGT, bilirubin (total and direct), C4, 
serum bile acids, hs-CRP, fibrinogen, ELF Score (total and components), PRO-C3, 
PRO-C5, total cholesterol LDL-C, HDL-C and triglycerides  
• QoL 
• Pruritus as measured by both the 5-D Itch Scale and a study-specific 10-point NRS 
SCREENING 
• • • 
0-56 
01 
W2 
W4 
ON-TREATMENT STUDY PERIOD 
Seladelpar 10 mg PO QD 
(n=25) 
Seladelpar 25 mg PO QD 
(n=25) 
·II •. _. I 
• 
• 
W8 
W12 
• 
W18 
I I 
W24 
(EQT) 
4 Wk Post-Treatment 
Safety Follow-up Visit 
OR 
12-Month Open-Label 
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• Incidence and severity of PSC-related symptoms or procedures defined as acute 
cholangitis, pruritus, fatigue, stent-placement, balloon dilatation and 
cholangiocarcinoma 
• Incidence and severity of IBD-related symptoms as defined by the Mayo Partial IBD 
Score 
• Hepatic disease progression as defined by the first occurrence of the following events: 
o Liver transplantation 
o Model for End-Stage Liver Disease (MELD) score ≥ 15 
o Incidence and severity of hepatic decompensation events including 
uncontrolled ascites, variceal bleeding, hepatic encephalopathy (as defined by 
a West Haven score ≥ 2), spontaneous bacterial peritonitis (confirmed by 
culture from diagnostic paracentesis) 
o Hepatocellular carcinoma 
• PK parameters to determine exposure as well as exposure-response and exposure-
safety relationships 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3. 
RATIONALE FOR DOSE SELECTION OF SELADELPAR IN 
PSC PARTICIPANTS 
The proposed doses of seladelpar to be evaluated in this study are 5, 10, and 25 mg, given as a 
single oral daily dose. The doses selected for the Phase 2 trial in PSC are supported by both the 
nonclinical and clinical data generated to date. The proposed doses are within the current safety 
margins established in the chronic toxicology (Section 2.3.1 ). The dose range for the first in 
human Phase 1 clinical trial (1, 5, 15, 60, 120, and 360 mg) was based on a dose calculation 
considering the pharmacology of seladelpar and the NOAEL in the toxicology program. All 
doses were safe and well tolerated, thus establishing the initial clinical safety of this dose range. 
Chronic dosing of seladelpar has been tested in a broad range of patient populations, including 
patients with mixed dyslipidemia (50 mg and 100 mg once a day for eight weeks), HoFH 
(50 mg, 100 mg, and 200 mg once a day over 12 weeks), NASH (10 mg, 20 mg, and 50 mg once 
a day for 52 weeks), and PBC (2 mg, 5 mg, 10 mg once a day for more than 52 weeks, and 
50 mg and 200 mg once a day for up to 12 weeks).  
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Patients with PSC are expected to have similar seladelpar exposures as PBC patients based on 
the similar underlying cholestatic conditions. Seladelpar has been studied in PBC participants at 
doses 2 mg, 5 mg, 10 mg, 50 mg and 200 mg and demonstrated rapid and significant 
improvements in cholestasis (AP, GGT, total bilirubin) and inflammation (liver transaminases, 
hs-CRP) while also demonstrating no worsening or possible improvement in pruritus. However, 
three cases of Grade 3 ALT elevations were observed as early as Week 2 in the high dose PBC 
study (CB8025-21528); one in the 50 mg dosing group and two in the 200 mg dosing group. 
While the transaminase elevations were not associated with clinical symptoms and were fully 
reversible following drug discontinuation, these events support a safety threshold at doses 
< 50 mg in a cholestatic populations. As of 23 July 2018, there have been no Grade 3 ALT 
elevations in PBC patients treated with 5 mg and 10 mg for up to 52 weeks. Additionally, 
seladelpar exposure in PSC patients is expected to be approximately 50–60% higher than 
non-cholestatic participants (healthy volunteers and NASH). Currently, doses of 10 mg, 25 mg, 
and 50 mg are being evaluated in an ongoing Phase 2 study in NASH participants, with no ALT 
elevations meeting liver safety monitoring criteria at any dose. The 25 mg maximal dose 
proposed in PSC remains within the safety margins based on both the PBC and NASH 
exposures.  
Both animal and human data support that seladelpar is cleared both through biliary and renal 
excretion, an important factor in the setting of cholestasis. Following administration of a single 
oral dose of [14C]-seladelpar to Sprague-Dawley rats, urine and feces were collected at 
designated intervals up to 166 hours post-dose for radioactivity analysis. Both Phase 1 and 
Phase 2 (glucuronide-conjugated) metabolites were identified in both urine and feces, supporting 
both hepatic and renal clearance. More recently, a Phase 1 single dose study in healthy 
participants (n= 4 male and 4 female) was conducted to determine the pharmacokinetics, 
disposition and mass balance of seladelpar and its metabolites following a single [14C]-labeled 
oral dose. An overall mean of 73.4% of the dose was recovered in urine and 19.5% of the dose 
was recovered in feces through the last collection interval. Furthermore, seladelpar is extensively 
metabolized and the resulting metabolites are largely excreted in urine. These data suggest that in 
diseases with decreased biliary excretion, seladelpar and its metabolites can be cleared by renal 
elimination and thus, should not result in significant alterations in exposure and safety margins in 
the PSC population. 
Additionally, a drug-induced liver injury (DILI) safety monitoring algorithm based on the Food 
and Drug Administration’s (FDA) Guidance for Industry for DILI has been incorporated into the 
study. A Data Safety Monitoring Committee (DSMC) will perform ongoing safety reviews at 
key timepoints throughout the study. Additionally, the Week 12 interim analysis will be to 
review the preliminary safety and tolerability of these doses in PSC. 
 
 
 
 
3.4. 
RATIONALE FOR A PLACEBO CONTROL ARM 
This study incorporates the use of a placebo comparator arm as it is the most rigorous test of 
treatment efficacy and safety profile for evaluating an experimental therapy in complex patient 
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populations. UDCA has been studied in multiple prospective clinical studies and is considered 
the only pharmacologic treatment option with some degree of biochemical response. However, 
EASL as well as AASLD currently do not make a recommendation for general use of UDCA in 
PSC (Beuers 2009; Chapman 2010). Additionally, there are currently no medications approved 
for the treatment of patients who are unresponsive to UDCA. Therefore, most randomized, 
blinded studies for experimental therapies utilize placebo as the comparator arm, independent of 
whether UDCA is used as a background medication, as there is not an accepted standard of care 
in PSC. 
3.5. 
BENEFIT/RISK ASSESSMENT 
3.5.1. 
Potential Benefit 
In a completed PBC study, participants receiving the high dose of seladelpar (50 mg and 
200 mg/day) exhibited a pronounced decrease in AP. These pronounced decreases in AP were 
also observed with lower doses of seladelpar (5 mg and 10 mg/day), after 26 weeks; the decrease 
in AP was equal across regimen at -43%, -45%, and -43%, in the 5 mg (N=13), 5 mg to 10 mg 
(N=6), and 10 mg (N=19) groups, respectively, with overall AP normalization of 29%. 
Seladelpar also has demonstrated a reduction in other biochemical markers such as ALT, AST, 
total bilirubin and GGT with the 5 mg and 10 mg doses, in addition to producing potentially 
beneficial metabolic and anti-inflammatory effects.  
Previous studies in PBC participants indicate the potential of seladelpar to improve pruritus, an 
important clinical outcome in patients with cholestatic liver diseases. PBC participants who had a 
substantial level of itching at Day 1 and were treated with seladelpar 10 mg had a significant 
decrease in pruritus VAS following treatment. These data suggest treatment with seladelpar may 
also be associated with an improvement in PSC-related itch, given the overlapping pathogenesis 
with PBC-related pruritus. 
Participants who successfully complete this study will be offered the opportunity to enroll into an 
OLE study. The OLE study will allow participants to continue their seladelpar treatment for an 
additional 12 months or until the program is discontinued. Participants on placebo will be 
switched to the active treatment with seladelpar for a total of 12 months.   
3.5.2. 
Potential Risk 
Across the clinical development program, the doses of seladelpar tested have ranged from single 
dose studies in healthy volunteers (1 mg, 5 mg, 15 mg, 60 mg, 120 mg and 360 mg), to daily 
long-term dose in Phase 2 studies in patients with mixed dyslipidemia (50 mg and 100 mg once a 
day), HoFH (ascending doses 50 mg, 100 mg, and 200 mg once a day), NASH (10 mg, 20 mg 
and 50 mg once a day), or PBC (2 mg, 5 mg, 10 mg, 50 mg, and 200 mg once a day). In these 
studies, dosing durations have ranged from 8 to 12 weeks in completed studies and up to 
52 weeks in the ongoing ‘low dose’ PBC study (CB8025-21629). In an ongoing long-term safety 
study in PBC (CB8025-31731), designed to provide continued access to seladelpar for those 
PBC participants who completed a prior seladelpar study, 4 participants to date have received 
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Seladelpar has been associated with increases in liver transaminases (ALT and AST) in 
participants with PBC treated with seladelpar at doses 50 mg and 200 mg. The transaminase 
increases appear to be dose and population dependent and were fully reversible upon treatment 
discontinuation. A single PBC participant taking seladelpar 200 mg per day discontinued 
treatment for acute muscle pain associated with increased muscle enzymes. This event was 
considered possibly related to treatment and was reversible upon treatment discontinuation. Mild 
increases (approximately 10%) in serum creatinine have been noted, consistent with those 
increases observed with other PPARα or mixed PPARα/δ class of medications. However, there 
are no concurrent change in cystatin-c or other markers of renal injury, supporting that the 
increase is not associated with renal toxicity and decreasing glomerular filtration rate (GFR). All 
three of these potential toxicities are easily monitored in the study, appear to be dose and 
population dependent, and are rapidly reversible upon discontinuation of seladelpar treatment. 
To date, there have not been any liver transaminase elevations meeting the pre-defined drug-
induced liver injury criteria, serum creatinine increases > 10% or muscle toxicity in PBC 
participants treated with 5 mg and 10 mg or in NASH participants treated with 10 mg, 20 mg or 
50 mg. 
3.5.3. 
Procedural Risks 
Participants will undergo MRI with contrast and MRCP as part of this study. The major risk 
from undergoing these procedures is related to gadolinium-based contrast administration. 
Patients with impaired renal function who receive certain gadolinium-based contrast agents are at 
risk for developing Nephrogenic Systemic Fibrosis (NSF). In order to mitigate this risk, study 
participants are required to have adequate renal function (eGFR ≥ 60 mL/min/1.73 m2). 
Additionally, only gadoxetate disodium will be used in this study. Gadoxetate disodium has a 
favorable safety profile with no cases of NSF reported to date. In addition, emerging data suggest 
that repeated exposure to gadolinium-based contrast agents can result in gadolinium deposition 
in the brain and other tissues, though no distinct clinical disease has been linked with deposition 
to date. However, the poorly understood, but likely low risk associated with tissue deposition of 
gadolinium is mitigated by the direct benefit of having a contrast-enhanced MRI to the patient. 
Patients with PSC are at risk for developing cholangiocarcinoma, and contrast-enhanced MRI is 
the most sensitive technique available for detecting cholangiocarcinoma. As a result, MRIs 
obtained in this study will benefit the individual participant by providing them with a highly 
sensitive screening for cholangiocarcinoma. 
3.5.4. 
Summary 
Seladelpar has demonstrated activity to improve liver histology and decrease markers of liver 
fibrosis in non-clinical studies. In clinical studies, seladelpar showed the ability to decrease 
markers of cholestasis (AP, GGT, bilirubin), hepatic and systemic inflammation (liver 
transaminases, hs-CRP), and bile-acid synthesis (C4, serum bile acids) in PBC participants, a 
study population relevant to PSC. These data support the assessment of seladelpar as a candidate 
for the treatment of PSC. Appropriate precautions have been incorporated into this protocol, with 
careful monitoring of potential DILI and muscle toxicity. In summary, as there are no approved 
treatments for PSC, the benefit/risk of seladelpar in PSC patients at doses of 5 mg, 10 mg, and 
25 mg is acceptable based the aggregate safety and treatment effect data to date. 


 
 
 
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4. 
PARTICIPANT SELECTION 
4.1. 
INCLUSION CRITERIA 
Patients who meet the following criteria may be included in the study: 
1. Males and females who are 18 years of age and older and are able to comprehend 
instructions and follow the study procedures and are willing to sign an Informed Consent 
Form (ICF) 
2. Confirmed diagnosis of PSC based on any two of the following three criteria:  
• Historical evidence of an elevated AP > ULN from any prior laboratory result 
• Liver biopsy consistent with PSC 
• Abnormal cholangiography consistent with PSC as measured by MRCP, ERCP, or 
PTC  
3. Participants must have the following specific additional laboratory parameters measured 
by the Central Laboratory at Screening: 
• AP ≥ 1.5 × ULN and < 8 × ULN 
• Total bilirubin ≤ 2 × ULN  
• ALT and AST ≤ 5 × ULN 
• eGFR ≥ 60 mL/min/1.73 m2 by modification of diet in renal disease (MDRD) 
calculation 
• Platelets ≥ 140 × 103/µL 
• INR ≤ 1.3 (in the absence of warfarin or other anticoagulant therapy) 
• Albumin ≥ 3.5 g/dL 
4. Participants taking UDCA will be allowed to enroll if meeting the following criteria: 
• Total daily dose of < 20 mg/kg/day 
• A minimum of 24 weeks of stable treatment 
• A minimum of 12 weeks off treatment prior to Screening if UDCA has been recently 
discontinued 
5. Participants with concomitant IBD may enroll upon meeting the following criteria: 
• A colonoscopy performed within 12 to 18 months (as defined by local country 
guidelines) of consent or during the Screening period, with no evidence of dysplasia 
• No episode of an IBD flare or IBD flare-related bloody diarrhea within 24 weeks of 
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• Stable regimen of biologic treatments, immunosuppressants, or systemic 
corticosteroids (≤ 10 mg/day prednisone or equivalent) for > 12 weeks prior to 
Screening and through Day 1 
6. FibroScan® values ≤ 14.4 kPa  
7. Participants must be able to comply with the instructions for study drug administration 
and be able to complete the study schedule of procedures 
4.2. 
EXCLUSION CRITERIA 
1. Clinically significant acute or chronic liver disease of an etiology other than PSC 
2. A diagnosis of overlapping AIH and PSC 
3. Small-duct PSC 
4. Secondary or IgG4 related sclerosing cholangitis 
5. Presence of a cholangiocarcinoma on MRCP or MRI at Screening as determined by the 
central radiologist and the Principal Investigator (PI) or Medical Monitor 
6. Bile duct stent or percutaneous bile duct drain placement within 12 weeks of Screening 
7. Balloon dilation procedure of a stricture within 12 weeks of Screening 
8. History, evidence, or high suspicion of cholangiocarcinoma or other hepatobiliary 
malignancy based on imaging, screening laboratory values, and/or clinical symptoms 
9. Presumptive or diagnosed acute cholangitis within 12 weeks of Screening and through 
Day 1   
10. Evidence of compensated or decompensated cirrhosis based on histology, relevant 
medical complications, or laboratory parameters:  
a. Historical liver biopsy demonstrating cirrhosis (e.g., Ludwig Stage 4 or Ishak Stage 
≥ 5) 
b. Current or prior history of decompensated liver disease, including ascites, hepatic 
encephalopathy, variceal bleeding or other clinical conditions consistent with 
cirrhosis and/or portal hypertension 
c. FibroScan® values > 14.4 kPa 
d. Combined low platelet count (< 140 × 103/µL) with one or more of the following: 
o Albumin < 3.5 g/dL, 
o INR > 1.3 (not due to antithrombotic agent use), or 
o Total bilirubin > ULN 
11. Variability > 40% in any one of the following laboratory parameters: AP, ALT, AST, or 
total bilirubin values between at least two visits during Screening approximately 4 weeks 
apart  
a. If a lab value at Screening Visit 2 is > 40% higher than the lab value at Screening 
Visit 1, a third sample may be drawn. If the difference between the third sample and 


 
 
 
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the value from Screening Visit 1 is also > 40% higher, the participant is excluded 
from the study  
12. Prior or actively listed for liver transplantation 
13. Any contraindication or inability to obtain a MRCP, MRI with contrast, FibroScan®, or 
colonoscopy (if required) 
14. Females who are pregnant or nursing  
• Specific criteria for defining child-bearing potential, acceptable methods of birth 
control and male partner recommendations are outlined in detail in Section 7.5.1 of 
the protocol 
15. ECG with clinically significant abnormalities as determined by the Investigator 
16. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or 
anti-human immunodeficiency virus (HIV) antibody 
17. History of malignancy diagnosed or treated within 2 years 
• Recent localized treatment of squamous or non-invasive basal cell skin cancers is 
permitted 
• Cervical carcinoma in-situ is allowed if appropriately treated prior to Screening 
• Participants under active evaluation for malignancy are not eligible 
18. Clinically relevant drug or alcohol abuse within 24 weeks of Screening. A positive drug 
screen will exclude participants unless it can be explained by a prescribed medication 
19. Any prohibited medication as listed in Section 5.2.2  of the study protocol 
20. Prior exposure to seladelpar 
21. Use of obeticholic acid, vancomycin, minocycline, fibrates or any other experimental or 
unapproved agent for the treatment of PSC within 12 weeks of Screening and throughout 
the study period 
22. Participation in a study of another investigational agent within 4 weeks of the last study 
visit for that study or five half-lives of the investigational drug (whichever is longer) prior 
to Screening 
23. History of clinically significant unstable or untreated illness or any other acute or chronic 
medical condition that may interfere with participant treatment, assessment, or 
compliance with the protocol 
24. Presence of any other conditions (e.g., geographic or social), actual or projected, that the 
investigator feels would restrict or limit the patient’s participation for the duration of the 
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5. 
SCHEDULE OF STUDY PROCEDURES 
The Schedule of Study Procedures are outlined in Table 5-1. 
The study for an individual participant consists of the following periods: 
• Screening Period: Day -56 to Day -1 
• Randomization and Treatment Initiation: Day 1 
• Study Treatment Period: Day 1 through Week 24  
• 
 
 
The visits should occur as close to the intended dates as possible and within a ± 3-day window 
for individual scheduled visits. Participants attending any visits out of windows should be 
brought back into compliance with the overall study visit schedule as soon as possible thereafter. 
 
 
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Table 5-1:  
Schedule of Study Procedures  
Study Procedure 
D –56 to –1 (Screening) 
D1 
W2  
(±3 
days) 
W4 
(±3 
days) 
W8 
(±3 
days) 
W12 
(±3 
days) 
W18 
(±3 
days) 
W24/ET 
(EOT)a 
(±3 days) 
W28 
(EOS)b 
(±3 days) 
Screening 
Visit 1  
Screening 
Visit 2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Adverse event evaluationsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, Medical Hx 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
Body Weight, Vital Signs, PE  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogramd 
X 
 
X 
 
 
 
 
 
X 
X 
Colonoscopy (if required)e 
X 
 
 
 
 
 
 
 
 
 
MRCPf  
X 
 
 
 
 
 
 
 
X 
 
MRI with contrastf 
X 
 
 
 
 
 
 
 
X 
 
FibroScan® 
X 
 
 
 
 
 
X 
 
X 
 
PK blood and urine samplesg 
 
 
Xg 
X 
X 
X 
Xg 
X 
X 
 
Chemistry and Hematology 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Viral Screen 
X 
 
 
 
 
 
 
 
 
 
Prothrombin time (PT) and 
INR 
X 
 
X 
 
X 
 
X 
 
X 
X 
p-ANCA 
X 
 
 
 
 
 
 
 
 
 
Fasting lipid panel  
X 
 
X 
 
 
 
X 
 
X 
X 
Pregnancy testi 
X 
 
X 
 
 
 
X 
 
X 
 
ELF Panel 
 
 
X 
 
X 
 
X 
 
X 
X 
Cystatin-C 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
 
 
X 
 
X 
X 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
5-D Pruritus Scale 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PSC PRO 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Mayo Partial IBD Score 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Pruritus NRSk 
X 
 
 
 
X 
 
X 
X 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
X 
X 
X 
 
 
 
Study drug compliance  
 
 
 
X 
X 
X 
X 
X 
X 
 
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Table 5-1 Schedule of Study Procedures (cont’d) 
Abbreviations: C4 = 7 Alpha-hydroxy-4-cholesten 3 one; D = Day; ELF = Enhanced Liver Fibrosis; EOS = End of 
Study; EOT = End of Treatment; ET = early treatment withdrawal; hs-CRP = high sensitivity C reactive protein; 
IBD = Inflammatory Bowel Disease; Hx = History; MRCP = magnetic resonance cholangiopancreatography; NRS = 
Numeric Rating Scale; p-ANCA = perinuclear anti-neutrophil cytoplasmic antibodies; PDK4= pyruvate 
dehydrogenase kinase 4; PE = Physical Exam; PK = pharmacokinetic; PRO = Patient Reported Outcomes; PRO-C3 
= procollagen III N-terminal peptide; PRO-C5 = C-terminal pro-peptide of type V collagen; PT/INR = Prothrombin 
Time/International Normalized Ratio; W = Week.  
Footnotes: 
a At Week 24 (EOT), participants will be offered enrollment into an OLE study and will be reconsented. Refer to 
Section 8  for Early Treatment Withdrawal (ET) procedures. 
b Week 28 (EOS) study visit will only be performed in participants not participating in the OLE study. 
c AEs will be evaluated and recorded starting from the time the participant signs the informed consent. 
d A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest and ECGs must be sent to the 
Sponsor at
 
e Colonoscopy will be performed during Screening in IBD patients who do not have an available report within 12 to 
18 months of consent. 
f MRCP and MRI with contrast will be performed in all participants during Screening and at Week 24. MRCP and 
MRI with contrast are to be performed at the same imaging facility for a given patient during the trial. Both imaging 
procedures are to be scheduled and performed on the same day for a given visit. MRCP imaging is to be performed 
before MRI with contrast at all visits.   
g PK blood samples will be collected before dosing the study medication in the clinic (pre-dose). In a subset of 
participants, full 24-hour PK will be collected at pre-dose and at 0.5, 1, 2, 4, 8, 12 and 24 hours after dosing at Day 1 
and Week 12. Urine samples will also be collected over the 24 hours interval. 
h Screening Visit 2 will occur approximately 4 weeks after Screening Visit 1 to measure serum AP, ALT, AST and 
total bilirubin to satisfy Exclusion Criterion #11. 
i A serum pregnancy test will be performed on all female participants of child-bearing potential at Screening and 
Week 24. A urine pregnancy test will be performed on all female participants at Day 1 (pre dose) and Week 12 
(pre-dose). Additional tests may be added as indicated. 
j 
 
 
k NRS will be dispensed at listed visits with the data recorded and collected by the site as outlined in Section 5.5.13 
of the protocol 
 
 
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5.1. 
STUDY VISIT PROCEDURES 
5.1.1. 
Day -56 to Day -1 Procedures (Screening Visits 1 and 2) 
5.1.1.1  
Screening Visit 1 
The following Screening Visit 1 procedures will be performed for all potential participants at a 
visit (or visits) conducted within 56 days prior to dosing. 
• Obtain informed consent. 
• 
 
• Record AEs (starting from the time the participant signs the informed consent). 
• Register participant in Interactive Web Response System (IWRS). 
• Collect demographic data. 
• Review and record medical history. 
• Obtain historical AP results, MRI, MRCP, ERCP, PTC and/or liver biopsy reports as 
required for PSC diagnosis and dominant stricture assessment. 
• Record prior and concomitant medications. 
• Assess inclusion/exclusion criteria. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination (PE).  
• Measure height. 
• Obtain 12-lead ECG (after participant has been supine for at least 5 minutes). 
• In patients with concomitant IBD, obtain colonoscopy report from eligible historical 
colonoscopy or undergo a colonoscopy procedure to obtain a new report if outside the 
48- to 72-week window.  
• Obtain new MRCP.  
• Obtain new MRI with contrast.  
• Perform FibroScan® assessment.  
• Obtain clinical laboratory samples for the following: 
o Chemistry 
o Hematology 
o HIV antibody and hepatitis B and C screening tests  
o PT/INR 
o Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) 
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o Lipids  
o Serum pregnancy test as indicated 
 Obtain urine samples for the following: 
o Urinalysis 
o Selected drugs of abuse, excluding cannabinoids 
 Perform 5-D Pruritus Scale (See Appendix D). 
 Perform the PSC PRO (See Appendix C). 
 Perform Mayo Partial IBD Score (See Appendix B). 
 Dispense Pruritus NRS diary with instructions to initiate approximately 7 days prior 
to their Day 1 visit. 
For all Screening laboratory assessments or procedures, the PI has the discretion to repeat them if 
he/she believes there is a good chance the results were spurious and do not accurately represent 
the participant’s true values. Repeat laboratory assessments or procedures must be performed 
within the 8-week Screening Period, prior to randomization, and a participant may only have 
these laboratory assessments or procedures repeated once for an individual lab or procedure at 
least two weeks from the previous testing date as an unscheduled visit. 
5.1.1.2  
Screening Visit 2 
The following Screening Visit 2 laboratory assessments will be conducted approximately 4 
weeks after Screening Visit 1 to satisfy Exclusion Criterion #11.  
 Record AEs. 
 Record prior and concomitant medications. 
 Obtain clinical laboratory samples for the following: 
o Chemistry: AP, ALT, AST and total bilirubin 
A repeat measurement is permissible if any one of the laboratory values from Screening Visit 2 
is > 40% higher compared to Screening Visit 1 values. The repeat assessments should be 
collected at an unscheduled visit a minimum of 1 week after Screening Visit 2. 
5.1.2. 
Day 1 Procedures 
Participants will report to this visit fasted for 8 hours with only water allowed. 
The following procedures will be performed at the Day 1 visit: 
 Assess for AEs from Screening period. 
 Assess for concomitant medications. 
 Reassess inclusion/exclusion criteria. 
 Measure body weight. 


 
 
 
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• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Obtain 12-lead ECG (after participant has been supine for at least 5 minutes). 
• Obtain 8 hour fasted clinical laboratory samples for the following: 
o Pre-dose PK blood sample  
o Chemistry 
o Hematology 
o PT/INR 
o Lipids 
o ELF panel 
o C4 and serum bile acids 
o Fibrinogen 
o hs-CRP 
o Pyruvate dehydrogenase kinase 4 (PDK4) 
o PRO-C3  
o PRO-C5 
o Cystatin-C 
o Back-up plasma and serum samples 
• Obtain urine samples for the following: 
o Pre-dose pregnancy test 
o Urinalysis 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Collect Pruritis NRS daily diary from Screening 
• Randomize participant (including entry of stratification criteria for UDCA use 
(Yes/No) and by averaged Screening total bilirubin value (≤ ULN vs > ULN but ≤ 2 × 
ULN) 
• Dispense initial study drug bottle(s) and diary for recording of date/time of study drug 
dosing.  
• Schedule participant for Week 2 visit. 
 
 


 
 
 
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Week 2 Procedures 
Participants will report to this visit fasted for 8 hours with only water allowed.  
The following procedures will be performed at the Week 2 visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Obtain 8 hour fasted clinical laboratory samples for the following:  
o PK blood sample 
o Chemistry 
o Hematology 
o Cystatin-C 
o Back-up serum and plasma samples 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Dispense diary.  
• Collect empty study drug bottles and diary and conduct reconciliation. 
• Schedule participant for Week 4 visit. 
 
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5.1.3. 
Week 4 Procedures 
Participants will report to this visit fasted for 8 hours with only water allowed.  
The following procedures will be performed at the Week 4 visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct complete physical examination. 
• Obtain 8 hour fasted clinical laboratory samples for the following:  
o PK blood sample 
o Chemistry 
o Hematology 
o PT/INR 
o ELF panel 
o C4 and serum bile acids 
o Fibrinogen 
o hs-CRP 
o PDK4 
o PRO-C3 
o PRO-C5  
o Cystatin-C 
o Back-up serum and plasma samples 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Dispense Week 4 Pruritis NRS daily diary. Participant will collect data for the 7 days 
following their Week 4 visit. 
• Dispense new study drug bottle and diary.  
• Collect empty study drug bottle(s) and diary and conduct reconciliation. 
• Schedule participant for Week 8 visit. 
 


 
 
 
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5.1.4. 
Week 8 Procedures 
Participants will report to this visit fasted for 8 hours with only water allowed.  
The following procedures will be performed at the Week 8 visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Obtain 8 hour fasted clinical laboratory samples for the following: 
o PK blood sample 
o Chemistry 
o Hematology 
o Cystatin-C 
o Back-up serum and plasma samples 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Collect Pruritis NRS daily diary from Week 4.  
• Dispense new study drug bottle(s) and diary. 
• Collect empty study drug bottle(s) and diary and conduct reconciliation. 
• Schedule participant for Week 12 visit. 
5.1.5. 
Week 12 Procedures 
Participants will report to this visit fasted 8 hours with only water allowed. 
The following procedures will be performed at the Week 12 visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Perform FibroScan® assessment. 


 
 
 
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• Obtain 8 hour fasted clinical laboratory samples for the following: 
o PK blood sample 
o Chemistry 
o Hematology 
o PT/INR 
o Lipids 
o ELF panel 
o C4 and serum bile acids 
o Fibrinogen 
o hs-CRP 
o PDK4 
o PRO-C3 
o PRO-C5 
o Cystatin-C 
o Back-up serum and plasma samples 
• Obtain urine samples for the following: 
o Pre-dose pregnancy test 
o Urinalysis 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO. 
• Perform Mayo Partial IBD Score. 
• Dispense Week 12 Pruritis NRS daily diary. The participant should be instructed to 
record their daily assessments for the 7 days following their Week 12 visit. 
• Dispense new study drug bottle(s) and diary. 
• Collect empty study drug bottle(s) and diary and conduct reconciliation. 
• Schedule participant for Week 18. 
 
 
 
 
 
 
 
 
 
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5.1.6. 
Week 18 Procedures 
Participants will report to this visit fasted for 8 hours with only water allowed.  
The following procedures will be performed at the Week 18 visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Obtain 8 hour fasted clinical laboratory samples for the following: 
o PK blood sample 
o Chemistry 
o Hematology 
o Cystatin-C 
o Back-up serum and plasma samples 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Collect Pruritis NRS daily diary from Week 12.  
• Dispense Week 18 Pruritis NRS diary. Participants should be instructed to record 
their daily assessments for the 7 days prior to their Week 24 visit. 
• Dispense diary. 
• Collect empty study drug bottle(s) and diary and conduct reconciliation. 
• Schedule participant for Week 24 visit. 
5.1.7. 
Week 24 Procedures 
Participants will report to this visit fasted 8 hours with only water allowed.   
The following procedures will be performed at the Week 24 or Early Treatment Withdrawal (ET) 
visit (if applicable): 
• Assess for AEs. 
• Assess for concomitant medications. 
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• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a complete physical examination. 
• Obtain 12-lead ECG (after participant has been supine for at least 5 minutes). 
• Perform MRCP. 
• Perform MRI with contrast. 
• Perform FibroScan® assessment. 
• Obtain 8 hour fasted clinical laboratory samples for the following: 
o PK blood sample 
o Chemistry 
o Hematology 
o PT/INR 
o Lipids 
o Serum pregnancy test as indicated 
o ELF panel 
o C4 and serum bile acids 
o Fibrinogen 
o hs-CRP 
o PDK4 
o PRO-C3 
o PRO-C5  
o Cystatin-C 
o Back-up serum and plasma samples 
• Obtain urine samples for urinalysis. 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
• Collect Pruritis NRS daily diary from Week 24.  
• Collect empty study drug bottle(s) and diary and conduct reconciliation. 
• 
 
 
 
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5.1.8. 
Week 28 (EOS) Procedures 
Participants will report to this visit fasted 8 hours with only water allowed.   
The following procedures will be performed at the Week 28 or End of Study (EOS) visit: 
• Assess for AEs. 
• Assess for concomitant medications. 
• Measure body weight. 
• Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse). 
• Conduct a full physical examination. 
• Obtain 12-lead ECG (after participant has been supine for at least 5 minutes). 
• Obtain 8 hour fasted clinical laboratory samples for the following: 
o Chemistry 
o Hematology 
o PT/INR 
o Lipids 
o ELF panel 
o C4 and serum bile acids 
o Fibrinogen 
o hs-CRP 
o PDK4 
o PRO-C3 
o PRO-C5  
o Cystatin-C 
o Back-up serum and plasma biomarkers 
• Obtain urine samples for urinalysis. 
• Perform 5-D Pruritus Scale. 
• Perform the PSC PRO.  
• Perform Mayo Partial IBD Score. 
5.1.9. 
Unscheduled (UNS) Visits 
Unscheduled visits may be conducted at the Investigator’s discretion and/or when repeat of 
laboratory assessments or procedures are needed. The following information may also be 
collected at the Investigator’s discretion and as indicated by the reason for the unscheduled visit: 
• TEAEs.  


 
 
 
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• Concomitant medications and procedures.  
• Vital signs and body weight.  
• Blood samples biochemistry and hematology (either partial or complete panels). 
• PK blood samples if visit is safety related. 
• A symptom-directed complete physical examination.  
• 12-lead ECG (in participants with symptoms suggestive for cardiac origin).  
• Compliance to study drug.  
• Dispense new study drug as needed. 
• Additional assessments may be performed, as determined by the Investigator. 
5.2. 
CONCOMITANT AND PROHIBITED MEDICATIONS 
5.2.1. 
Concomitant Medications 
Any medication taken within 4 weeks prior to Screening and during the study period, as well as 
the indication, will be recorded in the source documents and the electronic Case Report Form 
(eCRFs). Any AEs related to the administration of these medications or procedures must also be 
documented on the appropriate section in the eCRF. 
Participants should refrain from the use of any new prescription medications or products or 
change in the dose or frequency of existing therapies within 4 weeks prior to Day 1 until EOS. 
The Sponsor’s Medical Monitor should be informed of any changes or addition of medications 
during this time period. 
5.2.2. 
Prohibited Medications 
The following medications are prohibited from 4 weeks prior to Day 1 and through the end of 
treatment: 
• Investigational agents, other than seladelpar, or investigational devices for any 
indication 
• Agents with significant risk of hepatotoxicity 
o Concomitant medication can be screened at http://livertox.nih.gov 
o Patients on stable doses of a medication that may be hepatoxic for a minimum 
of 12 weeks can be considered for enrollment as long as there has been no 
evidence of hepatoxicity 
• Agents which can significantly increase or decrease AP 
o Patients on stable doses of a medication that may impact AP for a minimum 
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o Medications which may impact AP should not be started at any time-point 
during the Screening or study period. 
• Agents used for the treatment of any condition listed in the exclusionary enrollment 
criteria (see Section 4.2 ) 
• Off-label use or experimental therapies for PSC (such as obeticholic acid, fibrates, 
oral vancomycin) within 12 weeks of Screening through the EOS visit 
• Any herbal medications for liver health or known to be hepatotoxic, other than 
standard vitamin supplements 
In addition: 
• Participants taking medications for IBD must have been on a stable regimen of these 
medications for at least 12 weeks prior to Day 1 and should maintain, if possible, a 
stable regimen and dosing during the study period. 
• Participants taking UDCA are eligible but must have been on stable doses of 
< 20 mg/kg/day for at least 26 weeks prior to their Screening. A minimum of 12 
weeks off treatment prior to Screening is required if UDCA has been recently 
discontinued. Participants should not initiate new UDCA therapy at any timepoint 
during the study period. 
5.3. 
CONCOMITANT PROCEDURES 
A concomitant procedure is any therapeutic intervention (e.g. surgery, biopsy, physical therapy) 
or diagnostic assessment (e.g. blood gas measurement, bacterial cultures) performed during 
participants’ participation in this trial. Participants will be allowed to receive required procedures 
to treat new or existing medical conditions. 
All concomitant procedures must be documented on the participant’s eCRF. AEs related to the 
administration of these medications or procedures must also be documented on the appropriate 
section in the eCRF. 
5.4. 
DIET AND ACTIVITY CONTROL 
Participants should maintain their normal level of physical activity, diet, and lifestyle throughout 
the entire study (i.e., will not begin a new exercise program or participate in any unusually 
strenuous physical exertion). 
5.5. 
CLINICAL EVALUATIONS 
5.5.1. 
Medical History and Physical Examinations (PEs) 
A detailed medical history and PSC-related medical history will be taken at Screening.  
Complete PEs will be performed as outlined in Table 5-1. Complete physical examinations will 
include a full review of the following systems: general, skin, eyes, nose/sinuses, ears, 
mouth/throat, neck, breasts 
 and respiratory, cardiac, gastrointestinal, 
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peripheral vascular, genitourinary 
 musculoskeletal, neurologic, mental 
health, endocrine and hematologic. Complete PEs will be performed at all visits. 
Any clinically significant change in physical examination findings that occurs after signing the 
ICF will be recorded as an AE. The physical examination may be performed by a physician, 
trained physician’s assistant, or a nurse practitioner, as acceptable according to local regulation. 
5.5.2. 
Height and Weight  
Height measurement will be performed at Screening only; weight will be taken at each study 
visit per the Schedule of Study Procedures (Table 5-1). 
5.5.3. 
Vital Signs 
Vital signs (including temperature, respiratory rate, and seated blood pressure and pulse) will be 
obtained at Screening and at all study visits as outlined in the Schedule of Study Procedures 
(Table 5-1). 
Seated blood pressure and pulse will be measured after the participant has been seated for at least 
5 minutes.  
Vital signs may be obtained more frequently if a condition develops that warrants additional 
monitoring. 
5.5.4. 
Electrocardiograms 
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest at Screening 
and at all study visits as outlined in the Schedule of Study Procedures (Table 5-1). 
5.5.5. 
Clinical Laboratory Assessments 
Blood samples for laboratory testing from Day 1 and onward will be collected at study visits 
after at least an 8-hour overnight fast and prior to dosing. If the participant forgets to fast, the site 
will document, continue to draw labs and proceed with the visit. Additional details about sample 
collection, processing, handling and laboratory determination techniques are provided in the 
Laboratory Manual. 
Laboratory tests will be collected be taken at each study visit per the Schedule of Assessments 
(Table 5-1) and will include the following parameters: 
Biochemistry:  
Albumin, ALT, Amylase, AP, AST, Bicarbonate, blood urea nitrogen (BUN)/Urea, Chloride, CK, 
Bilirubin (total, direct, indirect), Creatinine, Cystatin-C, eGFR, Free Fatty Acid, GGT, Glucose, 
HDL-C, LDH, LDL-C, Lipase, non-HDL-C, p-ANCA, Potassium, Total Protein, Sodium, Total 
Cholesterol, Triglycerides, Uric Acid 
 
 
 
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Hematology:  
Erythrocyte Count (RBC), Hemoglobin, Hematocrit, Leukocyte Count (white blood cell count 
[WBC]), WBC Differential (absolute and percentage), Platelets, PT, INR  
 
 
 
Back-Up Blood Sample:  
Three additional blood samples (2 plasma and 1 serum) will be collected at each study visit. These 
samples can be stored for up to 5 years following completion of the study and used for additional 
safety assessments, measure drug levels, potential new biochemical markers, and/or to replace any 
missing or discarded samples.  
Pregnancy Tests: Serum pregnancy test will be tested in female participants of childbearing 
potential only at Screening and Week 24. Urine pregnancy test will be conducted on Day 1 prior 
to randomization and first dose of study drug and at the Week 12 visit. This can be tested at 
additional visits as recommended by the PI and/or local regulations . 
HIV Antibody, Hepatitis B and C Testing: At Screening only. The hepatitis tests will include 
HBsAg and HCV antibody (HCV-RNA only if HCV antibody is positive). 
Urine Drug Screen: At Screening only. Cannabinoids are not included in this drug screen.  
5.5.6. 
Pharmacokinetic Sample Collection and Processing 
Blood samples for PK analysis of seladelpar levels will be collected before dosing at all study 
visits as outlined in the Schedule of Study Procedures (Table 5-1).   
 
 Samples will be 
collected at pre-dose and 0.5, 1, 2, 4, 8, 12 and 24 hours after dosing. Additional blood and urine 
will be collected at specified time-points to assess additional PD and PK parameters. Participants 
will remain in clinic through the 8-hour timepoint and return to clinic for the 12- and 24-hour 
sample collection. The window for PK sample collection for the pre-dose is within 15 minutes of 
dosing, ± 5 minutes for the 0.5-hour through the 8-hour samples, and ± 30 minutes for the 12- 
and 24-hour samples. 
Urine will also be collected over the 24-hour period to assess the renal clearance of seladelpar 
and the primary metabolites. 
Processing, storage, and shipping instructions for these PK blood and urine samples will be 
presented in a separate lab manual. 
 
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5.5.7. 
Colonoscopy 
Current guidelines recommend that patients with PSC without IBD should undergo surveillance 
colonoscopy every 5 years. However, patients with PSC and IBD are recommended to undergo 
surveillance colonoscopy every 1–2 years from the time of diagnosis of PSC due to the high risk 
of colonic dysplasia in ulcerative colitis patients with PSC (Chapman 2010). Therefore, 
participants with concomitant IBD in this study should have a colonoscopy with no evidence of 
dysplasia within 12 to 18 months of consent (as defined by local guidelines). Participants who 
have had a colonoscopy within the 12 to 18 months of consent will not be required to have a new 
colonoscopy if the report is available for review. Participants without a colonoscopy report 
available will be required to have a colonoscopy performed during Screening. The colonoscopy 
results will be reviewed, interpreted and reported locally at the study site. 
5.5.8. 
Magnetic Resonance Cholangiopancreatography (MRCP) 
MRCP is a noninvasive technique for evaluating the intrahepatic and extrahepatic bile ducts and 
the pancreatic duct. The imaging protocol will vary depending on the specific magnetic 
resonance magnet being used, including its field strength (e.g., 1.5 versus 3T) and the 
manufacturer, as well as institutional experience and preferences. However, all acquisition 
protocols obtain heavily T2 weighted images as thick slabs and the images are reformatted in 
planes to optimize depiction of the extrahepatic ducts. Volume rendered images may be used to 
depict the intra- and extrahepatic bile ducts.  
MRCP imaging will be performed with gadolinium contrast at Screening and Week 24 in all 
participants with fasting. The results will be read centrally for assessment of enrollment criteria 
and any clinically significant findings. Any clinical findings on any MRCP will be reported to 
the sites and the Sponsor’s Medical Monitor by the central radiologist. Details of the MRCP 
procedures, data upload and report delivery will be summarized in a separate imaging manual. 
5.5.9. 
Magnetic Resonance Imaging (MRI) with Contrast 
Contrast-enhanced MRI is the most sensitive technique available for assessing 
cholangiocarcinoma. International guidelines recommend surveillance for cholangiocarcinoma in 
patients with PSC every 6-12 months, although practices vary from using serum measures and 
clinical assessments to imaging to a combination of the two. Since participants will undergo 
MRCP to assess their biliary systems in this study, contrast-enhanced MRI can be performed in 
the same session in the MRI scanner to assess for cholangiocarcinoma appearing as a liver mass 
rather than a biliary stricture. However, MRI with contrast must be performed sequentially after 
MRCP imaging. These MRIs will include a comprehensive dynamic MRI protocol. They will 
also include delayed phase imaging after administration of the gadoxetate disodium contrast 
agent, which maximizes detection of focal masses. Contrast-enhanced MRI will be performed in 
fasted participants at Screening and Week 24 (EOT)/Early Treatment Withdrawal (ET). 
5.5.10. 
Liver Transient Elastography (TE) by FibroScan® 
Liver TE exam will be used to evaluate liver fibrosis through a noninvasive imaging technique. 
FibroScan® is the most commonly used liver TE method which uses a modified ultrasound 
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depicting the stiffness generated from the wave propagation information. FibroScan® is 
considered to be a reliable, highly accurate, and precise method for assessing liver stiffness as a 
marker of liver fibrosis. FibroScan® has demonstrated to independently assess liver stiffness and 
link fibrosis stage with high diagnostic accuracy for severe fibrosis and cirrhosis in patients with 
PSC (Corpechot 2014).  
Participants will undergo liver TE exams by FibroScan® at Screening, Week 12 and Week 24 
(EOT)/ET visits. Clinical sites will determine the logistics of scheduling the liver TE exam and 
complete within the study visit window. Participants will be instructed to fast for 4 or more hours 
(if possible) prior to the scheduled liver elastography examination but will be allowed to take 
necessary medications and small quantities of water. Details of the FibroScan® procedures, data 
upload and report delivery will be summarized in a separate imaging manual. 
5.5.11. 
PSC PRO 
The PSC PRO (Appendix C) is a 42-item instrument that contains two modules (Symptoms and 
Impact of Symptoms) which was recently developed and undergone external validation 
(Younossi 2018). PSC PRO is self-administered and developed according to FDA guidelines. 
Reliability and validity have been established using clinical data from patient cohorts and clinical 
trials as well as comparative evaluations to multiple other commonly used instruments. The PSC 
PRO has been evaluated in a broad range of PSC patients, including patients with and without 
IBD, as well as both cirrhotics and non-cirrhotics.  
The PSC PRO is to be administered at all study visits as outlined in the Schedule of Study 
Procedures (Table 5-1). 
5.5.12. 
5-D Pruritus Scale 
The 5-D Pruritus Scale (Appendix D) is a modified version of the Total Neuropathy Scale 
(Elman 2010). It is a brief multidimensional questionnaire used to measure the chronic itch. The 
instrument claims to serve as a monitoring instrument for the long-term course of pruritus. This 
instrument has been evaluated in numerous cohorts of participants with either primary or 
secondary pruritus, though none had PBC or PSC. The 5-D Pruritus Scale has five questions that 
assess degree, duration, direction, disability, and distribution of pruritic symptoms.   
The 5-D Pruritus Scale is to be administered at all study visits as outlined in the Schedule of 
Study Procedures (Table 5-1). 
5.5.13. 
Pruritus Numeric Rating Scale (NRS) 
An 11-point NRS scale for pruritus will be completed by participants at the following timepoints: 
• Dispense at Screening and instruct the participants to record daily for approximately 
7 days prior to Day 1 
• Dispense at Week 4 and instruct the participants to record daily for 7 days after the 
visit 
• Dispense at Week 12 and instruct the participants to record daily for 7 days after the 
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 Dispense at Week 18 and instruct the participants to record daily for 7 days prior to 
the Week 24 visit 
Participants will use the scale (Appendix E) to rate severity ranging from 0 “none” to 10 “worst 
possible.” The participants will initiate collecting the daily diary at the beginning of the study 
week and complete the final assessment at the specified study visit in clinic. 
5.5.14. 
Mayo Partial IBD Score 
The Mayo Partial IBD Score (Appendix B) is a non-invasive 9-point partial Mayo score used as 
an outcome measure for clinical trials assessing therapy for ulcerative colitis (Lewis 2008). The 
partial score evaluates changes in stool frequency, rectal bleeding, and physician assessment of 
disease severity, with defined changes in the score correlating with clinical responses to 
treatment. The Mayo Partial IBD Score will be assessed by study site personnel as outlined in the 
Schedule of Study Procedures (Table 5-1). 
5.5.15. 
Imaging Procedures and Laboratory Assessments Results Reporting 
All results from imaging procedures will be unblinded and reported to sites throughout the 
duration of the study.  
Screening AP and GGT values will be collected and reported to the sites in order to determine 
participant eligibility, as outlined in Section 4. Sites will be provided with absolute values from all 
Screening visits and the relative change of AP, ALT, AST and total bilirubin values between 
Screening Visit 1 and all other Screening visits. AP and GGT laboratory values will be blinded to 
the sites and participants from the Day 1 visit and all subsequent study visits.  
If AP or GGT levels exceed the predefined safety thresholds, sites will be notified and provided 
with the values in order to manage participant safety. All other biochemical laboratory 
assessments will be collected and reported unblinded to sites for all study visits. 


 
 
 
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6. 
CLINICAL SUPPLIES 
6.1. 
INVESTIGATIONAL PRODUCT 
Seladelpar, as well as matched placebo, will be supplied in a blinded fashion as 5 mg, 10 mg, and 
25 mg capsules. The study drug (seladelpar or placebo) will be administered orally, once daily 
for 24 weeks. The study drug should be taken in the fasted state, approximately 2 hours before or 
after a meal. The participant will take one capsule every day, approximately at the same time 
each day. Study drug will be dispensed at Day 1 and Week 4, 8 and 12 visits and will be 
reconciled at all visits. 
The Sponsor will provide the Investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. The supplies will be shipped in accordance with the 
Pharmacy Manual. 
6.2. 
STUDY DRUG ACCOUNTABILITY 
The PI is responsible for ensuring that a current record of inventory/drug accountability is 
maintained. Inventory records must be readily available for inspection by the study monitor and 
are open to inspection by regulatory authorities at any time. Each shipment of drug supply for the 
study will contain a shipping manifest to assist the PI in maintaining current and accurate 
inventory records. 
6.3. 
STUDY DRUG STORAGE 
All supplies of study drug must be stored as defined in the Pharmacy Manual. 
6.4. 
RANDOMIZATION AND STRATIFICATION 
This will be a double blind, placebo-controlled study with participants stratified based on UDCA 
use and average total bilirubin values during Screening. Randomization will be managed through 
an IWRS. Once all laboratory and imaging are available and the participant has been confirmed 
to meet all the inclusion and none of the exclusion criteria, the participant will be invited to Day 
1 visit. Randomization will occur at Day 1 visit via the IWRS system and dosing of placebo, 5 
mg, 10 mg, or 25 mg seladelpar will be initiated. 
6.5. 
DOSE REDUCTION AND TEMPORARY INTERRUPTION OF 
STUDY MEDICATION 
Participants who meet specific safety monitoring criteria in Section 7.4  are eligible for the dose 
down-titration. Participants who are initially assigned to 25 mg will be down-titrated to 10 mg, 
participants initially assigned to 10 mg will be down-titrated to 5 mg, and participants initially 
assigned to 5 mg will be down-titrated to placebo. Participants initially assigned to placebo will 
remain on placebo. Participants who experience a significant AE that, in the investigator’s 
judgement, warrants a dose reduction are also eligible for a similar dose titration. Dose 
down-titration must be approved by the Sponsor’s Medical Monitor or their designee and will be 
performed in a blinded manner. Participants may only be down-titrated a single time during the 
study period. Participants who have a temporary interruption from study drug due to an AE may 


 
 
 
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resume their originally assigned dose if the AE of interest has resolved and was determined to be 
unrelated to study drug. Study drug may be held temporarily for appropriate medical procedures, 
illness, travel restrictions or other activities that may hinder the participant’s ability to dose per 
protocol (PP). The temporary interruption should not exceed 7 days, and the Sponsor’s Medical 
Monitor should be advised of any interruption as soon as possible. 
6.6. 
REMOVAL OF STUDY BLIND 
In the event of a medical emergency, where knowledge of the participant’s treatment assignment 
is necessary per the medical judgment, the investigator or the Sponsor can break the blind. 
Randomization blind will be managed through an IWRS. The unblinding must be clearly 
justified and explained by a comment in the source documentation, along with the date on which 
the code was broken and the identity of the person authorizing the unblinding. The date and time 
when the PI removed the study blind for an individual participant will be documented by the 
IWRS, and an automated notification will be sent to the Sponsor. The contract research 
organization’s pharmacovigilance team may also be required to break the blind for regulatory 
reporting purposes. 
7. 
ADVERSE EVENTS 
7.1. 
DEFINITION OF ADVERSE EVENTS 
An AE is any medical occurrence in a participant administered a pharmaceutical product in a 
clinical study, regardless of a causal relationship with this treatment. An AE can, therefore, be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to the 
medicinal product. 
An AE includes any condition (including a pre-existing condition) that: 1) was not present prior 
to study treatment, but appeared or reappeared following initiation of study treatment, or 2) was 
present prior to study treatment, but worsened during study treatment. This would include any 
condition resulting from concomitant illnesses or reactions to concomitant medications.  
A TEAE will be defined as any AE that newly appeared, increased in frequency, or worsened in 
severity after initiation of the study drug. For adverse event reporting purposes, UDCA is not 
considered as a study drug. 
7.2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
An SAE is any medical occurrence that: 
• Results in death 
• Is life-threatening (was at risk of death) at the time of the event  
• Requires in-patient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity defined as a substantial 
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• Is a congenital anomaly/birth defect 
• Is an important medical event that, when based upon appropriate medical judgment, 
may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed above in the definition for an SAE. Examples of 
such events include allergic bronchospasm, requiring intensive treatment at an 
emergency room or at home, blood dyscrasias, convulsions that do not result in in-
patient hospitalization, or the development of drug dependency or drug abuse. 
7.3. 
ASSESSMENT OF ADVERS EVENTS 
7.3.1. 
Severity 
The severity of an AE will be graded from 1 to 5 according to NCI CTCAE criteria (version 5.0, 
27 November 2017) (Appendix A).  
The CTCAE general guideline will be used to assess AE severity. Not all grades are appropriate 
for all AEs. Therefore, some AEs listed in the CTCAE have fewer than five options for grade 
selection. 
Grade 
Clinical Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.  
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
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.  
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE 
7.3.2. 
Outcome 
Participants will be followed until AEs have either resolved, returned to baseline status, or are 
deemed stable or commensurate with ongoing disease processes, per Investigational judgment. 
One of the four outcomes listed below must be recorded: 
• Resolved – The participant has fully recovered from the event with no residual 
effects observable or returned to baseline status. 
• Resolved with sequelae – The participant has recovered from the event with some 
residual side effects observable. 
• Ongoing – Effects of the event are still present, regardless of whether the effect is 
changing or stable and persistent. 
• Fatal outcome (for serious adverse events only) 


 
 
 
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7.3.3. 
Relationship to Study Drug 
The relationship or association of the AE to a study drug will be characterized as “unrelated”, 
“unlikely”, “possible”, “probably”, or “definite”.   
Relationship 
Attribution 
Description 
Unrelated to the study 
drug 
Unrelated 
The AE is clearly not related to the study drug 
Unlikely 
The AE is doubtfully related to the study drug 
Related to the study drug 
Possible 
The AE maybe related to the study drug 
Probably 
The AE is likely related to the study drug 
Definite 
The AE is clearly related to the study drug 
7.3.4. 
Action Taken with Study Medication 
The action taken with the study drug due to an AE can be categorized as one of the following: 
• None: no changes were made to study drug administration or dose 
• Permanently discontinued: study drug was stopped and not restarted 
• Temporarily interrupted: dosing was temporarily interrupted or delayed due to the AE 
and restarted at the same dose 
• Temporarily interrupted: dosing was temporarily interrupted or delayed due to the AE 
and restarted at the decreased dose 
• Not applicable: e.g., in case the AE occurred after signing the ICF but before the 
administration of study drug was commenced and/or during the follow-up period. 
7.3.5. 
Recording, Reporting, and Follow-Up of Adverse Events 
7.3.5.1. 
Non-Serious Adverse Events 
All AEs must be recorded by the Investigator in the eCRF, regardless of association with the use 
of the study treatment. An AE will be recorded any time after the time of signed ICF and 
captured until the last study visit.  
To avoid colloquial expressions, the AE should be reported in standard medical terminology. 
Whenever possible, the AE should be evaluated and reported as a diagnosis rather than as 
individual signs or symptoms. If a definitive diagnosis is not possible, the individual signs and 
symptoms should be recorded.  
For each AE, the Investigator or an adequately qualified designee will evaluate and report the 
onset, duration, severity, seriousness, and relationship to (association with) the study treatment, 
and indicate the action taken. 
Abnormal laboratory findings will be determined by review of all laboratory data collected on 
the participants. At each visit, the Investigator is responsible for assuring that the participant is 
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Any laboratory abnormalities deemed clinically significant by the Investigator should be 
reported as an AE. A clinically significant abnormality is a confirmed abnormality that is 
changed sufficiently from baseline, so that in the judgment of the Investigator, a change in 
management is warranted. This alteration may include monitoring the laboratory test further, 
initiating other diagnostic tests or procedures, or administering treatment. Whenever possible, the 
etiology of the abnormal findings will be documented in the eCRF. Repeated, additional tests 
and/or other evaluations required to establish the significance and etiology of an abnormal result 
should be obtained when clinically indicated. 
Any clinically significant laboratory abnormalities that are either unexplained or considered 
treatment-related should be promptly reported to the Sponsor. Any additional relevant laboratory 
results obtained by the Investigator during this study will be supplied to the Sponsor and 
recorded in the eCRF. 
7.3.5.2. 
Serious Adverse Events 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
investigators of SAEs including suspected unexpected serious adverse reactions (SUSARs) per 
the International Council for Harmonisation (ICH) of Technical Requirements for 
Pharmaceuticals for Human Use guidelines E2A and E6, and per the United States 21 CFR § 
312.32. Country specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations. 
Any SAE that occurred from the signing of ICF through, regardless of relationship to the study 
treatment, must be reported immediately (no later than 24 hours) by the Investigator to the 
Sponsor’s representative (safety vendor) using the SAE Report Form. Planned hospitalizations or 
procedures will not be considered as SAEs. 
The criteria for seriousness will be indicated on the SAE Report Form as defined in 
Section 7.3.1.  
The outcome for the event will be listed on the SAE Report Form as defined in Section 7.3.2. 
If additional information regarding a previously submitted SAE is obtained, a follow-up SAE 
must be sent to the Sponsor’s representative (safety vendor). The Sponsor and/or its designee 
will identify and report to regulatory authorities within the required timeframes, all SUSARs and 
clinically important increases in rate of serious suspected adverse reactions. 
SAEs must be collected and reported by the Investigator for the whole period from the signing of 
ICF until the last study visit. An SAE deemed related to study drug even if it occurs after last 
visit should be reported to the Sponsor. 
The Investigator will document all available information on the SAE form. The Investigator 
should not wait to receive additional information to fully document the event before notifying the 
Sponsor’s representative of an SAE. The initial notification should minimally include sufficient 
information to permit identification of the following: 
 


 
 
 
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• Participant’s study number  
• Time and date of study drug administrations 
• Time and date of the start of the event and either the date and time of the resolution of 
the event or a statement that the event is ongoing  
• A brief description of the event and countermeasures taken  
• Investigator’s opinion of the relationship of the event and the investigational product  
Follow-up report(s) should follow the initial report, using the SAE form in eCRF detailing 
relevant aspects of the adverse events in question. Where applicable, information from relevant 
hospital case records and autopsy reports should be obtained. All source information provided to 
the Sponsor must be appropriately anonymized. SAEs recorded during the study will be followed 
by the Investigator until resolution or stabilization. After the Follow-up Visit, non-serious AEs 
should be followed up until they resolve or have failed to resolve, for a duration determined by 
the Investigator. Follow-up procedures will be determined by the nature of the event and the 
judgment of the Investigator. Details about the distribution of safety responsibilities are 
presented in the Safety Reporting Plan. 
7.4. 
SAFETY MONITORING 
Enrolled participants with the following lab abnormalities should be monitored closely and the 
dose may be decreased, or the study drug may be interrupted and/or discontinued if criteria are 
met. The Sponsor’s Medical Monitor should be contacted as soon as possible if any of these 
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Table 7.4.1-1: DILi Criteria for Participants with Normal Baseline ALT and AST 
ALT or AST during 
Other Concurrent Parameters 
Study Treatment 
Required during Study 
Study Action 
Duration 
Treatment Duration 
NORMAL BASELINE ALT and AST 
ALT or AST > 8 x ULN 
--
ALT or AST > 5 x ULN 
for more than 2 weeks 
--
ALT, AST and Total 
Stop study drug 
Bilimbin < ULN 
ALT or AST > 3 x ULN 
AND total bilimbin > 2 x ULN 
permanently 
OR INR > 1.5 
ALT or AST > 3 x ULN 
AND clinical symptoms* 
* Clinical symptoms: appearance of fatigue, nausea, right upper quadrant pan 01· tenderness, fever, rash, 
jaundice and/or eosinophilia (> 5%). 
Table 7.4.1-2: DILi Criteria for Participants with Abnormal Baseline ALT and AST 
ALT or AST during 
Other Concurrent Parameters 
Study Treatment 
Required during Study 
Study Action 
Duration 
Treatment Duration 
ABNORMAL BASELINE ALT and AST 
ALT or AST > 2 x 
AND concomitant total bilimbin > 
baseline measurement 
2 x BLM OR INR increase by 0.2 
ALT and AST > 
ffiLM) 
Stop study drug 
ULN 
Regardless of ALT or 
Clinical symptoms* AND 
permanently 
AST levels 
concomitant total bilimbin (> 2 x 
BLM) 
ALT and AST < 2 x 
ALT or AST > 5 x BLM 
ULN 
ALT and AST 2: 2 x 
ALT or AST > 3 x BLM 
Interrupt study 
ULN but < 5 x ULN 
--
drug 
ALT and AST 2: 5 x 
ALT or AST > 2 x BLM 
ULN 
* Clinical symptoms: appearance of fatigue, nausea, right upper quadrant pan or tenderness, feve1·, rash, 
jaundice and/or eosinophilia (> 5%). 
• 
Interrupt study drug: Repeat AST, ALT, total bilirnbin, and PT/INR within 3 days and 
closely observe the participant (see Appendix F). Study dmg can be resta1ted at the same 
dose level only if a fnm competing etiology is identified and liver tests return to baseline. 
Down titration to a lower dose can also be considered at this time. 
• 
Stop study drug permanently: Repeat AST, ALT, total bilirnbin, and PT/INR within 3 
days and closely observe the participant (see Appendix F). 
• 
If close observation of a participant is not possible, stop study drug permanently. 
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7.4.1. 
Muscle Injury Safety Monitoring 
The following algorithm should be followed to assess potential dmg-induced muscle injmy . 
Table 7.4.2-1: Muscle Injury Safety Criteria for Study Drug Interruption or Stopping Rules 
Grade 3 
Creatine Kinase 
CTCAE 
(CK) dmi ng Study 
Myalgia or 
Repeat CK Test Results 
Study Action 
Treatment 
Myopathy 
CK > 2.5 x ULN 
Not observed 
CK level is~ 2.5 x ULN 
• Study drug may be reinitiated at this time 
at the cmTent dose level. 
• Study drug should remain held and CK 
testing should be perfo1med weekly until 
CK > 2.5 x ULN 
Not observed 
CK level is > 2.5 x ULN 
CK ~ 2.5 x ULN. Study drug may then be 
reinitiated at this time at a decreased dose 
level as outlined in Section 6.5 of the study 
protocol. 
• Study drug should remain held and CK 
testing should be perfo1med weekly until 
CK~ 2.5 x ULN. Study drug may then be 
reinitiated at this time at a decreased dose 
level as outlined in Section 6.5 of the study 
protocol. 
CK > 2.5 x ULN 
Observed 
CK level is > 2.5 x ULN 
• If symptoms reappear after re-challenge and 
there is no clinical explanation, then tlte 
study drug should be permanently 
discontinued. 
• The participant should continue to be 
routinely monitored until complete 
resolution of symptoms or study 
completion, whichever comes first. 
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7.4.2. 
Renal Safety Monitoring 
The following algorithm should be followed to assess potential dmg-induced renal injmy. 
Table 7.4.3-1: Renal Safety Criteria for Study Drug Interruption or Stopping Rules 
Altemative 
Semm Creatinine (sCr) during 
Repeat sCr Test 
Etiology 
Study Action 
Study T1·eatment 
Results 
Identified? 
sCr < 1.5 x ULN 
NIA 
• Continue study drug. 
• Intermpt study drug. 
• Participant should be monitored 
sCr > 1.5 x ULN 
Yes 
weekly until event resolution. 
• Study drug may be reinitiated 
sCr > 1.5 x ULN but::; 2.0 x ULN 
after sCr retums to baseline levels 
at the current dose level. 
• Stop study dmg permanently. 
sCr > 1.5 x ULN 
No 
• Pa1ticipant should be monitored 
weekly until event stabilization or 
resolution. 
• Stop study dmg permanently. 
sCr > 2.0 x ULN 
sCr > 2.0 x ULN 
NIA 
• Pa1ticipant should be monitored 
weekly until event stabilization or 
7.4.3. 
resolution. 
Pancreatic Safety Monitoring 
• 
If senun lipase > 3 x ULN with clinical symptoms of acute pancreatitis, intenupt 
study dmg and repeat the test within 3 days. 
• 
If test is confmned, perfonn abdominal imaging to exclude an alternative cause for 
the event. 
• 
Study chug may be reinitiated at the same or lower dose if there is no evidence of 
acute pancreatitis or an alternative etiology for the pancreatitis is identified. 
• 
Study chug pennanently discontinued if related to study dmg and paiiicipant closely 
monitored the paiiicipant until the event resolves. 
7.5. 
PRECAUTIONS 
7.5.1. 
Pregnancy 
No specific human clinical studies have been perfo1med to dete1mine the reproductive and 
developmental toxicity of seladelpar. 
As a precaution, female paiiicipants of child-bearing potential receiving study drng must use one 
ban-ier contraceptive and a second effective biiih control method dming the study and for at least 
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30 days after the last dose. A female participant is considered to be of childbearing potential 
unless she is post-hysterectomy or post-menopausal (defined as 2 years since their last menstrual 
period for women ≥ 55 years of age). Male participants who are sexually active with female 
partners of reproductive potential must use barrier contraception and their female partners must 
use a second effective birth control method during the study and for at least 90 days after the last 
dose. Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the participant. 
A second effective birth control method may include:  
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
• intrauterine device  
• intrauterine hormone-releasing system  
• bilateral tubal occlusion  
• vasectomized partner 
Pregnancy should be reported to the clinical monitor and to the Sponsor immediately upon 
learning of the event. Pregnancies will be followed up through delivery or termination of the 
pregnancy. 
8. 
STUDY WITHDRAWAL OF INDIVIDUAL PARTICIPANTS 
Participants will be informed that they are free to withdraw from the study at any time and for 
any reason. The PI may remove a participant from the study if it is not in the best interest of the 
participant to continue the study. The participant should be informed of new approved and 
available treatment to make an informed decision regarding continuation in the study. The 
availability of a new standard of care does not automatically terminate a participant from study 
participation.   
 
 


 
 
 
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Participants may be also be discontinued for the following reasons:  
o Enrolled into the study in violation of this protocol 
o Required the use of a prohibited concomitant medication. Participant may 
continue in the study if an acceptable alternative acceptable medication can be 
prescribed  
o Withdrawal of informed consent 
o At the discretion of the investigator for medical reasons  
o Female participants who become pregnant  
o At the discretion of the investigator or Sponsor for noncompliance  
o Significant protocol deviation  
o Administrative decision by the investigator or Sponsor or designee  
o Lost to follow-up 
o The following CTCAE stopping criteria are achieved: 
• Evidence of hepatic decompensation, including variceal bleeding, hepatic 
encephalopathy and ascites,  
• CTCAE Grade 3 or higher, possible or probably related to study drug, or  
• CTCAE Grade 4 or higher, regardless of attribution to study drug 
Notification of discontinuation will be made immediately to the Sponsor’s Medical Monitor.  In 
case of premature discontinuation of study participation, efforts will be made to perform all final 
Week 24 (EOT) and Week 28 (EOS) visits and required assessments. The date the participant is 
withdrawn from the study and the reason for discontinuation will be recorded on the participant’s 
eCRF. All withdrawn participants will be followed until resolution of any AEs or until any 
unresolved AEs are judged by the PI to have stabilized. 


 
 
 
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9. 
STUDY STOPPING CRITERIA 
The entire study may be paused, and clinical data may be reviewed by the DSMC for safety if: 
• Three participants develop the same Grade 3 CTCAE related to study drug,   
• Two participants develop any Grade 4 CTCAE related to study drug, or 
• One participant develops a Grade 5 CTCAE 
The entire study may be discontinued at the discretion of the Sponsor based on the occurrence of 
the following: 
• AEs with respect to their nature, frequency, severity, and/or duration 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of seladelpar drug development 
10. 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS 
10.1. 
DATA MANAGEMENT 
A data validation manual (DVM) will specify all relevant aspects of data processing and 
handling for the study, including how data will be managed and cleaned.  Relevant sections of 
the DVM includes the following:  standard operating procedures to be followed; eCRF data entry 
and flow, tracking and filing; coding and coding review plan; reconciliation of SAEs; external 
and vendor data integration, import, and reconciliation; and general listing review. 
10.2. 
STATISTICAL ANALYSIS 
10.2.1. 
Sample Size 
A sample size of 25 participants randomized per treatment group was chosen in order to gather 
sufficient proof-of-concept treatment response and safety data on seladelpar in this population.  
The sample size yields 20 completing participants per treatment group, assuming 20% dropout 
rate, from randomization to Week 24. A sample size of 20 in each group will have at least 90% 
power to detect a difference in means of 25% in change of AP from baseline assuming that the 
common standard deviation is 20% using a two-sample t-test with a 0.0166 two-sided 
significance level, where the significance level of 0.0166 is the multiplicity-adjusted level using 
Bonferroni approach. Assumptions underlying the means are based on studies evaluating UDCA 
as a first line therapy and in studies where secondary or combination therapies with UDCA have 
been utilized. 
 


 
 
 
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10.2.2. 
Interim Analysis (IA) 
An IA will be conducted when approximately 10 participants/cohort have completed the Week 
12 visit. At the IA, the evidence regarding the safety and efficacy of seladelpar in the PSC 
indication will be assessed, in order to evaluate the appropriateness of continuing the study and 
dose selection for the OLE study.  
A separate Statistical Analysis Plan (SAP) for the IA will be generated, describing the conduct of 
the IA in detail. 
10.2.3. 
Analysis Sets 
The analysis sets are detailed below. Details of any others will be described in the SAP. 
10.2.3.1. Randomized Set 
All randomized participants will be included in the Randomized Set. In analyses using this set, 
participants will be grouped according to randomized treatment.  
10.2.3.2. Safety Set 
All randomized participants who receive at least one dose of study drug will be included in the 
Safety Set. In analyses using this set, participants will be grouped according to actual treatment 
received. 
All safety analyses will be performed using the Safety Set. 
10.2.3.3. Full Analysis Set (FAS) 
All randomized participants who receive at least one dose of study drug and have at least one 
valid, non-missing post dose AP assessment will be included in the FAS. This will be the set for 
the primary analyses of efficacy and PD endpoints. In FAS analyses, participants will be grouped 
according to randomized treatment, i.e. participants will be analyzed by the intention-to-treat 
approach. 
10.2.3.4. Per Protocol (PP) 
The PP Set will constitute a subset of the FAS. It will include participants who have at least one 
valid, non-missing post dose AP measurement. In addition, FAS participants who deviate from 
the conduct of the study or have an AE deemed by the Medical Monitor to be impactful on the 
primary endpoint will be excluded from the PP Set. In associated analyses, participants will be 
grouped according to actual treatment received, if it differs from the randomized treatment. 
The PP Set may be used to perform sensitivity analysis on efficacy endpoints. 
10.2.3.5. Pharmacokinetic Set 
All randomized participants who receive at least one dose of study drug, had a pre-dose 
(Baseline) blood draw, and provided at least one qualified (above the limit of quantification) 
post-dose sample will be included in the PK Set. Participants with protocol violations will be 
assessed by the Medical Monitor for inclusion in this set. In associated analyses, participants will 


 
 
 
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be grouped according to the actual treatment received, if it differs from that to which the 
participant was randomized. 
10.2.4. 
Efficacy and Pharmacodynamics Analysis 
The primary efficacy endpoint, relative change in AP from Baseline to Week 24, will be 
analyzed using the ANCOVA model with treatment arm, UDCA stratification group (Yes/No) 
and total bilirubin stratification group (≤ ULN vs > ULN but ≤ 2 × ULN) as factors. Baseline 
AP, as a covariate, on the observed cases on the FAS population will also be included in the 
model. The statistical comparison of each seladelpar treatment arm against the placebo group on 
the primary endpoint will be made at a two-sided significance level of 0.0166, where the 
significance level of 0.0166 is the multiplicity-adjusted level using Bonferroni approach.  
A sensitivity analysis for the primary efficacy endpoint will be performed using a mixed model 
for repeated measures (MMRM) approach assuming missing data is missing at random. The 
model will include treatment arm, study visit (Week 2, 4, 8, 12, 18, 24), UDCA stratification 
group (Yes/No) and total bilirubin stratification group (≤ULN vs > ULN but ≤ 2 × ULN) as 
factors. Baseline AP, as a covariate, and the interaction between treatment arms and study visits 
will also be included in the model. The model will assume an unstructured covariance matrix. 
The MMRM analysis will be conducted using the observed cases on the FAS population. 
The secondary endpoints will be analyzed descriptively. The confidence intervals of differences 
between each seladelpar treatment arm and the placebo arm will be provided. The ANCOVA and 
MMRM approaches used for the primary endpoint may also be applied to the secondary 
endpoints when applicable. 
Details of statistical parameters and methods to be applied will be provided in an SAP prior to 
database lock (unblinding). 
10.2.5. 
Safety and Tolerability Analysis 
Safety and tolerability analysis will be conducted on the Safety Set. AEs, including SAEs, will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AE summaries will 
be restricted to TEAEs only, defined as AEs that commence after the time of start of first dose of 
study drug and up to 30 days after the last dose of study drug. The number and percentage of 
participants experiencing a TEAE will be summarized for each system organ class (SOC) and 
preferred term by treatment group. Separate summaries will be provided for TEAEs by severity, 
causality, and relationship to study drug. AEs will also be listed.   
Observed values and changes from Baseline for select clinical laboratories will be summarized at 
each PP time point for each treatment group. Shift tables may also be presented for select 
chemistry and hematology parameters. Laboratory values will also be listed, with out of range 
and clinically significant laboratory values identified. 
Descriptive statistics for physical examination results, vital signs and other safety endpoints will 
also be provided. 
Detailed analysis methods for safety and tolerability will be provided in the SAP. 
 


 
 
 
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10.3. 
PHARMACOKINETIC ANALYSIS 
The parameters describing the PK will be derived from plasma concentrations and actual sample 
draw times from the noncompartmental analysis with the software program Phoenix 
WinNonlin® (Version 6.4 or later). 
Plasma concentration data for seladelpar and metabolites M1, M2, and M3 will be displayed 
graphically on the linear and semi-logarithmic scales. The following graphs will be presented for 
the concentration-time data: 
• Individual participant plasma concentration profile versus time 
• Mean concentration (± SD) versus time, designated by cohort 
PK parameters for seladelpar, M1, M2, and M3 may be calculated, listed, and summarized with 
descriptive statistics as detailed in the SAP. Pharmacokinetic parameter listings and statistical 
summaries will be generated separately for each dose group. A statistical analysis of PK 
parameters for seladelpar, M1, M2, and M3 will be carried out with an analysis of variance 
model on log-transformed PK parameters, Cmax and AUClast. 
Urine samples will also be collected over the 24-hour period and similar PK analyses will be 
performed. 
All summaries will be prepared with the PK analysis set.    
11. 
ADMINISTRATIVE ASPECTS 
11.1. 
PROTOCOL ADHERENCE 
The PI must adhere to the protocol as detailed in this document and agree that the Sponsor must 
approve any changes to the protocol prior to seeking approval from the EC. No alterations in the 
protocol will occur without agreement between the Sponsor and the PI. No alterations in the 
protocol affecting participant safety will occur without the express written approvals of the 
Sponsor, PI, and EC. 
11.2. 
STUDY MONITORING 
The Sponsor’s or designee’s monitor (i.e., “the monitor”) will be responsible for monitoring this 
clinical trial. The monitor will visit to initiate the study, prior to the first treatment of the first 
participant, and at agreed upon times throughout the study, including at the end of the study. 
Study drug dispensing and clinical drug supply records will be 100% verified at the study sites 
by the monitor. It is understood that all participant specific information is confidential and no 
documentation that can link study information to the specific participant will be collected or 
retained by the Sponsor. 
The monitor will specifically review the study conduct, proper eCRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, the monitor will 


 
 
 
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visit the study sites at suitable intervals and be in frequent contact through verbal and written 
communication. The PI will grant access to all documents (related to the study and the individual 
participants) at any time these are requested by the sponsor or designee. In turn, the monitor will 
adhere to all requirements for participant confidentiality as outlined in the ICF. The PI and PI’s 
staff will be expected to cooperate with the monitor, to be available during a portion of the 
monitoring visit to answer questions, to resolve discrepancies, and to provide any missing 
information. 
11.2.1. 
Source Documents 
The investigators and institution(s) will permit trial-related monitoring of the eCRF data by 
CymaBay Therapeutics Inc. or their assignee by providing direct access to source data and/or 
documents. The study monitor will verify the eCRFs against the source documentation. 
11.2.2. 
Case Report Forms 
Participants who have signed the ICF will be assigned a participant number and will have study 
data entered into an eCRF. eCRF completion is important to the medical monitoring of the trial 
and should be completed promptly after each participant visit. 
11.2.3. 
Protocol Deviations 
Protocol deviations are not permitted, and protocol waivers will not be granted. Deviations to the 
protocol should be avoided, except when the investigator considers participant safety to be at risk 
if action is not taken. The Sponsor is to be notified of any protocol deviations that occur.  
Deviations from the will be noted in the source documentation, in the eCRF and a 
complementary database. The Sponsor will assess any protocol deviation and decide whether any 
of these non-compliances should be reported to regulatory authorities as a serious breach of 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and the 
protocol. 
11.3. 
AUDITS AND INSPECTIONS 
Regulatory authorities, IEC, and/or CymaBay Therapeutics Inc. or its designee(s) may request 
access to all source documents, eCRF data, and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the investigator, who must 
provide support at all times for these activities.  
It is understood that all participant specific information is confidential and no documentation that 
can link study information to the specific participant will be collected or retained by the Sponsor. 
11.4. 
ETHICS 
11.4.1. 
Ethics Review 
This protocol, the informed consent document, recruitment advertisements and all relevant 
supporting data, as well as amendments to any of these documents, must be submitted to the 
Institutional Review Board (IRB)/Ethics Committee (EC) for approval. IRB/EC approval of 


 
 
 
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these documents must be obtained before the study may be initiated. The study will not start 
before written approval by IRB/EC has been obtained and the local regulatory requirements have 
been complied with. 
The IRB/EC must meet all the appropriate ICH requirements for composition, documentation, 
and operational procedures.  
The PI is responsible for keeping the IRB/EC advised of the progress of the study and of any 
changes made to the protocol as deemed appropriate but, in any case, at least once a year. The PI 
is also responsible for notifying the IRB/EC of any reportable AEs that occur during the study. 
11.4.2. 
Ethical Conduct 
The study will be conducted in strict accordance with the Declaration of Helsinki, ICH GCP 
guidelines, applicable laws and regulations, and the procedures outlined in IEC approved version 
of this protocol. 
11.4.3. 
Informed Consent 
This study will be conducted in compliance with ICH E6 Good Clinical Practice: Consolidated 
Guidelines pertaining to informed consent.  At the first visit, prior to initiation of any study 
related procedures, patients must give their written consent to participate in the study after 
having been informed about the nature and purpose of the study, participation/termination 
conditions, and risks and benefits. Such meetings must be carried out on an individual basis and 
adapted to the educational background and previous knowledge of the participant. Participation 
in this meeting should be documented in the participant’s file. The participant must be allowed 
ample time to inquire about details and to decide whether or not to participate in the study. 
Written informed consent will be obtained for all participants screened in the trial and before 
study related activities are performed on a participant. The process of obtaining written informed 
consent will be documented in the source documents of the participant. Only ICFs approved by 
the IEC will be used. 
The informed consent document must be signed and dated by the patient and PI, or designee, 
prior to study participation.  A copy of the informed consent document must be provided to the 
participant. Signed consent forms must remain in the participant’s study file and be available for 
verification by Sponsor or its representative at any time. 
11.5. 
RECORDS 
The results from Screening and data collected during the study will be recorded in the 
participant’s eCRF. To maintain confidentiality, the participants will be identified only by 
numbers. The completed eCRFs will be transferred to the Sponsor or designee. Copies of each 
eCRF will be retained by the PI. All source documents, records, and reports will be retained by 
the clinic. 
All primary source data or copies thereof (e.g., laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records) that are a result of the original observations 
and activities of the study and are necessary for the reconstruction and evaluation of any study 
report will be retained in the clinic archives. 


 
 
 
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The Sponsor will inform the PI of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest (longest) 
standard applicable to that site for the study, as dictated by any institutional requirements or local 
laws or regulations, or the Sponsor’s standards/procedures; otherwise, the retention period will 
default to the retention period of 15 years following completion of the clinical trial.   
11.6. 
QUALITY ASSURANCE 
Clinical data will be recorded in eCRF. Data will be verified and confirmed by the investigators. 
All data that will be used in the safety analyses and adverse events will be source documents 
verified by the monitors. Additionally, the Sponsor will conduct audit reviews of monitored 
eCRFs. A final audit of the electronic database against the final eCRF will be done. 
11.7. 
DISCLOSURE 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of 
CymaBay Therapeutics, Inc. The investigator may use this information for the purposes of the 
study only. It is understood by the investigator that CymaBay Therapeutics, Inc. will use 
information developed in this clinical study in connection with the development of the 
investigational medication and, therefore, may disclose it as required to other clinical 
investigators and to regulatory agencies. In order to allow the use of the information derived 
from this clinical study, the investigator understands that he/she has an obligation to provide 
complete test results and all data developed during this study to the Sponsor.  
The investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from CymaBay Therapeutics, Inc. CymaBay Therapeutics, 
Inc. agrees that, before it publishes any results of the study, it shall provide the investigator with 
at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript, to the publisher. 
11.8. 
DATA SAFETY MONITORING COMMITTEE (DSMC) 
A DSMC will be established in order to protect participant welfare, preserve study integrity, and 
provide recommendations as needed regarding study conduct. The DSMC will be comprised of 
two external liver disease clinical experts as well as a statistician and a medical team member 
from the Sponsor. The DSMC will meet at predefined time points and on an as needed basis 
based on enrollment, treatment milestones, and safety. The DSMC will also review all SAEs, 
liver-related safety events, elevations in ALT/AST, sCr, CK and lipase that meet safety 
monitoring criteria. Formal minutes and recommendations will be provided by the DSMC to the 
Sponsor regarding additional data requests and the continuation of the conduct of the study as 
outlined in the current protocol. The DSMC will operate under the guidance of an agreed upon 
charter. 
 


 
 
 
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11.9. 
FINANCING INSURANCE 
The financing and insurance for this study are outlined in the Clinical Trial Agreement. 
 
 


 
 
 
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INVESTIGATOR PROTOCOL REVIEW AND SIGNATURE FORM 
 
Protocol Number: 
CB8025-21845 
 
Protocol Title: A Phase 2, Randomized, Double Blind, Placebo Controlled, Multiple Center 
Study to Evaluate the Safety, Tolerability, and Efficacy of Seladelpar Administered for 24 
Weeks in Adult Patients with Primary Sclerosing Cholangitis (PSC) 
 
I have read the above-mentioned Protocol dated 05 June 2019. 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practice and applicable regulatory requirements, and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
 
__________________________________________ 
Principal Investigator (Please PRINT) 
 
 
 
__________________________________________ 
__________________ 
Principal Investigator (Signature) 
 Date 
 
 
__________________________________________ 
Name of Institution (Please PRINT) 
 
 


CymaBay Therapeutics. Inc. 
SPONSOR PROTOCOL APPROVAL AND SIGNATURE PAGE 
Protocol Number: CB8025-2 l 845 
Protocol CB8025-21845 
Protocol Title: A Phase 2, Randomized, Double Blind, Placebo Controlled, Multiple Center 
Study to Evaluate the Safety, Tolerability, and Efficacy of Seladelpar Administered for 24 
Weeks in Adult Patients with Primary Sclerosing Cholangitis (PSC) 
I have read the above-mentioned Protocol dated 05 June 2019. 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practice and applicable regulatory requirements, and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
[PPD 
PPD 
ate 
Protocol Version 2.0, 05-JUN-2019 
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12. 
REFERENCES 
Bays HE, Schwartz S, Littlejohn T III, et al. MBX-8025, a novel peroxisome proliferator 
receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients 
treated with and without atorvastatin. J Clin Endocrinol Metab. 2011;96(9):2889-97. 
Beuers U, Boberg KM, Chapman RW, et al. EASL Clinical Practice Guidelines: management of 
cholestatic liver diseases. J Hepatol. 2009;51:237–67. 
Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing 
cholangitis. Hepatology. 2010;51:660–78. 
Christensen B, Micic D, Gibson PR, et al. Vedolizumab in patients with concurrent primary 
sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but 
is safe and effective for the bowel disease. Aliment Pharmacol Ther. 2018 Mar;47(6):753-762. 
Choi Y, Song J, Johnson JD, et al.  Seladelpar Improves Hepatic Steatohepatitis and Fibrosis in a 
Diet-Induced and Biopsy-Confirmed Mouse Model of NASH. Abstract #1311. Presented at: The 
Liver Meeting; Nov 9-13, 2018; San Francisco, CA, USA 
Corpechot C, Gaouar F, El Naggar A, et al. Baseline Values and Changes in Liver Stiffness 
Measured by Transient Elastography Are Associated With Severity of Fibrosis and Outcomes of 
Patients With Primary Sclerosing Cholangitis. Gastroenterology. 2014 146(4): 970-979. 
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J 
Dermato. 2010 162(3):587-93. 
FDA’s Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
Fickert P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in 
primary sclerosing cholangitis. J Hepatol. 2017 Sep;67(3):549-558. 
 
Fricker ZP, Lichtenstein DR. Primary Sclerosing Cholangitis: A Concise Review of Diagnosis 
and Management. Dig Dis Sci. 2019 Feb 6. doi: 10.1007/s10620-019-05484-y. 
Haczeyni F, Wang H, Barn V, et al. The Selective Peroxisome Proliferator–Activated Receptor-
Delta Agonist Seladelpar Reverses Nonalcoholic Steatohepatitis Pathology by Abrogating 
Lipotoxicity in Diabetic Obese Mice. Hepatology. 2017; 1(7): 663-674. 
Hirschfield GM, Chazouillères O, Drenth JP, et al. Effect of NGM282, an FGF19 analogue, in 
primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled 
phase II trial. J Hepatol. 2018 Nov 9. pii: S0168-8278(18)32519-4. doi: 
10.1016/j.jhep.2018.10.035. [Epub ahead of print]. 


 
 
 
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Iwaisako K, Haimer M, Paik YH, et al. Protection from liver fibrosis by a peroxisome 
proliferator-activated receptor δ agonist. PNAS. 2012; 109(21):E1369-76. 
Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, et al. Seladelpar 
(MBX-8025), A Selective PPAR-δ Agonist, in Patients with Primary Biliary Cholangitis with an 
Inadequate Response to Ursodeoxycholic Acid: A Double-blind, Randomised, Placebo-
controlled, Phase 2, Proof-of-Concept Study. Lancet Gastroenterol Hepatol. 2017;2(10):716-726.  
Kaplan MM, Gershwin ME. Primary Biliary Cirrhosis. N Engl J Med. 2005;353(12):1261-1273. 
Karlsen TH, Folseraas T, Thorburn D and M. Vesterhus M. Primary sclerosing cholangitis - a 
comprehensive review. J Hepatol. 2017;67(6):1298-1323. 
Khan SA., Davidson BR, Goldin RD, Heaton N, et al. Guidelines for the diagnosis and treatment 
of cholangiocarcinoma: an update. Gut. 2012;61(12): 1657-1669. 
Kowdley KV, Bowlus CL, Levy C, et al. The AESOP Trial: A Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Study of Obeticholic Acid in Patients with Primary Sclerosing 
Cholangitis. Abstract LB-2. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, 
D.C. 
Lazaridis KN, LaRusso NF (2016). Primary Sclerosing Cholangitis. N Engl J Med. 
2016;375(12): 1161-1170. 
Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the Non-
invasive Components of the Mayo Score to Assess Clinical Response in Ulcerative Colitis. 
Inflamm Bowel Dis. 2008 December ; 14(12): 1660–1666. 
Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: Primary Sclerosing 
Cholangitis. Am J Gastroenterol. 2015; 110(5): 646-659. 
Mayo MJ, Bowlus C, Galambos M, et al. PS-122: Seladelpar for the treatment of primary biliary 
cholangitis: Experience with 26 cirrhotic patients. European Association for the Study of the 
Liver (EASL) Meeting in Vienna, Austria, 2019. 
Mertz, A., et al., Primary sclerosing cholangitis and inflammatory bowel disease comorbidity: an 
update of the evidence. Ann Gastroenterol. 2019. 32(2): p. 124-133. 
Molodecky NA, Kareemi H, Parab R, et al. Incidence of primary sclerosing cholangitis: a 
systematic review and meta-analysis. Hepatology. 2011;53(5): 1590-1599. 
Muir AJ, Levy C, Janssen HLA, et al. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 
Study Results with Insights on the Natural History of the Disease. Hepatology 2019; 
Feb;69(2):684-698 
 
Mukundan L, Odegaard J, Morel CR, et al. PPAR-δ senses and orchestrates clearance of 
apoptotic cells to promote tolerance. Nature Medicine 2009; 15(11): 1266-1273. 


 
 
 
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Saffioti F, Gurusamy KS, Hawkins N, et al. Pharmacological interventions for primary 
sclerosing cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev. 2017 
Mar 28;3:CD011343. doi: 10.1002/14651858.CD011343.pub2. 
Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in 
Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol. 2018. Mar 
27;9:609. doi: 10.3389/fimmu.2018.00609. 
Stanich PP, Bjornsson E, Gossard AA, et al. Alkaline phosphatase normalization is associated 
with better prognosis in primary sclerosing cholangitis. Dig Liver Dis 2011;43:309–13. 
Tabibian JH, Lindor KD. Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal 
is bad, then administration is good (right?). Hepatology 2014;60:785–8. 
Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal FXR agonist cilofexor (GS-
9674) improves markers of cholestasis and liver injury in patients with PSC. Hepatology 2019 
Jan 19. doi: 10.1002/hep.30509. 
Xia X, Jung D, Webb P, et al. Liver X Receptor /J and Peroxisome Proliferator-Activated 
Receptor J Regulate Cholesterol Transport in Murine Cholangiocytes. Hepatology 
2012;56:2288-2296. 
Younossi ZM, Afendy A, Stepanova M, et al. Development and validation of a primary 
sclerosing cholangitis-specific patient-reported outcomes instrument: The PSC PRO. 
Hepatology. 2018 Jul;68(1):155-165. 
Zamora-Valdes D, Heimbach JK. Liver Transplant for Cholangiocarcinoma. Gastroenterol Clin 
North Am. 2018 Jun;47(2):267-280. 
 
 


 
 
 
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APPENDICES 
 
APPENDIX A - NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) 
APPENDIX B - MAYO PARTIAL IBD SCORE 
APPENDIX C – PATIENT REPORTED OUTCOMES (PRO) 
APPENDIX D – 5-D PRURITUS SCALE 
APPENDIX E - NUMERIC RATING SCALE FOR ITCH 
APPENDIX F - CLOSE OBSERVATION CRITERIA 
 
 


 
 
 
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APPENDIX A - NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) 
The NCI CTCAE will be used to assess an AE severity.  
The NCI CTCAE will be provided as a separate document with the study protocol.  
The NCI CTCAE may also be accessed here:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
 
 


 
 
 
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APPENDIX B - MAYO PARTIAL IBD SCORE 
Components of the Partial Mayo Score 
Stool Frequency 
 0 = Normal 
 1 = 1–2 stools/day more than normal 
 2 = 3–4 stools/day more than normal 
 3 = >4 stools/day more than normal 
Rectal bleeding a 
 0 = None 
 1 = Visible blood with stool less than half the time 
 2 = Visible blood with stool half of the time or more 
 3 = Passing blood alone 
Physician rating of disease activity 
 0 = Normal 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
a 
A score of 3 for bleeding required patients to have at least 50% of bowel motions 
accompanied by visible blood and at least one bowel motion with blood alone. 
 
 
 
 


 
 
 
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APPENDIX C – PATIENT REPORTED OUTCOMES (PRO) 
Questions included in the final PSC PRO. 
Module 1 – PSC Symptoms 
 
Scores: 0 = “no symptoms” to 10 = “symptoms as bad as you could imagine”; recall period 24 
hours. 
 
1. Are you currently experiencing a flare-up of your PSC symptoms (also known as acute 
cholangitis or an infection in the bile ducts)? Y/N 
2. Over the past 24 hours, how bad was the pain in your upper abdomen due to PSC at its worst? 
3. Over the past 24 hours, how bad was the discomfort in your upper abdomen due to PSC at its 
worst? 
4. Over the past 24 hours, how bad was your itching at its worst? 
5. Over the past 24 hours, how bad was your physical tiredness at its worst? 
6. Over the past 24 hours, how bad was the yellowing of your eyes or skin at its worst? 
7. Over the past 24 hours, how bad was your difficulty concentrating at its worst? 
8. Over the past 24 hours, how bad was your nausea at its worst? 
9. Over the past 24 hours, how bad was your mental tiredness at its worst? 
10. Over the past 24 hours, how bad was the darkening (brown or tea color) of your urine at its 
worst? 
11. Over the past 24 hours, how bad were your fever (high temperature) symptoms? 
12. Over the past 24 hours, how bad were your chills? 
13. Over the past 24 hours, how bad were your sweats? 
 
Module 2 - Impacts of Symptoms 
 
Scores: 1 = “Never” to 5 = “Always”; recall period 7 days. 
 
Physical Function 
1. Over the past 7 days, how often was it difficult for you to go up or down stairs because of your 
PSC? 
2. Over the past 7 days, how often did you have to rest or take breaks because of your PSC? 
3. Over the past 7 days, how often were you limited in what you could do physically because of 
your PSC? 
4. Over the past 7 days, how often was it difficult for you to lift or carry objects because of your 
PSC? 
 
Activities of Daily Living 
5. Over the past 7 days, how often was it difficult for you to complete household chores because 
of your PSC? 
6. Over the past 7 days, how often did you have difficulty falling or staying asleep because of 
your PSC? 
7. Over the past 7 days, how often was it difficult to run errands or get things done outside the 
home because of 
your PSC? 


 
 
 
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8. Over the past 7 days, how often did you avoid certain foods because of your PSC? 
 
Work Productivity 
9. Are you currently employed or self-employed? Y/N (if N then skip the section) 
10. Over the past 7 days, how often did PSC interfere with your productivity at work? 
11. Over the past 7 days, how often did you limit your hours at work because of your PSC? 
12. Over the past 7 days, how often was it an extra effort to do your work because of your PSC? 
13. Over the past 7 days, how often was it difficult to concentrate on your work because of your 
PSC? 
 
Role Function 
14. Over the past 7 days, how often did you need to ask for help around your home because of 
your PSC? 
15. Over the past 7 days, how often did you feel like a burden on your family because of your 
PSC? 
16. Over the past 7 days, how often were you limited in the activities you could do with your 
family because of 
your PSC? 
17. Over the past 7 days, how often was it difficult to enjoy time with your family because of 
your PSC? 
 
Emotional Impact 
18. Over the past 7 days, how often were you worried about your health because of your PSC? 
19. Over the past 7 days, how often were you depressed about your health because of your PSC? 
20. Over the past 7 days, how often did you feel emotional stress because of your PSC? 
21. Over the past 7 days, how often did you feel scared about the future because of your PSC? 
 
Social/Leisure Impact 
22. Over the past 7 days, how often did you limit your social activities because of your PSC? 
23. Over the past 7 days, how often did you limit the things you did for enjoyment because of 
your PSC? 
24. Over the past 7 days, how often did you isolate yourself from other people because of your 
PSC? 
25. Over the past 7 days, how often did you have limited energy for sexual activity because of 
your PSC? 
Quality of Life 
26. Over the past 7 days, how often was it difficult to work towards your goals in life because of 
your PSC? 
27. Over the past 7 days, how often were you unable to enjoy life because of your PSC? 
28. Over the past 7 days, how often did you feel like you missed out on meaningful activities 
because of your 
PSC? 
29. Over the past 7 days, how often did you feel discouraged about your quality of life because 
of your PSC? 
 
 


 
 
 
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APPENDIX D - 5-D PRURITUS SCALE 
 
5-D Pruritus Scale 
1. Duration : During the last 2 weeks, how many hours a day have you been itching? 
Less than 6hrs/day 6-12 hrs/day 
12-18 hrs/day 
18-23 hrs/day 
1 
2 
3 
4 
2. Degree : Please rate the intensity of your itching over the past 2 weeks 
Not present 
1 
Mild 
2 
Moderate 
Severe 
3 
4 
All day 
5 
Unbearable 
5 
3. Direction : Over the past 2 weeks has your itching gotten better or worse compared to the 
previous month? 
Completely 
resolved 
1 
Much better, but 
Little bit better, 
still present 
but still present 
2 
3 
Unchanged 
Getting worse 
4 
5 
4. 
Disability: Rate the impact of your itching on the following activities over the last 2 
weeks 
Sleep 
Never 
affects sleep 
1 
N/A 
Leisure/Social 
D 
Housework/ 
D 
Errands 
Work/School 
D 
Occasionally 
delays 
falling asleep 
2 
Frequently 
delays 
falling asleep 
Rarely 
affects 
3 
Delays falling asleep 
and occasionally 
wakes me up 
at night 
4 
Delays falling 
asleep and frequently 
wakes me up 
at night 
5 
Always 
affects 
Never 
affects 
this activity 
this activity 
Occasionally 
affects 
this activity 
Frequently 
affects 
this activity 
this activity 
1 
2 
3 
4 
5 
2 
3 
4 
5 
1 
2 
3 
4 
5 
5. Distribution: Mark whether itching has been present in the following parts of your body 
over the last 2 weeks. If a body part is not listed, choose the one that is closest 
anatomically. 
Head/Scalp 
Face 
Chest 
Abdomen 
Back 
Buttocks 
Thighs 
Lower legs 
Tops of Feet/Toes 
Present 
Soles 
Palms 
Tops of Hands/Fingers 
Forearms 
Upper Arms 
Points of Contact w/ Clothing 
(e.g waistband, undergarment) 
Groin 
Present 


 
 
 
CymaBay Therapeutics, Inc. 
Protocol CB8025-21845 
 
Protocol Version 2.0, 05-JUN-2019 
CONFIDENTIAL 
Page 85 of 86 
 
APPENDIX E - NUMERIC RATING SCALE FOR ITCH 
 
Itch Scale 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
itching 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
itching 
 
 
 


 
 
 
CymaBay Therapeutics, Inc. 
Protocol CB8025-21845 
 
Protocol Version 2.0, 05-JUN-2019 
CONFIDENTIAL 
Page 86 of 86 
 
APPENDIX F - CLOSE OBSERVATION CRITERIA*  
1. Comprehensive Medical History and Health Status Review 
a. Provide detailed history of current liver-related symptoms (e.g., right upper quadrant 
pain or tenderness, nausea, vomiting, fatigue, loss of appetite, dark urine, or 
jaundice).  
b. Provide all current diagnoses, diseases, procedures, and symptoms 
c. Provide comprehensive medical history including prior diagnoses, procedures and 
symptoms 
d. Provide concomitant drug use, including: prescription medications, nonprescription 
medications, herbal supplements, dietary supplements, alcohol use, recreational drug 
use, special diets and exposure to environmental chemical agents 
e. Provide comprehensive medication and drug use history, including: nonprescription 
medications, herbal supplements, dietary supplements, alcohol use, recreational drug 
use, special diets and exposure to environmental chemical agents 
2. Laboratory Testing 
a. Repeat ALT, AST, Bilirubin (total), and PT/INR within 5-Days  
b. Monitor the participant every 2 to 3 days until the lab abnormality stabilization 
c. After lab abnormality is stabilized, monitor the participant once a week until the event 
resolution 
3. Rule out the following diagnoses: 
a. Acute viral hepatitis types A, B, C, D and E  
b. Autoimmune or alcoholic hepatitis 
c. NASH 
d. Hypoxic/ischemic hepatopathy 
e. Biliary Tract Disease besides PBC 
 
*As recommended by the FDA’s Guidance for Industry – Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009