Clinical trial NCT04620733
Conditions: Primary Biliary Cholangitis
Keywords: Primary Biliary Cholangitis (PBC) PBC
Sponsor: Gilead Sciences
Start date: 2021-04-21; Completion date: 2023-08-11
Enrollment: 193 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purposes of this study are to evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on ALP and total bilirubin and to evaluate the safety of seladelpar over 12 months of treatment compared to placebo.

The study also checked the effect of treatment on the symptoms of PBC, including pruritus.

Detailed description:

Arms: arm 1: Participants will receive placebo to match seladelpar, orally, once daily, for a duration of up to 12 months. arm 2: Participants will receive seladelpar 10 mg (or 5 mg down-titrated, for those participants who met specific safety monitoring criteria or had tolerability issues), orally, once daily, for a duration of up to 12 months.
Interventions: intervention 1: Seladelpar 10 mg intervention 2: Placebo intervention 3: Seladelpar 5 mg
Intervention descriptions: intervention 1: Seladelpar 10 mg one capsule daily for double-blind period, for a duration of up to 12 months intervention 2: One capsule daily for double-blind period, for a duration of up to 12 months intervention 3: If down-titration needed, one capsule daily for double-blind period, for a duration of up to 12 months

Protocol documents:
Prot_000.pdf: 
 
 
 
PROTOCOL TITLE: 
RESPONSE: A Placebo-controlled, Randomized, Phase 3 Study 
to Evaluate the Efficacy and Safety of Seladelpar in Patients with 
Primary Biliary Cholangitis (PBC) and an Inadequate Response to 
or an Intolerance to Ursodeoxycholic Acid (UDCA) 
PROTOCOL NUMBER: 
CB8025-32048 
VERSION NUMBER: 
4.0 
DATE OF PROTOCOL: 
09-February-2022 
SHORT TITLE:  
 
 
RESPONSE: Response to Seladelpar in Subjects with Primary  
 
 
 
 
Biliary Cholangitis (PBC) and an Inadequate Control to or an  
 
 
 
 
Intolerance to Ursodeoxycholic Acid (UDCA) 
SPONSOR: 
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
United States of America 
SPONSOR CONTACT:  
 
Vice President of Clinical Development 
IND: 125,795 
EudraCT Number: 2020-004348-27 
NCT Number:  NCT04620733 
 
 
Confidentiality Statement: 
The information contained in this document, particularly unpublished data, is the confidential information of 
CymaBay Therapeutics, Inc., and is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your employees, and an applicable Institutional Review Board or Independent 
Ethics Committee. You agree that the information is only to be used in connection with authorized clinical 
studies of the investigational drug described in the protocol. You will not disclose any of the information to 
others without written authorization from CymaBay Therapeutics, Inc., except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. These terms do not replace or 
supersede any other separately signed non-use and non-disclosure agreement which shall continue to apply in 
accordance with its own terms. 
PPD
__ b ' , 
CYMABAY 
Tl-IE RAPE UTI CS 


DocuSign Envelope ID: BEF98568-DCA6-4801-A96C-32A686B3673E 
CymaBay Therapeutics, Inc. 
Protocol CB8025-32048 
Protocol Approval - Sponsor Signature 
PROTOCOL TITLE: RESPONSE: A Placebo-contrnlled, Randomized, Phase 3 Study to 
Evaluate the Efficacy and Safety of Seladelpar in Patients with Prima1y 
Biliaiy Cholangitis (PBC) and an Inadequate Response to or an 
Intolerance to Ursodeoxycholic Acid (UDCA). 
Protocol Number: 
CB8025-32048 
Protocol Version: 
Version 4.0 
Protocol Date: 
09-Febrnaiy-2022 
Protocol accepted and approved by: 
,
oocuSigned by: 
I -
PPD 
ll[J 
Signer Name: PPD 
......, __ 
L
Signing Reason: I approve this document 
Signing Time 09-Feb-2022 I 17:52 PST 
11406EEE4352411A862E9FD33C7E1 7O2 
PPD 
Chief Medical Officer 
CymaBay Therapeutics, Inc. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
SYNOPSIS .................................................................................................................12 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Primary Biliary Cholangitis ........................................................................................26 
2.2. 
Seladelpar ...................................................................................................................27 
2.2.1. 
Overview .....................................................................................................................27 
2.2.2. 
Mechanism of Action .................................................................................................27 
2.3. 
Nonclinical Studies .....................................................................................................27 
2.4. 
Human Experience ......................................................................................................28 
2.4.1. 
Studies in Patients With PBC .....................................................................................28 
3. 
STUDY OBJECTIVES ..............................................................................................33 
3.1. 
Primary Objectives .....................................................................................................33 
3.2. 
Secondary Objectives .................................................................................................33 
 
 
4. 
STUDY POPULATION .............................................................................................33 
4.1. 
Inclusion Criteria ........................................................................................................33 
4.2. 
Exclusion Criteria .......................................................................................................34 
5. 
STUDY DESIGN .......................................................................................................37 
5.1. 
Study Overview ..........................................................................................................37 
5.2. 
Treatment and Allocation of Subjects ........................................................................39 
5.3. 
Study Duration ............................................................................................................39 
5.4. 
Study Outcome Measurements ...................................................................................39 
5.4.1. 
Primary Measures .......................................................................................................39 
5.4.2. 
Key Secondary Measures ...........................................................................................40 
 
 
 
 
5.5. 
Rationale for Dose Selection ......................................................................................41 
5.6. 
Rationale for Placebo Arm .........................................................................................42 
5.7. 
Benefit/Risk Assessment ............................................................................................42 
5.7.1. 
Potential Benefit .........................................................................................................42 
5.7.2. 
Potential Risks ............................................................................................................43 
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5.7.3. 
Summary .....................................................................................................................43 
6. 
STUDY MEDICATIONS ..........................................................................................44 
6.1. 
Investigational Product ...............................................................................................44 
6.1.1. 
Dose and Mode of Administration .............................................................................44 
6.1.2. 
Packaging, Labeling, and Shipping ............................................................................44 
6.1.3. 
Storage of Study Drug ................................................................................................44 
6.2. 
Accountability of Clinical Supplies ............................................................................44 
6.3. 
Ursodeoxycholic Acid ................................................................................................45 
6.4. 
Randomization and Stratification ...............................................................................45 
6.5. 
Emergency Unblinding ...............................................................................................45 
6.6. 
Compliance .................................................................................................................45 
7. 
CONCOMITANT MEDICATIONS AND PROCEDURES ......................................45 
7.1. 
Concomitant Medications ...........................................................................................46 
7.2. 
Allowed Concomitant Medication ..............................................................................46 
7.3. 
Prohibited Concomitant Medication ...........................................................................46 
7.4. 
Concomitant Procedures .............................................................................................47 
8. 
STUDY PROCEDURES ............................................................................................48 
8.1. 
Study Schedule ...........................................................................................................48 
8.1.1. 
Screening Period (W -5 to -2 [Day -35 to -15]) ..........................................................48 
8.1.2. 
Run-in Period (W -2 [Day -14]) .................................................................................50 
8.1.3. 
Treatment Period ........................................................................................................51 
8.1.3.1. 
Day 1 (Randomization) ...............................................................................................51 
8.1.3.2. 
Month 1 (W4 [Day 29]) ..............................................................................................52 
8.1.3.3. 
Month 3 (W12 [Day85]) .............................................................................................53 
8.1.3.4. 
Month 6 (W26 [Day183]) ...........................................................................................54 
8.1.3.5. 
Month 9 (W39 [Day 274]) ..........................................................................................55 
8.1.3.6. 
Month 12/End of Treatment (W52 [Day 365]) ...........................................................56 
8.1.4. 
Post-Treatment Safety Follow-up (2W [14 Days after W52]) ...................................57 
8.1.5. 
Early Termination .......................................................................................................57 
8.1.6. 
Unscheduled Visit .......................................................................................................59 
8.1.7. 
Annual Follow-Up for PBC outcomes Assessment ....................................................59 
8.2. 
Study Assessments ......................................................................................................59 
8.2.1. 
Demographics .............................................................................................................60 


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8.2.2. 
Medical History and Physical Examination ...............................................................60 
8.2.3. 
Vital Signs and Weight/Height ...................................................................................60 
8.2.4. 
Electrocardiograms .....................................................................................................61 
8.2.5. 
Laboratory Tests .........................................................................................................61 
8.2.6. 
Abdominal Ultrasound ................................................................................................62 
8.2.7. 
Liver Elastography ......................................................................................................62 
8.2.8. 
Liver Biopsy ...............................................................................................................63 
8.2.9. 
Pruritus Numerical Rating Scale ................................................................................63 
8.2.10. 
5-D Itch Scale .............................................................................................................63 
8.2.11. 
PBC-40 QoL ...............................................................................................................64 
8.2.12. 
PGI-S and PGI-C ........................................................................................................64 
9. 
ADVERSE EVENTS ..................................................................................................64 
9.1. 
Definition of Adverse Events .....................................................................................64 
9.2. 
Definition of Serious Adverse Events ........................................................................65 
9.3. 
Assessment of Adverse Events ...................................................................................65 
9.3.1. 
Severity .......................................................................................................................65 
9.3.2. 
Outcome ......................................................................................................................65 
9.3.3. 
Relationship to Study Drug ........................................................................................66 
9.3.4. 
Action Taken With Study Medication ........................................................................66 
9.4. 
Recording, Reporting, and Follow-up of Adverse Events ..........................................66 
9.4.1. 
Nonserious Adverse Events ........................................................................................66 
9.4.2. 
Serious Adverse Events ..............................................................................................67 
9.4.3. 
Follow-up on Reported AEs .......................................................................................68 
9.4.4. 
Distribution of Responsibilities ..................................................................................68 
10. 
SAFETY MONITORING ..........................................................................................69 
10.1.1. 
Liver Safety Monitoring .............................................................................................69 
10.1.2. 
Muscle Injury Safety Monitoring ...............................................................................70 
10.1.3. 
Renal Safety Monitoring .............................................................................................71 
10.1.4. 
Pancreatic Safety Monitoring .....................................................................................71 
10.1.5. 
Additional Withdrawal Criteria and Replacement of Subjects ...................................72 
11. 
PBC CLINICAL OUTCOMES ..................................................................................73 
12. 
STUDY STOPPING CRITERIA ...............................................................................74 
13. 
PRECAUTIONS .........................................................................................................74 


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13.1. 
Pregnancy ...................................................................................................................74 
14. 
DATA SAFETY MONITORING BOARD ...............................................................75 
15. 
CLINICAL EVENT REVIEW COMMITTEE ..........................................................75 
16. 
PATHOLOGY REVIEW COMMITTEE ...................................................................75 
17. 
STUDY TERMINATION ..........................................................................................76 
18. 
DATA HANDLING CONSIDERATIONS ...............................................................76 
18.1. 
Processing of Electronic Case Report Forms .............................................................76 
18.2. 
Database ......................................................................................................................76 
18.3. 
Data Discrepancies .....................................................................................................77 
19. 
STATISTICAL ANALYSIS ......................................................................................78 
19.1. 
General Statistical Considerations ..............................................................................78 
19.2. 
Determination of Sample Size ....................................................................................78 
19.3. 
Analysis Sets ...............................................................................................................78 
19.3.1. 
Safety Analysis Set .....................................................................................................78 
19.3.2. 
Intent-to-Treat Analysis Set ........................................................................................79 
19.3.3. 
Modified Intent-to-Treat Biopsy Analysis Set ...........................................................79 
19.3.4. 
Moderate to Severe Pruritus NRS Analysis Set .........................................................79 
19.3.5. 
Per-Protocol Analysis Set ...........................................................................................79 
19.3.6. 
Pharmacokinetics Analysis Set ...................................................................................79 
19.4. 
Analysis Time Points ..................................................................................................79 
19.5. 
Disposition, Demographics, and Baseline Characteristics .........................................79 
19.6. 
Efficacy Analysis ........................................................................................................80 
19.6.1. 
Primary Efficacy Analysis ..........................................................................................80 
19.6.2. 
Key Secondary Efficacy Endpoint Analysis ...............................................................80 
 
 
 
 
19.6.5. 
Sensitivity Analysis for the Primary and Key Secondary Efficacy Endpoints ...........81 
19.7. 
Safety Analysis ...........................................................................................................82 
19.8. 
Pharmacokinetic Analysis ..........................................................................................82 
20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................82 
20.1. 
Study Monitoring ........................................................................................................82 
20.1.1. 
Source Documents ......................................................................................................82 
20.1.2. 
Case Report Forms .....................................................................................................83 
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20.1.3. 
Protocol Deviations ....................................................................................................83 
20.2. 
Audits and Inspections ................................................................................................83 
20.2.1. 
Study Auditing ............................................................................................................83 
20.2.2. 
Study Monitoring ........................................................................................................83 
20.3. 
Ethics Committees ......................................................................................................84 
21. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................84 
22. 
ETHICS ......................................................................................................................84 
22.1. 
Ethics Review .............................................................................................................84 
22.2. 
Ethical Conduct of the Study ......................................................................................84 
22.3. 
Informed Consent .......................................................................................................84 
23. 
RETENTION OF RECORDS ....................................................................................85 
24. 
PROTOCOL AMENDMENTS ..................................................................................85 
25. 
DISCLOSURE OF INFORMATION AND PUBLICATION POLICY ....................85 
26. 
REFERENCES ...........................................................................................................86 
APPENDIX A. LABORATORY EVALUATIONS ...................................................................88 
APPENDIX B. CLOSE OBSERVATION CRITERIA ..............................................................89 
APPENDIX C. NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS .....................................................................90 
APPENDIX D. PRURITUS NRS ...............................................................................................91 
APPENDIX E. 5-D ITCH SCALE .............................................................................................92 
APPENDIX F. PBC-40 QOL ......................................................................................................93 
APPENDIX G. PATIENT GLOBAL IMPRESSION OF SEVERITY ......................................96 
APPENDIX H. PATIENT GLOBAL IMPRESSION OF CHANGE .........................................97 
APPENDIX I. CIRRHOSIS DETERMINATION ......................................................................98 
APPENDIX J. NORMAL RANGES FOR SAFETY LABORATORY PARAMETERS..........99 
APPENDIX K. INVESTIGATOR’S PROTOCOL SIGNATURE PAGE ...............................100 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................24 
Table 2: 
DILI Criteria for Participants With Normal Baseline ALT and AST ........................69 
Table 3: 
DILI Criteria for Participants With Abnormal Baseline ALT and AST ....................69 
Table 4: 
Muscle Injury Safety Criteria for Study Drug Interruption or Stopping Rules ..........70 
Table 5: 
Renal Safety Criteria for Study Drug Interruption or Stopping Rules .......................71 
Table 6: 
Pancreatic Safety Criteria for Study Drug Interruption or Stopping Rules ................72 
 
LIST OF FIGURES 
Figure 1: 
Mean Percent Changes in ALP in PBC Phase 2 Studies ............................................29 
Figure 2: 
Percent Change in ALT in PBC Phase 2 Studies .......................................................30 
Figure 3: 
Study CB8025-31735: Seladelpar Effects on ALP ....................................................31 
Figure 4: 
Study CB8025-31735: Seladelpar Effect on Pruritus .................................................32 
Figure 5: 
Study CB8025-32048: Study Diagram .......................................................................39 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AIH 
Autoimmune hepatitis 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMA 
Antimitochondrial antibody(ies) 
ANA 
Antinuclear antibody(ies) 
AST 
Aspartate aminotransferase 
C4 
7α-hydroxy-4-cholesten-3-one 
CERC 
Critical event review committee 
CI 
Confidence interval 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
Drug-induced liver injury 
DSMB 
Data safety monitoring board 
e-diary 
Electronic diary 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver fibrosis  
ELISA 
Enzyme linked immunosorbent assay 
EMR 
Electronic medical record 
EOT 
End of Treatment 
FGF19 
Fibroblast growth factor 19 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HoFH 
Homozygous familial hypercholesterolemia 
hs-CRP 
High sensitivity C-reactive protein 


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Abbreviation 
Definition 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDL-C  
Low density lipoprotein cholesterol  
LPLV 
Last patient last visit  
LS 
Least squares 
M1, M2, M3 
Seladelpar (MBX-8025) metabolites 
MBX-8025 
Seladelpar 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
mITTb 
Modified intent-to-treat biopsy 
MMRM 
Mixed models repeated measures 
MSPN 
Moderate to severe pruritus numerical rating scale 
n 
Number of subjects 
NASH 
Nonalcoholic steatohepatitis 
NCI  
National Cancer Institute  
NRS 
Numerical rating scale 
OCA 
Obeticholic acid 
PBC 
Primary biliary cholangitis 
PBC-40 QoL 
quality of life measure for use in primary biliary cholangitis 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PPAR 
Peroxisome proliferator-activated receptor 
PRC 
Pathology review committee 
PSC 
Primary sclerosing cholangitis 
PT 
Prothrombin time 
QoL 
Quality of life 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SAP 
Statistical analysis plan 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
UNS 
Unscheduled visit 
US 
United States 
VAS 
Visual analogue scale 
WBC 
Leukocyte count 
 
 


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1. 
SYNOPSIS 
Title of Study 
RESPONSE: A Placebo-controlled, Randomized, Phase 3 Study to Evaluate the 
Efficacy and Safety of Seladelpar in Patients with Primary Biliary Cholangitis (PBC) 
and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA) 
Protocol Number 
CB8025-32048 
Phase 
3 
Investigational 
Product 
Seladelpar 
Objectives 
Primary Objective:  
• 
Efficacy: To evaluate the treatment effect of seladelpar on composite 
biochemical improvement in cholestasis markers based on alkaline 
phosphatase (ALP) and total bilirubin at 12 months of treatment compared to 
placebo 
• 
Safety: To evaluate the safety of seladelpar over 12 months of treatment 
compared to placebo 
Key Secondary Objectives:  
• 
To evaluate the effect of seladelpar on the normalization of ALP values at 
12 months of treatment compared to placebo 
• 
To evaluate the effect of seladelpar on pruritus at 6 months of treatment 
compared to placebo in subjects with baseline moderate to severe pruritus 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Methodology/ 
Study Design 
This is an international, multicenter evaluation of seladelpar in a randomized, 
double-blind, placebo-controlled, parallel-group study in patients with PBC. 
Approximately 180 subjects will be randomized in 2:1 ratio (seladelpar: placebo) 
across approximately 180 sites worldwide. 
Enrolled subjects will have confirmed PBC as defined by having any 2 of the following 
3 diagnostic criteria: (1) history of ALP above 1.0× the upper limit of normal (ULN) 
for at least 6 months; (2) positive antimitochondrial antibody (AMA) titer (>1:40 on 
immunofluorescence or M2 positive by enzyme-linked immunosorbent assay [ELISA]) 
or positive PBC-specific antinuclear antibodies (ANAs); and (3) documented liver 
biopsy results consistent with PBC. 
Enrolled subjects must have received UDCA for at least 12 months (>3 months of 
stable dose prior to screening) or have intolerance to UDCA (last dose of UDCA 
>3 months prior to screening). During the study, the study drug will be administered as 
an add-on to UDCA therapy for subjects who tolerate UDCA; for subjects with UDCA 
intolerance, the study drug will be administered as a monotherapy. 
Subjects with the presence or history of cirrhosis with complications, Gilbert’s 
syndrome with elevated total bilirubin, primary sclerosing cholangitis (PSC), current 
features of autoimmune hepatitis (AIH), biopsy-confirmed nonalcoholic steatohepatitis 
(NASH), alcoholic liver disease, or chronic hepatitis B or C will be excluded. 
In order to establish the histological status of their liver before and after treatment, all 
subjects will be encouraged to have a liver biopsy during the Screening Period (unless 
a historical biopsy meeting quality standards can be supplied) and after 1 year of 
treatment, or at Early Termination if the subjects withdraw from the study, provided 
that they have received at least 6 months of treatment. A follow-up liver biopsy will be 
performed only in subjects with baseline liver biopsy. 
Transient elastography via FibroScan® will be performed to assess liver stiffness at 
baseline and during the Treatment Period or at Early Termination at select sites.  
On Day 1, subjects will be randomized into one of two treatment arms (seladelpar 
10 mg or placebo) in a 2:1 ratio. Subjects will be stratified at randomization according 
to ALP <350 U/L versus ≥350 U/L and pruritus numerical rating scale (NRS) 
(<4 versus ≥4) to ensure even distribution across the treatment groups.  
The total duration of participation in the study for each subject will be up to 
~14 months and consists of Screening Period (up to 3 weeks), a Run-in Period (up to 
2 weeks), a Treatment Period with a maximum duration of up to 12 months, and a 
Safety Follow-up Period (2 weeks [14 days +3] after the last dose of study drug, only 
for subjects who are not enrolled in the long-term study).  
The Screening Period will be up to 3 weeks, during which time subject eligibility will 
be confirmed. The Run-in Period will start 2 weeks prior to the planned Day 1 Visit; at 
this visit, subjects start their pruritus evaluation using an e-diary. Liver biopsy will be 
performed at any time between Screening and Day 1 for subjects willing to undergo the 
procedure and after their eligibility is confirmed (unless a historical biopsy meeting 
quality standards can be supplied). At Day 1, subjects will enter the Treatment Period. 
Subjects will receive double-blinded treatment for 12 months. After the completion of 
the Treatment Period, subjects will be invited to enroll into an open-label, long-term 
study (Study CB8025-31731-RE) in which each subject will be administered seladelpar 
and subjects on placebo will initiate seladelpar treatment. Subjects who do not 
participate in the long-term study will have a follow-up visit performed 2 weeks 
(14 days +3) after the last dose of study drug. 


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Methodology/ 
Study Design 
(continued) 
During the 12-month Treatment Period, subjects will have a visit at Month 1 and then 
every 3 months beginning from Month 3 through Month 12. Visits may occur in clinic, 
with the assistance of a home health service, or using virtual technologies. 
Subjects will be asked to use an electronic diary (e-diary) to evaluate pruritus and QoL 
during the study participation. E-diary will be dispensed at the Run-in Visit and will 
include the following questionnaires: pruritus NRS, 5-D Itch, Patient Global 
Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), and 
PBC-40. Subjects will perform an evaluation of their pruritus on a daily basis via 
pruritus NRS starting from the Run-in Visit through the first 6 months of treatment. 
After 6 months, pruritus will be evaluated on a monthly basis until Month 12 using 
pruritus NRS for 7 consecutive days each month. 5-D Itch scale will be evaluated 
biweekly from the Run-in Visit up for the first 6 months of treatment and monthly after 
that. PBC-40, PGI-S, and PGI-C will be evaluated after 1 month and every 3 months 
from the treatment initiation and over the whole study duration. 
During the study, subjects will be regularly evaluated for the progression of their 
disease by collecting information about PBC clinical outcomes.  
Subjects who discontinued study drug treatment for any reason other than a defined 
PBC clinical outcome will be asked to stay in the study without study drug intake.  
Subjects who discontinue study drug treatment anytime, and do not stay in the study, 
will complete an Early Termination Visit. For subjects who decline to stay in the study 
without study drug intake, or who do not participate in the long-term study, a phone 
call will be performed for PBC outcomes on an annual basis. Safety monitoring in the 
study implements individual and study stopping criteria, criteria to be considered for 
stopping the study, and safety criteria to monitor subjects with potential drug-induced 
liver injury (DILI), renal injury, muscle toxicity, or pancreatic injury with actions to 
either stop the study drug or to investigate the case prior to actions with the study drug 
based on protocol-specified monitoring criteria. The study design also defines PBC 
clinical outcome criteria to evaluate the subjects for the progression of PBC, for 
example, events related to hepatic decompensation. The study drug might be down-
titrated to a lower dose if deemed necessary by the investigator for safety or tolerability 
reasons. Subjects receiving 10 mg will be down-titrated to 5 mg, and subjects receiving 
placebo will be down-titrated to placebo. Down-titration will be performed in a blinded 
manner. Subjects who meet one of the defined PBC clinical outcome criteria will be 
terminated from the study and will complete an Early Termination Visit. 
PK Sample Collection 
Subjects will be invited to participate in a pharmacokinetic (PK) sample collection to 
evaluate the plasma concentrations of seladelpar and its metabolites. Subjects who 
consent to participate in this PK sample collection will provide 1 predose (-30 minutes 
prior to dosing) and 2 postdose samples at 1 hour ± 30 minutes and at 3 hours 
± 30 minutes at Month 3 and at Month 12.   
The primary efficacy outcome will be a responder analysis (composite biochemical 
response) after 12 months of treatment with study drug. 
A data safety monitoring board (DSMB) will be convened to review the study data on a 
regular basis during study conduct to ensure subjects’ welfare and preserve study 
integrity. 
A Critical Event Review Committee (CERC) will be established to analyze and 
adjudicate clinical events that occur during the study. 
A Pathology Review Committee (PRC) will be established to evaluate the biopsies in 
accordance with a defined histopathology plan. 


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Study Design Schema 
 
ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; 
EOT=End of Treatment; UDCA=ursodeoxycholic acid; ULN=upper limit of normal. 
a Seladelpar is an add-on to UDCA for patients with an inadequate response to UDCA in the 
prior 12 months.  
Subjects 
Approximately 180 subjects randomized 
Randomization 
2:1 (seladelpar 10 mg: placebo) 
Randomization will be stratified by the following factors: 
• 
ALP level <350 U/L versus ALP level ≥350 U/L 
• 
Pruritus NRS <4 versus NRS ≥4 
Study Sites 
Approximately 180 sites worldwide  
Test Product(s) 
Seladelpar or placebo will be supplied as a single capsule intended to deliver 5 mg (for 
down-titration, if needed), 10 mg, or placebo administered orally, once daily. 
Duration of 
Treatment 
Total duration: up to 14 months  
• 
Screening Period: Up to 3 weeks 
• 
Run-in Period: 2 weeks 
• 
Treatment Period: Maximum of 12 months with an option to enter an 
open-label long-term study (Study CB8025-31731-RE) 
• 
Safety Follow-up Period: Up to 17 days (only for subjects who are not 
enrolled in the long-term study) 
Population 
Subjects with PBC and an inadequate response to UDCA or intolerance to UDCA. 
Entry Criteria: 
ALP~ 1.67x ULN; ALT/AST 5 3x ULN; 
t 
Screening 
Period 
t 
Week-4 
Run- In 
Treatment Period* 
Placebo (n::::60) 
t 
t 
Dayl 
Month 6 
•seladelparisan add-on to UDCA for patients with iln inadequate response to UDCA ln the priorl2 months 
Total Bilirubin 5 2x ULN 
t 
EOT 
Month 12 
ASSURE: Open Label 
Long Term Study 
(CB8025-31731-RE) 
or 
Safety Follow Up 


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Criteria for 
Eligibility 
Inclusion Criteria: 
Subjects must meet the following criteria to be eligible for study participation: 
1. Must have given written informed consent (signed and dated) and any 
authorizations required by local law. 
2. 18 to 75 years old (inclusive). 
3. Male or female with a diagnosis of PBC based on any two of the following 
criteria: 
a. 
History of ALP above 1.0× ULN for at least 6 months. 
b. Positive AMA titer (>1:40 on immunofluorescence or M2 positive by 
ELISA) or positive PBC-specific ANA. 
c. 
Documented liver biopsy results consistent with PBC. 
4. UDCA for the past 12 months (stable dose for >3 months prior to screening) 
OR intolerant to UDCA (last dose of UDCA >3 months prior to screening). 
5. Laboratory parameters measured by the Central Laboratory at screening:  
a. 
ALP ≥1.67× ULN. 
b. Aspartate aminotransferase (AST) ≤3× ULN. 
c. 
Alanine aminotransferase (ALT) ≤3× ULN. 
d. Total bilirubin ≤2× ULN. 
e. 
Estimated glomerular filtration rate >45 mL/min/1.73 m2 (calculated 
by the Modification of Diet in Renal Disease study equation). 
f. 
International normalized ratio (INR) below 1.1× ULN  
For subjects on anticoagulation therapy, INR must be maintained in 
the range required for prophylaxis for their specific disease. 
g. Platelet count ≥100×103/µL. 
NOTE: PT, INR, and platelets can be performed locally at the Screening 
Visit, if deemed necessary by the investigator after consultation with the 
medical monitor, in cases where centrally read samples are deemed 
invalid. 
6. Females of reproductive potential (Section 8.1.1) must use at least 1 barrier 
contraceptive and a second effective birth control method during the study and 
for at least 90 days after the last dose. Male subjects 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.  
Exclusion Criteria: 
Subjects must not meet any of the following criteria to be eligible for study 
participation: 
1. Previous exposure to seladelpar (MBX-8025). 
2. A medical condition other than PBC that, in the investigator’s opinion, would 
preclude full participation in the study (e.g., cancer) or confound its results 
(e.g., Paget’s disease, any active infection).  
3. Advanced PBC as defined by the Rotterdam criteria (albumin below the lower 
limit of normal AND total bilirubin above 1.0× ULN). 


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Criteria for 
Eligibility (continued) 
4. Presence of clinically important hepatic decompensation, including the 
following: 
a. 
History of liver transplantation, current placement on liver 
transplantation list, or current Model for End-Stage Liver Disease 
(MELD) score ≥12. For subjects on anticoagulation medication, 
evaluation of the baseline INR, in concert with their current dose 
adjustments of their anticoagulant medication, will be taken into 
account when calculating the MELD score.  This will be done in 
consultation with the medical monitor. 
b. Complications of portal hypertension, including known esophageal 
varices, history of variceal bleeds or related interventions (e.g., 
transjugular intrahepatic portosystemic shunt placement), ascites, and 
hepatic encephalopathy. 
c. 
Cirrhosis with complications, including history or presence of 
spontaneous bacterial peritonitis, hepatocellular carcinoma, or 
hepatorenal syndrome. 
5. Other chronic liver diseases:  
a. 
Current features of AIH as determined by the investigator based on 
immunoserology, liver biochemistry, or historic confirmed liver 
histology. 
b. PSC determined by the presence of diagnostic cholangiographic 
findings. 
c. 
History or clinical evidence of alcoholic liver disease. 
d. History or clinical evidence of alpha-1-antitrypsin deficiency. 
e. 
History of biopsy confirmed NASH. 
f. 
History or evidence of Gilbert’s syndrome with elevated total 
bilirubin. 
g. History or evidence of hemochromatosis. 
h. Hepatitis B, defined as the presence of hepatitis B surface antigen. 
i. 
Hepatitis C, defined as the presence of hepatitis C virus ribonucleic 
acid. 
j. 
History, evidence, or high suspicion of hepatobiliary malignancy 
based on imaging, screening laboratory values, and/or clinical 
symptoms. 
6. Known history of human immunodeficiency virus (HIV) or positive antibody 
test at screening. 
7. Clinically important alcohol consumption, defined as more than 2 drink units 
per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 
30 g) in men, or inability to quantify alcohol intake reliably. 
8. History of malignancy diagnosed or treated, active or within 2 years, or 
ongoing evaluation for malignancy; localized treatment of squamous or 
noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed if 
appropriately treated prior to screening. 
9. Treatment with obeticholic acid (OCA), and fibrates (e.g., bezafibrate, 
fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior 
to screening. 
10. Treatment with colchicine, methotrexate, azathioprine, or long-term systemic 
corticosteroids (>2 weeks) during 2 months prior to screening. See Section 7 
for additional medications that may be excluded.  
11. Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, 
rifampicin, sertraline, or any experimental approach) must be on a stable dose 
within 1 month prior to screening. 


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12. Treatment with any other investigational therapy or device within 30 days or 
within 5 half-lives, whichever is longer, prior to screening  
13. For females, pregnancy or breastfeeding 
14. Any other condition(s) that would compromise the safety of the subject or 
compromise the quality of the clinical study, as judged by the investigator. 
15. Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or other 
immunosuppressive biologics).  
16. Other medications that effect liver or GI functions, such as absorption of 
medications or the roux-en-y gastric bypass procedure, may be prohibited and 
should be discussed with the medical monitor on a case-by-case basis. 
17. Active COVID-19 infection during Screening. 
 
Concomitant 
Medications 
All subjects will be instructed to remain on their current diet and lifestyle, including 
drinking habits, specifically alcoholic beverages, throughout the study.  
Subjects will continue UDCA intake in accordance with their prescribed dose. Dose 
adjustments or interruption in UDCA during the study will be documented.  
PBC symptomatic treatment (e.g., antipruritic drugs) should be discussed with medical 
monitor. Guidelines about PBC symptom management will be provided in a study 
manual. 
Subjects will be allowed to receive required medications to treat new or existing 
medical conditions. 
Prohibited Treatment 
• 
Obeticholic acid (OCA) 
• 
Fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, 
saroglitizar)  
• 
Colchicine, methotrexate, or azathioprine  
• 
Long-term systemic steroids (e.g., prednisone, prednisolone, budesonide) for 
>2 weeks 
• 
Experimental or unapproved treatment for PBC or related autoimmune 
diseases 
• 
Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or 
other immunosuppressive biologics)  
• 
Other medications that effect liver or GI functions such as absorption of 
medications may be prohibited and should be discussed with the medical 
monitor on a case-by-case basis 
Criteria for 
Evaluation – Safety 
Safety and tolerability will be assessed by monitoring adverse events (AEs) and 
concomitant medications. Additional assessments will include conducting physical 
examinations, collecting 12-lead electrocardiograms, measuring vital signs, collecting 
liver histology, and collecting clinical laboratory assessments. Specific safety 
monitoring algorithms for liver, renal, or pancreatic injury and muscle toxicity have 
been incorporated into the study. 


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Criteria for 
Evaluation – Efficacy 
and 
Pharmacodynamics 
Primary Measures: 
1. Proportion of subjects who are considered responders at 12 months based on 
the following composite endpoint of ALP and total bilirubin at 12 months 
requiring 
a. 
ALP <1.67× ULN 
b. ≥15% decrease in ALP 
c. 
Total bilirubin ≤1.0× ULN  
2. Assessment of treatment-emergent AEs (TEAEs) (National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0), 
biochemistry, and hematology  
Key Secondary: 
1. Proportion of subjects with ALP ≤1.0× ULN at 12 months (e.g., 
normalization) 
2. Change from baseline in weekly averaged pruritus NRS in subjects with 
baseline NRS ≥4 at 6 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Criteria for 
Evaluation – Efficacy 
and 
Pharmacodynamics 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Criteria for 
Evaluation – 
Pharmacokinetics  
Subjects participating in the PK sample collection (PK of seladelpar and its 
metabolites).  
Subjects who consent to participate in this PK sample collection will provide a predose 
sample (-30 minutes prior to dosing) and 2 postdose samples at (1 hour±30 minutes and 
at 3 hours±30 minutes) at Month 3 and at Month 12 to estimate the plasma 
concentrations of seladelpar and its metabolites. 
CCI
CCI
I 


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Statistical Methods 
Analysis Sets: 
The safety analysis set includes any subject who receives at least 1 dose of study drug. 
Safety analyses will be conducted on the safety analysis set according to the treatment 
received. 
The intent-to-treat analysis (ITT) analysis set includes any subject randomized into the 
study and receives at least 1 dose of study drug. The ITT analysis set will be the 
primary analysis set used for efficacy analyses, with the exception of secondary 
endpoints evaluated for subjects with moderate to severe pruritus.  
The modified intent-to-treat biopsy (mITTb) analysis set includes any subject who is in 
the ITT analysis set and has a baseline and Month 12/ET biopsy. The mITTb analysis 
set will be used to examine the histology changes or the lack thereof.  
The moderate to severe pruritus NRS (MSPN) analysis set includes any subject who is 
in the ITT analysis set and has a baseline NRS value ≥4. The MSPN analysis set will 
be the primary analysis set for secondary endpoints based on NRS evaluations.  
Subjects in the ITT and MSPN analysis sets will be analyzed according to randomized 
treatment assignment. 
The per-protocol (PP) analysis set includes any subject who is in the ITT analysis set, 
has at least 1 post-baseline ALP and total bilirubin evaluation, and does not have a 
protocol violation that is deemed to impact the primary efficacy evaluation. Selected 
analyses of efficacy will be conducted using the PP set. 
The pharmacokinetics analysis set includes any subject who participated in the  
PK sample collection.  
Unless stated otherwise, baseline values will be based on the last non-missing 
assessment evaluated prior to the first administration of study drug. Baseline for 
chemistry and hematology measures will be calculated as the arithmetic mean of 
multiple pretreatment measurements (Screening, Run-in, Day 1, and unscheduled 
assessments) preceding the first administration of study drug. Baseline pruritus NRS is 
defined as the mean of all daily recorded scores during the Run-in Period. 
Unless specified otherwise, statistical tests will be conducted at the 2-sided 0.05 
significance level (alpha), and all confidence intervals (CIs) will be reported at 2-sided 
95% confidence level. 
Descriptive statistics will be displayed by treatment group. For categorical parameters, 
the number and percentage of subjects in each category will be presented in data 
summaries. The denominators for percentages will be based on the number of subjects 
(n) appropriate for analysis. Continuous variables will generally be summarized based 
on the following: n, mean, standard deviation, median, minimum, and maximum. 
Categorical data will be summarized using frequency tabulations (number and 
percentage of subjects). Time-to-event data will be summarized using counts and 
Kaplan-Meier estimates with standard errors, where appropriate. All data will be listed 
for all patients. 
An independent DSMB will be convened to review the study data on a regular basis 
during the study conduct to ensure subjects’ welfare and preserve study integrity. 
Details of the format, content, and frequency of these meetings will be described in a 
DSMB charter. 


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Statistical Methods 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary analysis: 
The primary efficacy analysis for the proportion of subjects who are considered 
responders will be based on the proportion of subjects achieving the following 
composite endpoint evaluated at 12 months: 
• 
ALP <1.67× ULN 
• 
ALP decrease of ≥15% 
• 
Total bilirubin ≤1.0× ULN 
The treatment effect for the composite endpoint (seladelpar 10 mg versus placebo) will 
be evaluated at a 2-sided 0.05 significance level. 
Additional details, including a schematic for the testing sequence for the overall study, 
can be found in the statistical analysis section of the protocol.  
The primary efficacy analysis will be conducted on the ITT analysis set using the 
Cochran-Mantel-Haenszel (CMH) test. The CMH analysis will be stratified by the 
randomization stratum.  
In the primary analysis, subjects who do not provide an assessment at, or have 
discontinued treatment prior to, the specified time point for response evaluation or who 
otherwise have missing data will be considered non-responders. Additional sensitivity 
analyses of the primary efficacy endpoint will be detailed in the statistical analysis plan 
(SAP) and will assess the impact of missing data and other factors, such as protocol 
compliance, on robustness of study results.  
Key Secondary Analyses:  
• 
Normalization of ALP at 12 months (e.g., ALP ≤1.0× ULN) 
• 
Change from baseline in weekly averaged pruritus in subjects with NRS ≥4 at 
baseline at 6 months 
Type I error for the key secondary efficacy analysis will be maintained using the 
hierarchical fixed-sequence methodology. The fixed-sequence approach for the primary 
and secondary analyses is as follows: 
1. If the primary efficacy analysis is positive for seladelpar 10 mg versus placebo 
at a 2-sided 0.05 significance level, then the 2 key secondary endpoints will be 
analyzed hierarchically in the following order: 
2. Normalization of ALP at Month 12 (seladelpar 10 mg versus placebo): If 
negative at a 2-sided 0.05 significance level, no further inferential testing will 
be performed. Otherwise, if positive, then testing will proceed. 
3. Change from baseline to Month 6 in pruritus NRS (seladelpar 10 mg versus 
placebo) will be tested at a 2-sided 0.05 significance level. 
Normalization of ALP is a responder analysis and will be conducted in the ITT analysis 
set using the same approach specified for the primary efficacy analysis.  
Change from baseline in weekly averaged pruritus NRS at 6 months will be analyzed 
using a mixed-effect model for repeated measures (MMRM) for subjects in the MSPN 
analysis set. The model will include baseline NRS, randomization stratum, treatment 
group, week, and treatment-by-week interaction term. Treatment by baseline 
interaction will be explored and added as a term if interaction is noted to be present. 
Least squares (LS) means for the change by treatment and the associated standard 
errors, the LS means for the difference between treatment groups, and associated 
2-sided 95% CIs and 2-sided p-values, based on t-tests, will be derived from the 
MMRM model. Specifically, efficacy endpoints will be evaluated using the estimated 
treatment difference in mean change from baseline NRS for the week associated with 
their specified month. An unstructured covariance matrix will be tried first. If the 
model fails to converge, compound symmetry will be used in place of an unstructured 
covariance. The Kenward-Roger correction for the denominator degrees of freedom 
will be applied. 


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Statistical Methods 
(continued) 
Sensitivity analyses for key secondary endpoint analyses will be described in the study 
SAP and will include the methodologies proposed for the primary endpoint where 
appropriate (e.g., additional methods for missing data handling and alternate population 
analyses). 
Secondary efficacy endpoint proportions will be evaluated based on the method 
described for the primary efficacy analysis. 
Continuous secondary endpoints will be evaluated based on an MMRM model with 
baseline value, randomization stratum, treatment group, visit (or week of evaluation, if 
appropriate), and treatment-by-visit (or week) interaction term. Treatment by baseline 
interaction will be explored and added as a term if interaction is noted to be present as 
fixed effects. LS means for the change by treatment and their associated standard 
errors, the LS means for the difference between treatment groups, and associated 
2-sided 95% CIs and 2-sided p-values, based on t-tests, will be derived from the 
MMRM model. Secondary endpoints will initially be analyzed based on the MMRM 
through Month 12.  
Exploratory endpoints will be summarized primarily with descriptive statistics. Further 
details will be provided in the SAP. 
Safety data, including AEs, safety laboratory results, physical examination results, vital 
signs, and ECG will be summarized by treatment group and/or listed. 
Pharmacokinetic Analysis: 
Descriptive statistics will be provided for the concentration-versus-time data per visit 
number for seladelpar and metabolites. Further, pooling of the concentration data from 
this study with data from other studies will be done to facilitate development and/or 
updating of a population PK model and will be reported separately. 
Sample Size 
Determination: 
The planned sample size is approximately 180 subjects (120 subjects in seladelpar 
10 mg, 60 subjects in the placebo group). The placebo group response rate is estimated 
as 20%. The seladelpar 10-mg dose group response rate is estimated as 55%. With the 
use of a 2-sided test of equality of binomial proportions based on a Fisher’s exact test 
at the 0.05 level of significance, a sample size of 180 randomized subjects will provide 
>90% power to detect a difference between the 10 mg seladelpar group and the placebo 
group. 
Normalization of ALP is estimated to have a placebo response rate and seladelpar 
response rate of 2.5% and 25.5%, respectively. A sample size of 180 randomized 
subjects will provide >90% power to detect a difference between the seladelpar and 
placebo groups, based on a Fisher’s exact test at a 0.05 level of significance. 
Change from baseline in weekly averaged pruritus NRS at Month 6 sample size is based 
on a 2-sample 2-sided t-test at a significance level of 0.05. The standard deviation is 
estimated as 2. Under these assumptions, as well as a total of 48 randomized subjects 
having a baseline NRS ≥4, this test provides ≥80% power to detect a treatment difference 
of ≥2 between the 10 mg seladelpar and placebo groups. 
 


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Table 1: 
Schedule of Assessments 
Visit 
Screeninga 
Run-in 
Random-
ization 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12/ 
EOTa 
Follow-up 
ET 
UNS 
Target Day  
W-5 to -2 
(Day -35 to 
-15) 
W -2 
(Day -
14) 
±3 
days 
Day 1 
W 4   
(Day 29) 
±3 days 
W 12 
(Day 85) 
±7 days 
W 26 
(Day 183) 
±7 days 
W 39 
(Day 274) 
±7 days 
W 52   
(Day 365) 
±7 days 
2W (14 
days) 
After W 
52 
+3 days 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Medical historyb 
X 
 
 
 
 
 
 
 
 
 
 
AE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
X 
Xc 
Xc 
X 
Xc 
X 
X 
X 
Xc 
ECG 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Hematologyd, e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistryd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory measuresd 
Xf 
X 
Xf 
X 
X 
X 
X 
Xf 
X 
Xf 
 
PK sampleg 
 
 
 
 
X 
 
 
Xg 
 
 
Xg 
Hepatitis B, C and HIV 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Back-up blood sampled 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
COVID-19 testingi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus NRSj 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
5-D Itchj 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PBC-40 QoLj 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PGI-Sj 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PGI-Cj 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
PBC clinical outcomek 
 
 
 
X 
X 
X 
X 
X 
XK 
XK 
 
Abdominal ultrasound 
 
X 
 
 
 
 
 
X 
 
X 
 
FibroScan (selected sites)  
 
X 
 
 
 
X 
 
X 
 
X 
 
Liver biopsyl 
 
X 
 
 
 
 
 
X 
 
X 
 
Concomitant Proceduresm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispense 
 
 
X 
 
X 
X 
X 
 
 
 
 
Study drug compliance and 
accountability 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
UDCA compliance 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 


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AE=adverse event; AMA=antimitochondrial antibodies; e-diary=electronic diary; ECG=electrocardiogram; EOT=End of Treatment; ET=Early Termination; HIV=human 
immunodeficiency virus; INR=international normalized ratio; LTS=long-term study; NRS=numerical rating scale; PBC=primary biliary cholangitis; PBC-40 QoL=QoL measure 
for use in PBC; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; PK=pharmacokinetic(s); PT=prothrombin time; QoL=quality of life; 
UDCA=ursodeoxycholic acid; UNS=Unscheduled visit; W=week. 
a Screening: screening evaluations can be completed in up to 3 weeks. When all Screening evaluations are completed, subjects who are deemed to be eligible 
will move into the Run-in period; Month 12/EOT: Subjects will be invited to enter the LTS at the Month 12 Visit.  
b Including PBC medical history, liver biopsy, FibroScan, alcohol consumption, evidence of liver cirrhosis and other forms of liver disease, and HIV.  
c Symptom-directed (brief) physical examination.  
d Blood will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject forgets to fast prior to the blood collection, the site will record it 
in the source document, continue to draw laboratory tests, and proceed with the visit.  
e PT, INR, and platelets can be performed locally at the Screening Visit, at the Run-in Period, and during the Treatment Period if deemed necessary by the 
investigator after consultation with the medical monitor, in cases where centrally read samples are deemed invalid. 
f Screening Visit: Only AMA will be performed. Treatment Period: Fat-soluble vitamins will be performed at Day 1, Month 12, or ET only.  
g PK sampling will be performed once predose (-30 minutes prior to dosing) and twice postdose (1 hour±30 minutes and 3 hours±30 minutes after dosing) at 
Month 3 and Month 12. Prior to the visit, subjects will be reminded to not take the study drug at home. The time of PK blood collection and dosing will be 
documented. When possible, a PK sample should be drawn at the onset of SAEs or clinically meaningful AEs. 
h Applicable for women of child-bearing potential only: a serum pregnancy test will be performed at each visit. After Month 1, a urine pregnancy test will be 
performed at home monthly (every 30±3 days). Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or per local 
regulatory requirements. 
i COVID-19 testing will be performed locally and only if deemed necessary per local requirements. Subjects with a positive COVID-19 test during Screening 
may be eligible to re-screen after recovery.   
j Pruritus NRS, 5-D Itch, PBC-40, and PGI-S and PGI-C data will be collected via an e-diary. Subjects will be asked to complete (1) pruritus NRS: on a daily 
basis from the Run-in Visit and through the first 6 months of treatment. After 6 months, NRS will be collected for 7 consecutive days during each month up to 
EOT; (2) 5-D Itch will be collected biweekly from the Run-in Visit up until the Month 6 Visit; after Month 6, 5-D Itch will be collected once per month; and 
(3) The PGI-S and PBC-40 will start at Run-In and will continue at Randomization, then Month 1, then every 3 months through Month 12/ study participation.  
(4) PGI-C will start at Month 1 and will continue every 3 months through Month 12/ study participation.  (5) Pruritus NRS, 5-D Itch, PBC40, PGI-S, and PGI-
C are expected at Early Termination. (6) Pruritus NRS, 5-D Itch, PBC40, PGI-S, and PGI-C are available on the eDiary for Unscheduled Visit if deemed 
necessary. 
k PBC clinical outcomes will be evaluated per Section 11.  Subjects who terminate study participation for any reason other than a defined PBC clinical outcome 
will be asked to stay in the study without study drug intake. Subjects who decline to stay in the study without study drug intake, or who do not participate in 
the long-term study, a phone call will be performed for PBC clinical outcomes on an annual basis (per Section 8.1.7).  
l Baseline liver biopsy can be performed anytime between Screening and Day 1, but only after confirmation of subject’s eligibility. PT, INR, and platelets must 
be performed within 2 weeks prior to liver biopsy. For subjects who had a baseline liver biopsy and discontinued the study between 6 and 12 months of 
treatment, a follow-up liver biopsy will be performed at either the EOT or the ET visit. 
m A concomitant procedure is any therapeutic intervention (e.g., surgery, biopsy, or physical therapy) or diagnostic assessment (e.g., blood gas measurement or 
bacterial cultures) performed during subjects’ participation in this study. If a concomitant procedure is performed, document the procedure on the subject’s 
‘Concomitant Procedures’ eCRF. AEs related to the administration of these procedures must also be documented on the subject’s AE eCRF. 
 
 


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2. 
INTRODUCTION 
2.1. 
Primary Biliary Cholangitis 
Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) is a serious, rare, 
slowly progressive and potentially life-limiting autoimmune liver disease characterized by 
impaired bile flow (cholestasis) and accumulation of toxic bile acids. The disease occurs more 
frequently in women and presents most often in middle age. The disease course is usually slow 
but frequently impactful; patients at the greatest risk of future poor outcomes are identifiable 
based on patterns of presentation, including biochemical markers of disease at baseline and on 
treatment. 
The hallmark of PBC is cholestasis secondary to hepatobiliary injury and bile acid accumulation, 
with an accompanying elevation in disease-associated serum biomarkers, including alkaline 
phosphatase (ALP), gamma glutamyl transferase (GGT), and depending on the severity of the 
disease, bilirubin and liver transaminases. Serologically, PBC is characterized by the presence of 
antimitochondrial antibodies (AMA) in nearly all patients (1). Clinical symptoms of PBC include 
pruritus and fatigue, which can be disabling for many patients. PBC peak incidence occurs in the 
fifth decade of life and is uncommon in persons younger than 25 years old (2). The liver 
histopathology of patients with PBC is characterized by portal inflammation and 
immune-mediated destruction of intrahepatic bile ducts. These changes occur at different rates 
and with varying degrees of severity. The loss of bile ducts leads to decreased bile secretion and 
the retention hydrophobic bile acids within the liver, resulting in hepatocellular injury, fibrosis, 
cirrhosis, and, eventually, liver failure (3, 4, 5).  
The diagnosis of PBC often occurs at an early stage when following up on abnormal serum liver 
tests, especially elevated ALP. After excluding extra-hepatic biliary obstruction, the presence of 
either AMA (or less often, the histological confirmation by liver biopsy) establishes the 
diagnosis (6). Fifty to 60% of patients are asymptomatic at diagnosis. Overt symptoms develop 
within 2 to 4 years in most asymptomatic patients, although one-third may remain symptom-free 
for years (3). Fatigue and pruritus are the most common presenting symptoms (3). Fatigue has 
been noted in up to 78% of patients and can be a clinically important cause of disability. The 
severity of fatigue is independent of the severity of the liver disease, and there is no proven 
treatment (3). Cholestatic pruritus, the precise cause of which is uncertain, occurs in 20% to 
70% of patients and can be extremely debilitating (7). Perturbation in bile acid homeostasis is a 
likely factor in choleatic pruritus. Lysophosphatidic acid, for example, has been suggested as a 
potential pruritogen in cholestasis (8), whereas rapid relief in itch can be seen in patients with 
treatment-resistant cholestatic pruritus if they have an endoscopic nasobiliary drain placed (9). 
Other findings in patients with PBC can include jaundice, hypercholesterolemia, osteopenia, 
osteoporosis, and coexisting autoimmune diseases (3, 4). Portal hypertension is a late 
complication of the disease (3, 10). Generally, patients with untreated PBC progress to liver 
failure, transplant, or death. A meta-analysis of 4845 subjects in North American and European 
long-term studies demonstrated that subjects with untreated PBC had transplant-free survival of 
79% at 5 years, 59% at 10 years, and 32% at 15 years (11). Despite being a rare disease, PBC is 
1 of the top 6 indications for liver transplantation in the United States (US) and European Union 
(12). The recurrence of PBC following liver transplantation is reported in 11% to 45% of 


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transplantations, with an estimated prevalence of 30% at 10 years following transplantation, 
further demonstrating a need for effective therapies (13). A reported feature of PBC can be the 
development of esophageal varices prior to the onset of cirrhosis. Approximately 6% of early 
histological stage subjects with PBC have varices, and one-third of subjects with stage III to 
stage IV disease develop varices over a median of 5 to 6 years (6, 14). The 3-year survival 
following an initial variceal bleed is 46% (10).  
The first-line therapy for PBC is ursodeoxycholic acid (UDCA), a noncytotoxic bile acid that has 
been the mainstay of treatment for more than 20 years (15). However, up to 40% of patients have 
persistent elevation of ALP and/or bilirubin despite UDCA and are considered inadequate 
responders (16). 
Obeticholic acid (OCA), a synthetic analogue of chenodeoxycholic acid, was conditionally 
approved by the Food and Drug Administration and the European Medicines Agency in 2016 
based on clinically notable decreases in ALP levels while maintaining normal total bilirubin 
levels in subjects with PBC who are inadequate responders to UDCA or as a monotherapy in 
subjects with PBC who are intolerant to UDCA (17). OCA is associated with dose-dependent 
pruritus. 
In summary, despite the previously mentioned therapeutic interventions and recent conditional 
approval of OCA, it is evident that many patients with PBC do not respond adequately to therapy 
and continue to have a progression of their disease (3, 4, 10, 18) and that additional treatments 
are needed. 
2.2. 
Seladelpar 
2.2.1. 
Overview 
Seladelpar (MBX-8025) is an oral, once-daily administered, potent, and selective peroxisome 
proliferator-activated receptors (PPAR)δ agonist (19, 20). Seladelpar is being developed herein 
for the treatment of PBC in subjects with inadequate response to UDCA or intolerance to UDCA. 
2.2.2. 
Mechanism of Action 
PPARδ agonists have been shown to affect the transport, storage, and metabolism of lipids (21). 
Seladelpar improves cholestasis notably by decreasing the synthesis of bile acids in hepatocytes, 
thus preventing their toxic accumulation. The decreased synthesis results in part from the 
down-regulation of the gene for CYP7A1, the key enzyme for the synthesis of bile acids. 
Seladelpar also decreases the synthesis of cholesterol and inhibits its dietary absorption; these 
effects decrease the amount of cholesterol available as substrate for bile acid synthesis, thereby 
enhancing its effect on CYP7A1 in reducing total bile acid pools. Each of the above actions of 
seladelpar have been demonstrated in patients with PBC (20). In addition, seladelpar exerts 
anti-inflammatory effects (20) that are of potential benefit in the treatment of PBC. 
For more detailed information, see the Investigator’s Brochure (IB). 
2.3. 
 
Nonclinical Studies 
Please see the IB for details on the nonclinical studies conducted with seladelpar. 


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2.4. 
Human Experience 
Seladelpar has been evaluated in 16 clinical studies across healthy volunteers and subjects with 
hepatic impairment, mixed dyslipidemia, homozygous familial hypercholesterolemia (HoFH), 
nonalcoholic steatohepatitis (NASH), and PBC. Across these studies, seladelpar tested doses 
have ranged from single-dose studies in healthy volunteers (1, 5, 15, 60, 120, and 360 mg) to 
daily long-term dosing in Phase 2 and Phase 3 studies in subjects with mixed dyslipidemia 
(50 and 100 mg once daily), HoFH (ascending doses 50, 100, and 200 mg once daily), and PBC 
(2, 5, 10, 50, and 200 mg once daily) that have ranged from 8 weeks to over 2 years.  
These studies are supportive of the clinical development of seladelpar in patients with PBC.  
Please refer to the IB for additional detailed information on these studies.  
2.4.1. 
Studies in Patients With PBC 
As of 2020, CymaBay conducted 4 clinical studies with seladelpar in subjects with PBC who 
either have had an inadequate response to UDCA or are intolerant to UDCA. 
Study CB8025-21528 was the first clinical study of the seladelpar for the treatment of PBC (20). 
It was a double-blind, randomized, placebo-controlled, 12-week, dose-ranging study (referred to 
as the “high-dose” study) in adult subjects with PBC who had an inadequate response to UDCA. 
Subjects were randomly assigned to receive seladelpar 50 mg/day, seladelpar 200 mg/day, or 
placebo in a 1:1:1 ratio. The study was terminated approximately midway through enrollment 
(41 subjects had enrolled) after 3 subjects experienced rapid, asymptomatic, and reversible 
Grade 3 elevations in alanine aminotransferase (ALT) (1 subject on 50 mg and 2 subjects on 
200 mg). Although CymaBay elected to terminate the study early when a transaminase elevation 
signal was observed, all subjects receiving seladelpar, including subjects with transaminase 
elevation, exhibited a pronounced decrease in ALP that was evident after the first 2 weeks and 
was sustained for the duration of the study (Figure 1, Panel A). Subjects who received seladelpar 
beyond 2 weeks showed a consistent and continual decrease in ALP. All subjects who received 
seladelpar for 12 weeks normalized their ALP levels (20). This study also provided important 
information supporting the mechanism of action of seladelpar for the treatment of PBC. 
Treatment with seladelpar was associated with a decrease in 7α-hydroxy-4-cholesten-3-one (C4), 
which represents a serum marker for hepatic bile acid synthesis. C4 reflects the activity of 
CYP7A1, the rate-limiting enzyme for the synthesis of bile acids.  
Study CB8025-21629 was the second Phase 2 study in PBC. This study was an international, 
multicenter, open-label, randomized, parallel-group, 8-week, dose-ranging study with a 44-week 
extension period in adult subjects with PBC with an inadequate response or intolerance to 
UDCA. Subjects received oral doses of 2, 5, or 10 mg seladelpar once daily. Subjects were 
randomized to receive 5 or 10 mg seladelpar, whereas those in the 2-mg seladelpar group entered 
after being sequentially assigned their dose. After 12 weeks, subjects on 2 or 5 mg could escalate 
the dose if their ALP treatment goal were not achieved. By Week 52, 10 of 11 subjects in the 
2-mg dose group were up-titrated to 5 or 10 mg, and 30 of 49 subjects in the 5-mg dose group 
were up-titrated to 10 mg. 
A total of 119 subjects were enrolled into the study; of these, 112 subjects (94.1%) were 
analyzed for efficacy. The 5- and 10-mg doses showed consistent, meaningful, and reproducible 
decreases in ALP levels (Figure 1, Panel B). At baseline, the mean ALP was 300, 345, and 


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295 U/L in the 2-, 5-, and 10-mg dose groups, respectively. After 12 weeks of dosing, mean 
percent changes from baseline in ALP were -22.6%, -34.5%, and -43.2% for the 2-, 5-, and 
10-mg dose groups, respectively. Fmt he1more, 31 % of subjects with PBC in the 10-mg dose 
group achieved nonnalization of ALP by Week 12. After 52 weeks of dosing, mean percent 
changes from baseline in ALP were -32.7%, -40.1 %, and -44.2% for the 2-, 5-, and 10-mg dose 
groups, respectively. 
Figure 1: 
QI 
C ·-
Mean Percent Changes in ALP in PBC Phase 2 Studies 
Panel A: Study CB8025-21528 
Tim e (week s) 
2 0 
2 
4 
8 
12 
0 
-
QI 
-
Placebo 
1/) 
"' 
al 
-
5 0 mg 
-2 0 
E 
-
2 00 mg 
0 ... 
--
Me a n ±SEM 
QI 
-40 
Cl 
C 
"' 
.t::. 
U 
-6 0 
-8 0 
n : 12 
13 
10 
10 
8 
6 
6 
5 
4 
4 
3 
2 
Panel B: Study CB8025-21629 
0 12 4 6 8 
12 
16 
20 
26 
32 
39 
52 Weeks 
0 .... -------------------------
G> -10 
C) 
C 
IV 
U -20 
0 
Q. 
-30 
C 
IV 
Q) 
:E: -40 
-50 
Dose Titration 
-- 2mg 
l 
-- 5mg 
-- 10 mg 
ALP=alkaline phosphatase; PBC=primruy biliruy cholangitis; SEM=standard eITor of the means. 
Source: Table 14.2.1.2.1 
The increases in transaminases observed with seladelpar 50- and 200-mg doses in the high-dose 
study (Study CB8025-21528; Figure 2, Panel A) have not been observed with seladelpar 5- and 
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10-mg doses. As seen in Figure 2, Panel B, a decrease in median ALT levels over 12 weeks is 
observed in the subjects who had completed 12 weeks of seladelpar ti·eatment (up to 12 weeks, 
subjects maintained their assigned dose with no dose adjustment). This indicates that, instead of 
elevations in ti·ansaminases at higher doses, lower doses produce reductions in ti·ansaminase 
levels and an indication of decreased liver injmy . Decreases in ti·ansaminases likely reflect 
reduced hepatocellular sti·ess accompanying reductions in cholestasis and inflammation. This is 
consistent with seladelpar exe1ting an anti-inflammato1y effect that conti·ibutes to decreases in 
interface hepatitis and po1tal inflammation. Further, this result confnms that the ti·ansaminase 
elevation is a dose-related phenomenon. 
Figure 2: 
Percent Change in ALT in PBC Phase 2 Studies 
Panel A: Study CB8025- 21528 
QI 
60 
-
Placebo 
C: 
QI 
VI 
4 0 
"' 
CD 
E 
20 
0 ... ... 
QI 
0 
C, 
C: 
"' 
.c: 
-20 
u 
0 
C: 
-4 0 
"' 
'O 
QI 
n : 12 
13 
10 
1 0 
8 
6 
6 
5 
4 
4 
3 
2 
== 
-60 
2 
4 
8 
1 2 
Time (we e k s ) 
Panel B: Study CB8025-21629 
12 
52 Weeks 
-
2/5/10 mg (n = 10) 
-
5/10 mg (n = 42) 
-
10 mg (n = 48) 
-25% 
---..;:::::::::::-.1 .31% 
-40 
AL T=alarune aminotransferase; PBC=primary biliary cholangitis. 
January 2018 data cutoff. 
Values shown in Panel B are mean±standard eITor. 
Source: Tables 14.2.4.6 
-31% 
Seladelpar did not increase prnritus. The baseline median prnritus visual analogue scale (VAS) 
was 10 and 40 in the 5- and 10-mg group, respectively. Substantial improvement in prnritus was 
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observed at 1 year in subjects with moderate to severe/very severe baseline pruritus (58% and 
93% of subjects in the 5-mg dose group who up-titrated to 10 mg during the study [the 5/10 mg 
cohort] and 10-mg dose group, respectively). 
Seladelpar was generally safe and well tolerated, with no transaminase elevation safety signal. 
There were 6 serious adverse events (SAEs), and none was deemed related to seladelpar. The 
results of this study concluded that seladelpar doses of 10 mg, or 5 mg adjusted to 10 mg, 
demonstrate potent anticholestatic efficacy that is maintained over 52 weeks.  
Study CB8025-31735 (ENHANCE) was designed as a Phase 3, international, double blind, 
randomized, placebo-controlled study in adults subjects with PBC with an inadequate response 
or intolerance to UDCA. Subjects were randomly assigned to receive 5 mg/day seladelpar, 
10 mg/day seladelpar, or placebo in a 1:1:1 ratio. The primary efficacy analysis was planned to 
evaluate the response to the composite endpoint (ALP <1.67× upper limit of normal [ULN], ALP 
decrease of ≥15%, and total bilirubin ≤1.0× ULN) after 52 weeks of treatment. Key secondary 
analyses included normalization of ALP at 12 months (e.g., ALP ≤1.0× ULN) and change from 
baseline in the weekly averaged peak pruritus numerical rating scale (NRS) over 6 months. 
The study was terminated shortly after completion of enrollment (N=265) due to histology 
observations in an ongoing study in subjects with NASH (Study CB8025-21730; refer to the IB 
for details). Although the study was still blinded, the statistical analysis plan (SAP) was adjusted 
to move the primary and secondary endpoints from 12 to 3 months. 
As shown in Figure 3, Panel A, 57.1% and 78.2% subjects in the seladelpar 5- and 10-mg 
groups, respectively, met the composite endpoint versus 12.5% of subjects in the placebo group 
(p<0.0001) after 12 weeks of treatment, with seladelpar 10 mg demonstrating a statistically 
significant higher response than seladelpar 5 mg (p<0.05). Normalization of ALP (Figure 3, 
Panel B) was achieved in 27.3% of subjects in the 10-mg dose group versus 5.4% and 0% in the 
seladelpar 5-mg and placebo groups, respectively.  
After 3 months of treatment, the mean relative decreases in ALP of 36% (-106 U/L) and 
44% (-122 U/L) for the seladelpar 5- and 10-mg groups, respectively, were highly significant 
from a mean relative decrease in the placebo group (3.7% [-12 U/L]; p<0.0001). These are 
consistent with results from the Phase 2 studies. 
Figure 3: 
Study CB8025-31735: Seladelpar Effects on ALP 
Panel A: Composite Endpoint 
Panel B: ALP Normalization 
0
20
40
60
80
100
Proportion of Patients (%)
57.1%
78.2%
Placebo (n = 56)
5 mg (n = 56)
10 mg (n = 55)
12.5%
p < 0.0001
p < 0.0001
p < 0.05
 
0
10
20
30
40
50
Proportion of Patients (%)
5.4%
27.3%
Placebo (n = 56)
5 mg (n = 56)
10 mg (n = 55)
0%
ns
p < 0.0001
p < 0.01
3/56
15/55
 
ALP=alkaline phosphatase; CMH=Cochran-Mantel-Haenszel; ns=not significant. 
p-values by CMH test. 
Source: Table 14.2.1.1 and Table 14.2.3 
-
-
-
-
-
-


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Seladelpar effects on pruritus after 12 weeks of treatments are presented in Figure 4. The key 
secondary pruritus endpoint measured change from baseline in the weekly averaged peak 
pruritus NRS at Month 3 in subjects with PBC with moderate to severe baseline pruritus, defined 
as an NRS ≥4. The NRS is a scale used for self-reported itch that goes from 0 to 10, with 0 being 
no itch and 10 being the worst imaginable itch. Approximately 30% of subjects completing 
3 months of treatment had a mean baseline NRS of 6.2. A least squares (LS) mean decrease in 
NRS of 3.15 was observed for subjects in the seladelpar 10-mg group versus 1.64 for subjects in 
the placebo group (p=0.026). An LS mean decrease of 2.0 observed in subjects in the seladelpar 
5-mg group was not significantly different from placebo. 
Figure 4: 
Study CB8025-31735: Seladelpar Effect on Pruritus 
-4
-3
-2
-1
0
NRS Change
LS Mean (SE)
Placebo (n = 17)
5 mg (n = 17)
10 mg (n = 18)
ns
p < 0.05
ns
 
LS=least squares; NRS=numerical rating scale; ns=not significant; SE=standard error. 
Source: Table 14.2.4.1 
Similar to what was seen in the Phase 2 study CB8025-21629, 23%, 17%, and 4% decreases in 
LS mean ALT levels were observed in the seladelpar 5-mg, seladelpar 10-mg, and placebo 
groups, respectively.  
Seladelpar was well tolerated during the study, with balance in the incidence of adverse events 
(AEs) being reported across the dose groups: 63%, 65%, and 74% in the seladelpar 5-mg, 
seladelpar 10-mg, and placebo groups, respectively. There were no treatment-related AEs of 
Grade 3 or greater, including transaminase elevations. In addition, there were no treatment-
related SAEs, and 2 AEs in the 10-mg group and 1 in the placebo group led to study drug 
discontinuation. The only treatment-emergent AE (TEAE) occurring in ≤10% of subjects in any 
treatment group was pruritus, which was lower for subjects on seladelpar than on placebo. 
Study CB8025-31731 was a Phase 2/3, open-label, long-term study to evaluate the safety and 
tolerability of seladelpar (2, 5, and 10 mg) in subjects who participated in the previous PBC 
studies with seladelpar. Similar to Study CB8025-31735, this study was terminated early. The 
safety and efficacy profile were consistent with other PBC studies. Please refer to the IB for 
additional detailed information on these studies. 
 
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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objectives 
The primary objective of this study is to evaluate the treatment effect of seladelpar on composite 
biochemical improvement in cholestasis markers based on ALP and total bilirubin and to 
evaluate the safety of seladelpar over 12 months of treatment compared to placebo. 
3.2. 
Secondary Objectives 
The key secondary objectives of this study are to evaluate the effect of seladelpar on the 
normalization of ALP values at 12 months of treatment compared to placebo and to evaluate the 
effect of seladelpar on pruritus at 6 months of treatment compared to placebo in subjects with 
baseline moderate to severe pruritus. 
 
 
 
  
3.3. 
Exploratory Objectives 
 
 
 
4. 
STUDY POPULATION 
Patients with PBC with an inadequate response to UDCA or intolerance to UDCA who meet the 
following inclusion and exclusion criteria may be included in the study. 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study participation: 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law. 
2. 18 to 75 years old (inclusive). 
3. Male or female with a diagnosis of PBC based on any two of the following criteria: 
a. History of ALP above 1.0× ULN for at least 6 months. 
b. Positive AMA titer (>1:40 on immunofluorescence or M2 positive by enzyme 
linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear 
antibodies (ANAs). 
c. Documented liver biopsy results consistent with PBC. 
CCI
CCI


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4. UDCA for the past 12 months (stable dose for >3 months prior to screening) OR 
intolerant to UDCA (last dose of UDCA >3 months prior to screening). 
5. Laboratory parameters measured by the Central Laboratory at screening:  
a. ALP ≥1.67× ULN. 
b. Aspartate aminotransferase (AST) ≤3× ULN. 
c. ALT ≤3× ULN. 
d. Total bilirubin ≤2× ULN. 
e. Estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 (calculated by 
the Modification of Diet in Renal Disease study equation). 
f. International normalized ratio (INR) below 1.1× ULN.  
For subjects on anticoagulation therapy, INR must be maintained in the range 
required for prophylaxis for their specific disease. 
g. Platelet count ≥100×103/µL. 
NOTE: PT, INR, and platelets can be performed locally at the Screening Visit, if 
deemed necessary by the investigator after consultation with the medical monitor, in 
cases where centrally read samples are deemed invalid. 
6. Females of reproductive potential (refer to Section 8.1.1) must use at least 1 barrier 
contraceptive and a second effective birth control method during the study and for at 
least 90 days after the last dose. Male subjects 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.  
4.2. 
Exclusion Criteria 
Subjects must not meet any of the following criteria to be eligible for study participation: 
1. Previous exposure to seladelpar (MBX-8025). 
2. A medical condition other than PBC that, in the investigator’s opinion, would 
preclude full participation in the study (e.g., cancer) or confound its results (e.g., 
Paget’s disease, any active infection).  
3. Advanced PBC as defined by the Rotterdam criteria (albumin below the lower limit 
of normal AND total bilirubin above 1.0× ULN). 
4. Presence of clinically important hepatic decompensation, including the following: 
a. History of liver transplantation, current placement on liver transplantation list, or 
current Model for End-Stage Liver Disease (MELD) score ≥12. For subjects on 
anticoagulation medication, evaluation of the baseline INR, in concert with their 
current dose adjustments of their anticoagulant medication, will be taken into 
account when calculating the MELD score.  This will be done in consultation with 
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b. Complications of portal hypertension, including known esophageal varices, 
history of variceal bleeds or related interventions (e.g., transjugular intrahepatic 
portosystemic shunt placement), ascites, and hepatic encephalopathy. 
c. Cirrhosis with complications, including history or presence of spontaneous 
bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome. 
5. Other chronic liver diseases:  
a. Current features of autoimmune hepatitis as determined by the investigator based 
on immunoserology, liver biochemistry, or historic confirmed liver histology. 
b. Primary sclerosing cholangitis determined by the presence of diagnostic 
cholangiographic findings.  
c. History or clinical evidence of alcoholic liver disease. 
d. History or clinical evidence of alpha-1-antitrypsin deficiency. 
e. History of biopsy confirmed NASH. 
f. History or evidence of Gilbert’s syndrome with elevated total bilirubin. 
g. History or evidence of hemochromatosis. 
h. Hepatitis B, defined as the presence of hepatitis B surface antigen (HBsAg).  
i. Hepatitis C, defined as the presence of hepatitis C virus (HCV) ribonucleic acid 
(RNA). 
j. History, evidence, or high suspicion of hepatobiliary malignancy based on 
imaging, screening laboratory values, and/or clinical symptoms. 
6. Known history of human immunodeficiency virus (HIV) or positive antibody test at 
screening. 
7. Clinically important alcohol consumption, defined as more than 2 drink units per day 
(equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, 
or inability to quantify alcohol intake reliably. 
8. History of malignancy diagnosed or treated, actively or within 2 years, or ongoing 
evaluation for malignancy; localized treatment of squamous or noninvasive basal cell 
skin cancers and cervical carcinoma in situ is allowed if appropriately treated prior to 
screening. 
9. Treatment with obeticholic acid (OCA), and fibrates (e.g., bezafibrate, fenofibrate, 
elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior to screening. 
10. Treatment with colchicine, methotrexate, azathioprine, or long-term systemic 
corticosteroids (>2 weeks) during 2 months prior to screening. See Section 7 for 
additional medications that may be excluded. 
11. Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampicin, 
sertraline, or any experimental approach) must be on a stable dose within 1 month 
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12. Treatment with any other investigational therapy or device within 30 days or within 
5 half-lives, whichever is longer, prior to screening. 
13. For females, pregnancy or breastfeeding. 
14. Any other condition(s) that would compromise the safety of the subject or 
compromise the quality of the clinical study, as judged by the investigator. 
15. Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or other 
immunosuppressive biologics).  
16. Other medications that effect liver or GI functions, such as absorption of medications 
or the roux-en-y gastric bypass procedure, may be prohibited and should be discussed 
with the medical monitor on a case-by-case basis. 
17. Active COVID-19 infection during Screening. 
 


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5. 
STUDY DESIGN 
5.1. 
Study Overview 
This is a Phase 3, international, multicenter evaluation of seladelpar in a randomized, 
double-blind, placebo-controlled, parallel-group study when administered for up to 12 months as 
a daily oral capsule in patients with PBC. Approximately 180 subjects will be randomized across 
approximately 180 sites worldwide. 
Enrolled subjects will have confirmed PBC as defined by having any 2 of the following 
3 diagnostic criteria at screening: (1) history of ALP above 1.0× ULN for at least 6 months; 
(2) positive AMA titers (>1:40 on immunofluorescence or M2 positive by ELISA) or positive 
PBC-specific ANAs; and (3) documented liver biopsy results consistent with PBC. Please refer 
to Section 4 for the complete listing of the Inclusion and Exclusion Criteria. 
This study is a pivotal study to evaluate the safety of seladelpar and its effect (±UDCA) on 
cholestasis markers and on pruritus in subjects with inadequate response to UDCA or intolerance 
to UDCA. Enrolled subjects must have received UDCA for at least 12 months (>3 months of 
stable dose) or have intolerance to UDCA (no UDCA dose in the past >3 months). During the 
study, the study drug will be administered as an add-on to standard-of-care UDCA therapy for 
subjects who tolerate UDCA; for subjects with UDCA intolerance, the study drug will be 
administered as a monotherapy. The study population can also include subjects with an 
inadequate response to UDCA+OCA or who are intolerant to OCA. 
Subjects will be randomly assigned to receive placebo or seladelpar 10 mg. Subjects will be 
stratified by ALP (ALP level <350 U/L versus ALP level ≥350 U/L) and the presence of 
clinically important pruritus (pruritus NRS <4 versus NRS ≥4) to ensure even distribution across 
treatment groups. Subjects will be considered as formally enrolled in the study at the time of 
randomization. 
Study drug (placebo or seladelpar) will be taken in a blinded manner orally once daily for a 
period of up to 12 months. Subjects with an inadequate response to UDCA will continue on 
UDCA throughout the study. 
Subjects will be asked to use an electronic diary (e-diary) to evaluate pruritus and QoL during 
the study participation. E-diaries will be dispensed at the Run-in Visit and will include the 
following questionnaires: pruritus NRS, 5-D Itch, Patient Global Impression of Severity (PGI-S), 
Patient Global Impression of Change (PGI-C), and PBC-40. Subjects will perform an evaluation 
of their pruritus on a daily basis via pruritus NRS starting from the Run-in Visit through the first 
6 months of treatment. After 6 months, pruritus will be evaluated on a monthly basis until the 
Month 12/End of Treatment (EOT) Visit using pruritus NRS for 7 consecutive days each month. 
5-D Itch will be evaluated biweekly from the Run-in Visit for the first 6 months of treatment and 
on a monthly basis after that until the Month 12/EOT Visit. PBC-40, PGI-S, and PGI-C will be 
evaluated after 1 month and every 3 months after treatment initiation over the whole study 
duration.  
The total duration of participation in the study for each subject will be up to ~14 months. The 
Screening Period will be up to 3 weeks, the Run-in Period will be 2 weeks, and the Treatment 
Period will be up to 12 months. During the Treatment Period, subjects will be seen every 
3 months, except for the first on-treatment visit, which will be performed after 1 month after the 


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initiation of the study drug. After the completion of the Treatment Period, the subjects will be 
invited to enroll into an open-label, long-term study (Study CB8025-31731-RE) in which each 
subject will be administered seladelpar and subjects on placebo will initiate seladelpar treatment. 
Subjects who do not want to continue seladelpar treatment beyond this study and decline long-
term study participation will have a safety follow-up visit performed 2 weeks (14 days +3) after 
the last dose of the study drug. Subjects who discontinue study drug treatment for any reason 
other than a PBC clinical outcome will be asked to stay in the study without study drug intake.  
Subjects who discontinue study drug treatment anytime, and do not stay in the study, will be 
terminated from the study, and complete an Early Termination Visit. For subjects who decline to 
stay in the study without study drug intake, or who do not participate in the long-term study, a 
phone call will be performed for PBC outcomes on an annual basis (Section 8.1.7).  
Study visits may occur in clinic, with the assistance of a home health service, or using virtual 
technologies. 
In order to establish the histological status of their liver before and after treatment, all subjects 
will be encouraged to have a liver biopsy during the Screening Period (unless a historical biopsy 
meeting quality standards can be supplied) to evaluate PBC stage and histology changes at 
baseline and after 1 year of treatment. Subjects willing to undergo a procedure will have liver 
biopsy performed during the Screening Period. The follow-up liver biopsy will be performed at 
the Month 12 Visit or at Early Termination if the subject withdraws from the study, provided 
they have had at least 6 months of treatment. A follow-up liver biopsy will be performed only in 
subjects with baseline liver biopsy. Histology will be evaluated by a pathology review committee 
(PRC) as specified in a histopathology plan. 
During the study, subjects will be evaluated for the progression of their disease by collecting 
information about PBC clinical outcomes. All PBC clinical outcomes will be adjudicated by a 
critical event review committee (CERC).  
The study design implements safety criteria to monitor subjects with potential drug-induced liver 
injury, muscle injury, renal injury, and acute pancreatitis with actions to stop the study drug, to 
interrupt the study drug, to down-titrate the study drug, or to investigate the case prior to actions 
with the study drug.  
Subjects will be asked to participate in a pharmacokinetic (PK) sample collection to evaluate 
plasma concentrations of seladelpar and its metabolites. Subjects who consent to participate in 
this PK sample collection will provide a predose sample (-30 minutes prior to dosing) and 
2 postdose samples at (1 hour±30 minutes and at 3 hours±30 minutes) at Month 3 and at 
Month 12 per the assigned schedule.  
An independent data safety monitoring board (DSMB) will be convened to review the study data 
on a regular basis during the study conduct to ensure subjects’ welfare and preserve study 
integrity.  
A CERC will be established to analyze and adjudicate clinical events that occur during the study. 
A PRC will be established to evaluate the biopsies in accordance with a defined histopathology 
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The primary efficacy analysis will be a responder analysis of a composite of biochemical 
measures after 12 months of treatment with the study drug. Details of the conduct of the primary 
analysis will be provided in the SAP. 
Figure 5: 
Study CB8025-32048: Study Diagram 
 
ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; EOT=End of Treatment; 
UDCA=ursodeoxycholic acid; ULN=upper limit of normal. 
a Seladelpar is an add-on to UDCA for patients with an inadequate response to UDCA in the prior 12 months.  
5.2. 
Treatment and Allocation of Subjects 
Approximately 180 subjects with PBC will be enrolled into the study.  
Subjects will be randomized to seladelpar 10 mg or placebo in 2:1 ratio (approximately 
120 subjects in the seladelpar 10-mg group and 60 subjects in the placebo group). Subjects will 
be stratified by ALP level <350 U/L versus ALP level ≥350 U/L and by the presence of 
clinically important pruritus (pruritus NRS <4 versus NRS ≥4). 
5.3. 
Study Duration 
The study will be up to ~14 months of duration and consists of the following periods: 
• Screening Period: up to 3 weeks 
• Run-in Period: 2 weeks 
• Treatment Period: a maximum of 12 months with an option to enter an open-label 
long-term study (Study CB8025-31731-RE) 
• Safety Follow-up Period: Up to 2 weeks (14 days +3) (only for subjects who are not 
enrolled in the long-term study) 
5.4. 
Study Outcome Measurements 
5.4.1. 
Primary Measures 
1. Proportion of subjects who are considered responders at 12 months based on the 
following composite endpoint of ALP and total bilirubin at 12 months requiring 
a. ALP <1.67× ULN 
Entry Criteria: 
___ 
ALP~ 1.67x ULN; ALT/AST 5 3x ULN; 
t 
Screening 
Period 
t 
Week -4 
Run-In 
t 
Day 1 
Randomization 
Treatment Period* 
Placebo (n:::::60) 
t 
Month 6 
•seladelpa r is an add-on to UOCA for patients with an inadequate response to UOCA in the prior 12 months 
t 
EOT 
Month 12 
ASSURE: Open Label 
Long Term Study 
(CB8025-31731-RE) 
or 
Safety Follow Up 


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b. ≥15% decrease in ALP 
c. Total bilirubin ≤1.0× ULN 
2. Assessment of TEAEs (National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] Version 5.0), biochemistry, and hematology 
5.4.2. 
Key Secondary Measures 
1. Proportion of subjects with ALP ≤1.0× ULN at 12 months (e.g., normalization) 
2. Change from baseline in weekly averaged pruritus NRS in subjects with baseline 
NRS ≥4 at 6 months 
5.4.3. 
Other Secondary Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
I 
I 
I 
I 


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5.4.4. 
Exploratory Measures 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
5.5. 
Rationale for Dose Selection 
In a double-blind, placebo-controlled study in subjects with PBC randomized to placebo, 
seladelpar 5 mg, or seladelpar 10 mg, the seladelpar 10-mg dose (n=55) demonstrated superior 
efficacy (p<0.05) with comparable safety compared to seladelpar 5 mg (n=56) in the composite 
endpoint (78.2% versus 57.1%). Further, 10 mg was superior to 5 mg (p<0.01) in normalizing 
ALP (27.3% versus 5.4%), and in subjects with baseline NRS ≥4, seladelpar 10 mg showed 
improvement in pruritus (LS mean decrease in NRS of 3.15 versus 1.64 in placebo, p<0.03), 
whereas the seladelpar 5-mg effect was not statistically significant. AEs were reported in 74%, 
63%, and 65% of subjects receiving placebo, seladelpar 5 mg, and seladelpar 10 mg, 
respectively. 
In Phase 2 PBC studies, dose-dependent improvements in markers of cholestasis and 
inflammation as well as metabolic markers (e.g., decrease in triglycerides and LDL-C) have been 
established for seladelpar 2-, 5-, and 10-mg doses. However, in the Phase 2 dose-ranging study, 
by Week 52, 10 of 11 subjects receiving seladelpar 2 mg up-titrated to 5 or 10 mg, and 30 of 
53 subjects receiving seladelpar 5 mg up-titrated to 10 mg to improve clinical response. 
Seladelpar 10 mg has been well tolerated to date, with no meaningful differences in the safety 
profile compared to lower doses of seladelpar and placebo and is not associated with 
drug-induced pruritus. Refer to the IB for details. 
For all of the abovementioned reasons, a seladelpar dose of 10 mg/day is optimal and has been 
selected for this Phase 3 study.  
CCI


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5.6. 
Rationale for Placebo Arm 
This study incorporates the use of a placebo comparator arm on top of the first-line 
standard-of-care therapy UDCA, as it is the most rigorous test of treatment efficacy and safety 
profile for evaluating an experimental therapy in complex patient populations. 
A placebo-controlled, double-blinded pivotal study allows an unbiased estimate of the seladelpar 
treatment effect and full characterization of seladelpar’s safety. A placebo-controlled 
methodology is essential to provide sufficient efficacy and safety data to support widespread use 
in non-study settings.  
Subjects will continue to receive UDCA as the background therapy unless UDCA intolerance 
was diagnosed. UDCA has been the mainstay of therapy for PBC, has been studied in multiple 
prospective clinical studies, and has proved its beneficial effect.  
Enrolled subjects will be randomized into the study in seladelpar versus placebo group in a 
2:1 ratio to increase the subject’s chance to receive an active drug during the study participation.  
Although OCA is authorized in the US and European Union, its authorization is conditional, 
pending confirmation of benefit on clinical outcomes; its safety profile is not fully understood; 
and it is not available in all countries where the proposed clinical study is being conducted. 
The effects of seladelpar on pruritus is being evaluated in this study as a key secondary endpoint; 
an active control study with OCA would require the exclusion of patients with severe pruritus 
due to the warning and dosing limitation in its label. Further, because OCA is known to cause 
and/or worsen pruritus, the use of OCA as a comparator would make it infeasible to establish the 
effect of seladelpar on pruritus. 
This study includes biopsy to characterize histology in subjects with PBC treated with seladelpar 
and placebo, an important requirement for regulators. Coadministration with other PBC 
treatments such as OCA would confound the interpretation of histology, as well as the overall 
safety profile of seladelpar.  
5.7. 
Benefit/Risk Assessment 
The study being proposed is a placebo-controlled, double-blind, randomized study to evaluate 
safety and treatment effect of seladelpar with or without UDCA, the first-line standard of care, in 
subjects with PBC who either have an inadequate response after 12 months of receiving UDCA 
or are intolerant to UDCA. 
5.7.1. 
Potential Benefit 
In two placebo-controlled, PBC studies with seladelpar, subjects receiving placebo showed no 
relevant change in biochemical markers of cholestasis, whereas subjects receiving seladelpar 
exhibited a pronounced decrease in ALP. ALP is a biochemical marker for which lower values 
have been shown to be predictive of longer transplant-free survival for patients with PBC. After 
12 weeks of treatment with seladelpar 10 mg, 82% of subjects reached ALP <1.67× ULN versus 
18% of subjects with placebo (p<0.0001), and 27% of subjects had a normal ALP versus 0%, 
respectively. Importantly, 78% of subjects treated with 10 mg seladelpar met the composite 
responder endpoint compared to 12.5% of subjects receiving placebo (p<0.0001). Additional 
biochemical markers of cholestasis, such as GGT and 5’-nucleotidase, were also reduced by 


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seladelpar. Seladelpar also produced potentially beneficial metabolic and anti-inflammatory 
effects. These effects were sustained with long-term, open-label treatment with seladelpar. 
Seladelpar’s effect on quality-of-life measures such a pruritus, an important clinical outcome for 
patients, has been demonstrated in 2 clinical studies. In these studies, seladelpar improved 
pruritus when measured with either VAS or NRS. In an open-label setting, a decrease in the 
pruritus VAS was noted in the 10-mg group, in which approximately half of subjects had a 
substantial level of itching at baseline (VAS ≥40 mm or moderate to severe itch). These data 
were confirmed in placebo-controlled study where subjects with PBC with moderate to severe 
pruritus at baseline (defined as an NRS of ≥4) had a LS mean decrease in NRS of 3.15 when 
treated with seladelpar 10 mg, which was statistically significant compared to placebo (p=0.026). 
These data suggest that seladelpar treatment could improve PBC-associated itch. 
Subjects who will successfully complete this study will be offered open-label treatment in a 
long-term study (Study CB8025-31731-RE); subjects receiving placebo will be switched to the 
active treatment with seladelpar. 
5.7.2. 
Potential Risks 
Across the clinical development program, the doses of seladelpar tested have included 
single-dose studies in healthy volunteers (1, 5, 15, 60, 120, and 360 mg), to daily long-term dose 
in Phase 2 studies in subjects with mixed dyslipidemia (50 and 100 mg once daily), HoFH 
(ascending doses 50, 100, and 200 mg once daily), NASH (10, 20, and 50 mg once daily), and 
PBC (2, 5, 10, 50, and 200 mg once daily). In these studies, dosing durations have ranged from 8 
weeks to over 2 years.  
Seladelpar has been associated with increases in liver transaminases (ALT and AST) in subjects 
with PBC treated with seladelpar at doses of 50 and 200 mg. The transaminase increases appear 
to be dose and population dependent and were fully reversible upon treatment discontinuation. A 
single PBC subject taking seladelpar 200 mg/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 in serum creatinine 
have been noted, similar to observations with PPARα or pan-PPAR 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.  
5.7.3. 
Summary 
Seladelpar has demonstrated the potent and rapid decrease in biochemical markers of cholestasis 
(ALP, GGT, and total bilirubin), a decrease in a marker of inflammation (hs-CRP) and decreases 
in LDL-C in subjects with PBC who had an inadequate response or intolerance to UDCA. In 
addition, the current data showed that seladelpar improves PBC-related pruritus. Seladelpar 
doses 10 mg and below were generally safe and well tolerated. There was no evidence that 
seladelpar was associated with transaminase elevations at these doses. There was also no 
evidence that seladelpar induced or worsened pruritus. Appropriate precautions have been 
incorporated into this protocol, with careful monitoring of potential drug-induced liver, renal, or 
pancreatic injury and muscle toxicity. 
In summary, the benefit/risk of seladelpar in patients with PBC at doses up to 10 mg is 
acceptable based on the aggregate safety and treatment effect data to date. 


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6. 
STUDY MEDICATIONS 
6.1. 
Investigational Product  
6.1.1. 
Dose and Mode of Administration 
Dose: Subjects will receive seladelpar 10 mg, seladelpar 5 mg (if down-titrated), or matching 
placebo in a blinded fashion. 
Seladelpar, as well as matched placebo, will be supplied in a blinded fashion as 5- and 10-mg 
capsules.  
Administration: The study drug (seladelpar or placebo) will be administered orally, once daily, 
for a duration of up to 12 months. The subject will take 1 capsule every day, approximately at the 
same time each day. 
Down-Titration: Subjects who meet specific safety monitoring criteria in Section 10 or have 
tolerability issues may have a dose down-titration. Subjects who are initially assigned to 10 mg 
will be down-titrated to 5 mg in a blinded manner. Subjects initially assigned to placebo will 
have a blinded down-titration and will remain in the placebo group.  
Subjects who experience a clinically important AE that, in the investigator’s clinical judgment, 
warrants a dose reduction are also eligible for a similar dose down-titration. Dose down-titration 
must be approved by the medical monitor and will be performed in a blinded manner. Subjects 
who have a temporary interruption from study drug due to an AE may 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 subject’s ability to dose per protocol. The 
medical monitor should be advised of any interruption as soon as possible and consulted if study 
drug is to be restarted. 
6.1.2. 
Packaging, Labeling, and Shipping 
Blinded study drug will be supplied in bottles containing 5-mg, 10-mg, or placebo capsules. 
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. To ensure continuity of 
treatment, the option of delivering the investigational product directly from each site to the 
subject may be considered. Additional replacement study drug will be available as required. All 
replacement shipments must be accounted for in the same manner as the initial drug supply. 
6.1.3. 
Storage of Study Drug 
All supplies of study medication must be stored as defined in the pharmacy manual. 
6.2. 
Accountability of Clinical Supplies 
Study drug will be dispensed at Day 1 and quarterly thereafter (e.g., Months 3, 6, and 9) and will 
be reconciled at all visits. 


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The principal investigator 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 principal investigator in 
maintaining current and accurate inventory records. 
6.3. 
Ursodeoxycholic Acid 
UDCA will be taken as a background therapy as part of participation in the study.  
UDCA will be administered orally, 1 or multiple times per day at the prestudy dose and as 
recommended per investigator’s clinical judgment.  
The UDCA dose, compliance with UDCA, and any changes in dose during the study will be 
documented and monitored. Compliance will be evaluated by asking the subjects if they missed 
any doses of UDCA between the visits; the number of doses missed should be recorded. 
6.4. 
Randomization and Stratification  
Subjects will be randomized in a blinded manner to placebo or seladelpar 10 mg in a 2:1 scheme 
(seladelpar 10 mg: placebo). In addition, randomized subjects will be stratified by ALP level 
<350 U/L versus ALP level ≥350 U/L and by the presence of clinically important pruritus 
(pruritus NRS <4 versus NRS ≥4). 
The randomization procedure will be performed centrally via an interactive web response system 
(IWRS) at the Day 1 Visit. A subject will be considered formally enrolled in the study at the time 
of randomization and begin study drug dosing. 
6.5. 
Emergency Unblinding 
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 investigator removed the study blind for 
an individual subject 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. 
6.6. 
Compliance 
Compliance to the study drug will be assessed through drug accountability evaluation. Study 
drug accountability will be evaluated at the Month 3 through Month 12 Visits and the Early 
Termination Visit. 
7. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
The use of concomitant medications or procedures must be documented on the subject’s 
electronic Case Report Form (eCRF). AEs related to the administration of these medications or 
procedures must also be documented on the appropriate section in the eCRF. 


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All subjects will be instructed to remain on their optimal or best possible diet and lifestyle, 
including drinking habits, specifically alcoholic beverages, throughout the study. 
7.1. 
Concomitant Medications 
A concomitant medication is any drug of substance other than study drug and UDCA, including 
over-the-counter medications, herbal medications, and vitamin supplements, administered during 
subjects’ participation in this study. 
Any medication taken within 3 months prior to Screening and during the study period, as well as 
the indication, will be recorded in the source documents and the eCRFs. Any AEs related to the 
administration of these medications or procedures must also be documented on the appropriate 
section in the eCRF. 
7.2. 
Allowed Concomitant Medication 
Subjects will be allowed to receive required medication to treat new or existing medical 
conditions. 
Subjects will continue UDCA intake in accordance with their prescribed dose. Dose adjustments 
or interruption in UDCA during the study will be documented. 
PBC symptomatic treatment (e.g., antipruritic drugs) should be discussed with the medical 
monitor. Guidelines about PBC symptom management will be defined in a study manual. 
7.3. 
Prohibited Concomitant Medication 
The following medications are prohibited from use during the study: 
• Obeticholic acid (OCA) 
• Fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, 
saroglitazar) 
• Colchicine, methotrexate, or azathioprine 
• Long-term systemic steroids (e.g., prednisone, prednisolone, budesonide) for 
>2 weeks 
• Experimental or unapproved treatment for PBC or related autoimmune disease 
• Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or other 
immunosuppressive biologics)  
• Other medications that effect liver or GI functions, such as absorption of medications, 
may be prohibited and should be discussed with the medical monitor on a case-by-
case basis. 
 
 
 


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7.4. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery, biopsy, or physical 
therapy) or diagnostic assessment (e.g., blood gas measurement or bacterial cultures) performed 
during subjects’ participation in this study. Subjects 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 procedures must also be documented on the appropriate section in the 
eCRF. 


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8. 
STUDY PROCEDURES 
8.1. 
Study Schedule 
The schedule of study procedures is presented in Table 1. 
The study for an individual subject consists of the following periods: 
• Screening Period: Week -5 to Week -2 (up to 3 weeks) 
• Run-in Period: Week -2 to Day 1 
• Treatment Initiation: Day 1 
• Treatment Period: Day 1 through up to Month 12  
• Safety Follow-up Period: 2 weeks (14 days +3) after the last dose of the study drug 
(only applicable for subjects who are not willing to roll over to long-term study, 
Study CB8025-31731-RE). 
Additional visits may be scheduled to evaluate an abnormal laboratory value or reported AE. 
Study visits should be performed in the clinic. If study visits cannot be performed in the clinic, 
for example, due to COVID-19 restrictions, a plan will be detailed according to the guidance of 
the Food and Drug Administration, European Medicines Agency, other regulatory agencies, and 
local ethics committees. If needed and whenever possible, study visits may be performed through 
home health service or using virtual technologies (e.g., phone calls or video calls). Central 
laboratory must be used whenever possible, but if not feasible, local laboratory use can be 
considered after discussion with the medical monitor. 
8.1.1. 
Screening Period (W -5 to -2 [Day -35 to -15]) 
Subjects will review and sign the informed consent form (ICF) prior to any study-related 
procedures. Screening period begins on the date of signing the Informed Consent. The screening 
period can be completed in up to 3 weeks, between days -35 and -15 prior to 
Day1/Randomization. When all Screening evaluations are completed, subjects who are deemed 
to be eligible will move into the Run-in period.  
Subjects who cannot complete the Screening assessments in time due to logistical or COVID-
related reasons may be eligible to continue in Screening. However, these instances should be 
discussed with the medical monitor and will be evaluated on a case-by-case basis. 
The evaluations of eligibility will consist of the following: 
• Demographic information. 
• Assessment of all inclusion and exclusion criteria. 
• Review of medical history, including PBC medical history, results of prior liver 
biopsy, FibroScan, and alcohol consumption. The subject’s medical chart will be 
reviewed for evidence of liver cirrhosis and other forms of chronic liver disease, as 
well as for HIV infection. 
• Documentation of prior and concomitant medications including, but not limited to, 
previous exposure to UDCA, OCA, fibrates (e.g., bezafibrate, fenofibrate, 


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elafibranor, lanifibranor, pemafibrate, and saroglitizar), and other medications taken 
for PBC and its symptoms (including supplements and vitamins). 
• Vital signs (as described in Section 8.2.3). This will include temperature, heart rate, 
respiratory rate, and blood pressure.  
• Height and weight measurements will be performed. 
• Complete physical examination (as described in Section 8.2.2). This will include a 
full review of the following systems: general, skin, eyes, nose/sinuses, ears, 
mouth/throat, neck, breasts, respiratory, cardiac, gastrointestinal, peripheral vascular, 
genitourinary, musculoskeletal, neurologic, mental health, endocrine, and 
hematologic. 
• 12-lead electrocardiogram (ECG) after at least 5 minutes of rest. 
• Blood drawn for hematology, biochemistry, AMA, hepatitis B, hepatitis C and HIV 
as outlined in Section 8.2.5 and Appendix A. Prothrombin time (PT), INR, and 
platelets will also be performed locally. If unexpected elevation in INR is noted, 
re-test is allowed. 
• COVID-19 testing will be performed locally and only if deemed necessary per local 
requirements. Subjects with a positive COVID-19 test during Screening may be 
eligible to re-screen after recovery. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements.  
Note: for the purpose of this document, a woman is considered of childbearing 
potential, e.g., fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.24 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient (24). 
• Urine drug screen. 
• E-diary training. 
• Pruritus NRS evaluation. 
• UDCA dose will be recorded. Subjects will be instructed to continue UDCA regimen 
(dose and frequency) at dose as close as possible to prestudy dose and as 
recommended per investigator’s clinical judgment.  


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• Subjects who meet all inclusion criteria and do not meet any exclusion criteria will be 
invited for the Run-in Visit.  
If an untoward event occurs at any time after the ICF is signed, it will be recorded as AE. Any 
laboratory abnormality deemed clinically important by the investigator will be considered an AE. 
Subjects will be reminded of the following restrictions:  
• To comply with diet and lifestyle, including drinking habits. 
• Not to use prohibited concomitant medications. 
• Females of reproductive potential will be reminded to use at least 1 barrier 
contraceptive and a second effective birth control method during the study and for at 
least 90 days after the last dose. 
• Male subjects who are sexually active with female partners of reproductive potential 
will be reminded to 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. 
8.1.2. 
Run-in Period (W -2 [Day -14]) 
Subjects who have been deemed eligible during the Screening Period will return for the Run-in 
Visit. The visit will occur 14 days ±3 days prior to Day1/Randomization. 
Subjects who cannot complete the run-in period in time for logistical or COVID-related reasons 
may be eligible to continue in Run-in. However, these instances should be discussed with the 
medical monitor and will be evaluated on a case-by-case basis. 
All subjects will have the following evaluations performed:  
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of medications (including supplements and vitamins) since the last 
visit. 
• Vital signs and weight (as described at Section 8.2.3).  
• Symptom-directed (brief) physical examination (as described at Section 8.2.2).  
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 
• Back-up blood sample will be collected. 
• COVID-19 testing will be performed locally and only if deemed necessary. Subjects 
with a positive COVID-19 test during Screening may be eligible to re-screen after 
recovery. 


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• E-diary will be dispensed. Re-training will be performed, if needed.  
• Pruritus NRS, 5-D Itch, PBC-40, and PGI-S questionnaires will be performed via 
e-diary. The subject will be instructed to use e-diary to evaluate pruritus NRS on a 
daily basis and 5-D Itch on a biweekly basis at approximately same time during the 
day from the Run-in Visit through the first 6 months of study drug treatment. 
• FibroScan at selected sites. 
• Abdominal ultrasound focusing on the liver, gallbladder, common bile duct, portal 
vein, and spleen will be performed. 
• UDCA compliance. 
• Baseline liver biopsy: All subjects will be encouraged to undergo the procedure to 
evaluate PBC stage and activity. Liver biopsy might be performed anytime between 
Screening and Day 1 but only after confirmation of the subject’s eligibility. PT and 
INR must be performed within 2 weeks prior to liver biopsy.  
8.1.3. 
Treatment Period 
8.1.3.1. 
Day 1 (Randomization) 
Day 1 begins the Treatment Period and is the date against which all subsequent visits will be 
timed except for the Safety Follow-up Period. At this visit, subjects will be randomized into the 
study. A subject will be considered formally enrolled in the study at the time of randomization. 
On the scheduled visit days, subjects will be in the fasted state for laboratory assessments. If 
subjects forget to fast, this should be noted, and the blood sample should still be collected.  
The following evaluations will be performed: 
• Randomization. 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of medications (including supplements and vitamins) since the last 
visit. 
• Vital signs and weight (as described at Section 8.2.3).  
• Complete physical examination (as described at Section 8.2.2) and liver-related 
symptoms, including cirrhosis evaluation. 
• 12-lead ECG after at least 5 minutes of rest.  
• Blood drawn for hematology, biochemistry, and exploratory measures (including fat-
soluble vitamins) as outlined in Appendix A.  
• Back-up blood sample will be collected. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 


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• COVID-19 testing will be performed locally and only if deemed necessary. 
• PBC-40 and PGI-S questionnaires via ediary. 
• Pruritus NRS: review of previously collected data. Subjects will be reminded to use 
e-diary to evaluate pruritus on a daily basis during the first 6 months of treatment. 
• 5-D Itch scale via e-diary: review of previously collected data. Subjects will be 
reminded to use e-diary to evaluate pruritus on a biweekly basis up until the Month 6 
Visit. 
• UDCA compliance. 
• Study drug will be dispensed per the subject’s randomization with interactions to take 
orally once daily. The first dose of the study drug will be administered on site.  
If a subject terminates study participation at any point after Day 1, an Early Termination Visit 
will be completed. 
8.1.3.2. 
Month 1 (W4 [Day 29]) 
The visit will occur 4 weeks±3 days after Day 1, and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Symptom-directed (brief) physical examination (as described at Section 8.2.2), 
including ascites and encephalopathy information in support of the Child-Pugh score 
calculation.  
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be monitored based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). Unscheduled visit (UNS) might be scheduled if needed per the 
investigator’s clinical judgment. 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A. 
• Back-up blood sample will be collected. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 
• PBC-40, PGI-S, and PGI-C questionnaires via e-diary. 


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• Pruritus NRS: review of previously collected data. Subjects will be reminded to use 
e-diary to evaluate pruritus on a daily basis during the first 6 months of treatment. 
• 5-D Itch: review of previously collected data. Subjects will be reminded to use 
e-diary to evaluate pruritus on a biweekly basis up until the Month 6 Visit. 
• Study drug compliance and accountability. 
• UDCA compliance. 
8.1.3.3. 
Month 3 (W12 [Day85]) 
The visit will occur 12 weeks±7 days after Day 1, and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Symptom-directed (brief) physical examination (as described at Section 8.2.2), 
including ascites and encephalopathy information in support of the Child-Pugh score 
calculation. 
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be monitored based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A. 
• PK sample collection: Prior to the visit, subjects will be reminded not to take the 
study drug at home. Time of PK blood collection and dosing will be documented. PK 
sampling will be performed once predose (-30 min prior to dosing) and twice 
postdose (1 hour±30 minutes and 3 hours±30 minutes after dosing). 
• Back-up blood sample will be collected. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 
• PBC-40, PGI-S, and PGI-C questionnaires via e-diary. 
• Pruritus NRS: review of previously collected data. Subjects will be reminded to use 
e-diary to evaluate pruritus on a daily basis during the first 6 months of treatment. 


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• 5-D Itch: review of previously collected data. Subjects will be reminded to use 
e-diary to evaluate pruritus on a biweekly basis up until the Month 6 Visit. 
• Study drug compliance and accountability. 
• UDCA compliance. 
• Dispense study drug. 
8.1.3.4. 
Month 6 (W26 [Day183]) 
The visit will occur 26 weeks±7 days after Day 1, and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described in Section 8.2.3). 
• Complete physical examination (as described at Section 8.2.2), including ascites and 
encephalopathy information in support of the Child-Pugh score calculation. 
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be monitored based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• 12-lead ECG after at least 5 minutes of rest.  
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A.  
• Back-up blood sample collection. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 
• PBC-40, PGI-S, and PGI-C questionnaires via e-diary. 
• Pruritus NRS: review of previously collected data. Subjects will be instructed to use 
e-diary on a monthly basis for 7 consecutive days each month until Month 12. 
• 5-D Itch: review of previously collected data. Subjects will be instructed to evaluate 
pruritus via 5-D Itch in a monthly basis until Month 12.  
• FibroScan at the selected sites. 
• Study drug compliance and accountability. 


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• UDCA compliance. 
• Dispense study drug. 
8.1.3.5. 
Month 9 (W39 [Day 274]) 
The visit will occur 39 weeks±7 days after Day 1, and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Brief symptom-directed physical examination (as described at Section 8.2.2), 
including ascites and encephalopathy information in support of the Child-Pugh score 
calculation. 
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be monitored based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A. 
• Back-up blood sample collection. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Women of child-bearing potential will be provided with urine pregnancy tests in 
between visits for monthly testing. Results must be relayed to the clinical staff during 
the next visit/contact. Additional on-treatment pregnancy testing may be performed at 
the investigator’s discretion or per local regulatory requirements. 
• PBC-40, PGI-C, and PGI-S questionnaires via e-diary. 
• Pruritus NRS: review of previously collected data. Subjects will be instructed to 
continue to use e-diary on a monthly basis for 7 consecutive days each month through 
EOT visit. 
• 5-D Itch: review of previously collected data. Subjects will be instructed to evaluate 
pruritus via 5-D Itch in a monthly basis until Month 12.  
• Study drug compliance and accountability. 
• UDCA compliance. 
• Dispense study drug. 


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8.1.3.6. 
Month 12/End of Treatment (W52 [Day 365]) 
The visit will occur 52 weeks±7 days after Day 1, and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF.  
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Complete physical examination (as described at Section 8.2.2), including ascites and 
encephalopathy information in support of the Child-Pugh score calculation. 
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be evaluated based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• 12-lead ECG after at least 5 minutes of rest.  
• Blood drawn for hematology, biochemistry, and exploratory measures (including fat-
soluble vitamins) as outlined in Appendix A. 
• PK sample collection: Prior to the visit, subjects will be reminded not to take the study 
drug at home. Time of PK blood collection and dosing will be documented. PK 
sampling will be performed once predose (-30 min prior to dosing) and twice postdose 
(1 hour±30 minutes and 3 hours±30 minutes after dosing). 
• Back-up blood sample collection. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• PBC-40, PGI-S, and PGI-C questionnaires via e-diary. 
• Pruritus NRS and 5-D Itch: review of previously collected data. 
• E-diary will be collected. 
• FibroScan at the selected sites. 
• Abdominal ultrasound focusing on the liver, gallbladder, common bile duct, portal 
vein, and spleen will be performed. 
• Study drug compliance and accountability. 
• UDCA compliance. 
• Subjects who had baseline liver biopsy: Liver biopsy will be performed 
approximately 12 months after baseline liver biopsy (window: 48 to 56 weeks after 


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baseline liver biopsy). PT, INR, and platelets must be performed within 2 weeks prior 
to liver biopsy. 
At the end of the visit, subjects will be invited to participate in the long-term study 
(Study CB8025-31731-RE). 
8.1.4. 
Post-Treatment Safety Follow-up (2W [14 Days after W52]) 
The visit will occur 2 weeks (14 days +3 days) after the last dose of the study drug and is 
applicable only to subjects who do not participate in the long-term study. The following 
evaluations will be performed: 
• Documentation of AEs that occurred since the signing of the ICF. 
• Documentation of concomitant medications (including supplements and vitamins) 
since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Complete physical examination (as described at Section 8.2.2), including ascites and 
encephalopathy information in support of the Child-Pugh score calculation. 
• Liver-related symptoms, including cirrhosis evaluation and PBC clinical outcomes, 
will be evaluated based on the subject’s clinical evaluation, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• 12-lead ECG after at least 5 minutes of rest.  
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A.  
• Back-up blood sample collection. 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Women of child-bearing potential will have a serum pregnancy test performed. 
This will be the subject’s last visit. Any clinically important abnormalities should be followed up 
by the investigator, until resolution or stabilization of those abnormalities.  
Subjects who decline participation in the long-term study will be asked to be followed to collect 
information about PBC clinical outcomes (Section 8.1.7). 
8.1.5. 
Early Termination 
Subjects who discontinued study drug treatment for any reason other than a defined PBC clinical 
outcome will be asked to stay in the study without study drug intake. Subjects who decline to 
stay in the study without study drug intake should return for an Early Termination Visit, and the 
following evaluations should be performed: 
• Documentation of AEs that occurred since the signing of the ICF. 


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• Review and documentation of concomitant medications (including supplements and 
vitamins) since the last visit. 
• Vital signs and weight (as described at Section 8.2.3). 
• Complete physical examination (as described at Section 8.2.2), including ascites and 
encephalopathy information in support of the Child-Pugh score calculation. 
• Liver-related symptoms, including evaluation for cirrhosis and PBC clinical 
outcomes, will be monitored based the on subject’s clinical status, available medical 
history/AEs and concomitant medications, and available tests results (Section 11 and 
Appendix I). UNS visit might be scheduled if needed per the investigator’s clinical 
judgment. 
• 12-lead ECG after at least 5 minutes of rest. 
• Blood drawn for hematology, biochemistry, and exploratory measures (including 
fat-soluble vitamins) as outlined in Appendix A. 
• Back-up blood sample will be collected. 
• COVID-19 testing will be performed locally and only if deemed necessary, 
• Women of reproductive status will have serum pregnancy test performed.  
• Pruritus NRS, 5-D Itch, PBC-40, PGI-S, and PGI-C questionnaires via e-diary, 
• Pruritus NRS and 5-D Itch: review of previously collected data, 
• E-diary will be collected. 
• FibroScan at the selected sites. 
• Abdominal ultrasound focusing on the liver, gallbladder, common bile duct, portal 
vein, and spleen will be performed. 
• Study drug compliance and accountability. 
• UDCA compliance. 
• Subjects who had baseline liver biopsy and discontinued the study between 6 and 
12 months of treatment: Follow-up liver biopsy will be performed. PT, INR, and 
platelets must be performed within 2 weeks prior to liver biopsy. 
Any clinically important abnormalities should be followed up by the investigator until resolution 
or stabilization of those abnormalities. 
Subjects who discontinue from the study for any reason other than a defined PBC clinical 
outcome and decline to stay in study without study drug intake, or who do not participate in the 
long-term study will be followed to collect information about PBC clinical outcomes on an 
annual basis per Section 8.1.7.  


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8.1.6. 
Unscheduled Visit 
A UNS visit must be scheduled if safety monitoring criteria are met within the timeline outlined 
in Section 10 and if the dose is adjusted for safety reason. A UNS visit might be scheduled at any 
time during the study participation if deemed necessary per the investigator’s clinical judgment. 
At any UNS visit, the following evaluations will be performed:  
• Documentation of AEs that occurred since the signing of the ICF. 
• Review and documentation of concomitant medications (including supplements and 
vitamins) since the last visit. 
• Symptom-directed (brief) physical examination (as described at Section 8.2.2).  
• Vital signs and weight (as described at Section 8.2.3). 
• COVID-19 testing will be performed locally and only if deemed necessary. 
• Blood drawn for biochemistry and hematology. 
• Blood sample for PK. When possible a PK sample should be drawn at the onset of 
SAEs or clinically meaningful AEs. In these instances, document subject’s time of 
last dose. 
Additional assessments or study-required follow-up (e.g., unscheduled study drug dispensation 
and e-diary management) as determined by the investigator. 
8.1.7. 
Annual Follow-Up for PBC outcomes Assessment  
Subjects who discontinue study drug treatment for any reason other than a defined PBC clinical 
outcome will be asked to stay in the study without study drug intake. Subjects who decline to 
stay in the study without study drug intake, or who do not participate in the long-term study, a 
phone call will be performed annually (52 weeks ±45 days) after the subject’s last visit, or at the 
time of the study last patient last visit (LPLV), whichever is earlier. This does not apply to 
subjects who discontinue treatment but remain on study. 
During this phone call, the following information will be collected:  
• PBC clinical outcomes that have occurred in the previous year. 
• New PBC treatments that the subject may have been exposed to in the previous year.  
If the site becomes aware of a PBC clinical outcome event before the time of the Annual Follow-
up Call, the event should be communicated to the site and will be recorded, and the Annual 
Follow-up Phone call will not occur. Otherwise, the Annual Follow-up Phone calls will be 
expected until the time of the study LPLV.  
8.2. 
Study Assessments 
Supplementary study conduct information not mandated to be present in this protocol is provided 
in the accompanying study manual and other administrative guides, which will provide the study 
site personnel with administrative and detailed technical information that does not impact subject 
safety. 


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8.2.1. 
Demographics 
Demographic information will be collected and will include the subject’s date of birth, age, sex, 
child-bearing status, race, and ethnicity. 
8.2.2. 
Medical History and Physical Examination 
A detailed medical history and PBC medical history will be taken at Screening. Information 
about prior medications and concomitant medications will be collected, including information 
about prior UDCA use or UDCA intolerance.  
Complete physical examinations will be performed at Screening, Day 1, Month 6, Month 12, 
Follow-up, and Early Termination (if applicable) Visits. These will include a full review of the 
following systems: general, skin, eyes, nose/sinuses, ears, mouth/throat, neck, breasts (optional, 
per clinical judgment only), respiratory, cardiac, gastrointestinal, peripheral vascular, 
genitourinary (optional, per clinical judgment only), musculoskeletal, neurologic, mental health, 
endocrine, and hematologic.  
Symptom-directed (brief) physical examinations will be performed at Run-in, Month 1, Month 3, 
Month 9, and UNS Visits. Brief physical examinations will be performed for a condition that 
warrants the examination as determined by the investigator. Subjects with platelet level above 
500×103/µL on hematology panel will be evaluated for thrombolytic events.  
Ascites and Encephalopathy information will be requested as part of the physical examination at 
Month 1, Month 3, Month 6, Month 9, Month 12, Follow-up, and Early Termination (if 
applicable) Visits in support of the Child-Pugh score calculation. 
Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain and tenderness, 
fatigue, loss of appetite, dark urine, or jaundice) will be evaluated at each visit from Screening 
through Month 12 Visit or until the Follow-up Visit or Early Termination Visit (if applicable).  
Subjects will be regularly evaluated for cirrhosis status per Appendix I and for PBC clinical 
outcomes as outlined in Section 11.  
Subjects with symptoms consistent with acute pancreatitis will be educated to seek immediate 
medical care for evaluation for suspected acute pancreatitis. 
Any clinically important change in physical examination findings that occurs after signing the 
ICF will be recorded as an AE. 
8.2.3. 
Vital Signs and Weight/Height 
Vital sign measurements include temperature, heart rate, respiratory rate, and blood pressure, 
recorded in the sitting position after at least 5 minutes of rest.  
Vital signs and weight will be assessed on all in-clinic visits, from Screening through Month 12 
Visit, or until the Follow-up Visit or Early Termination Visit (if applicable). Height 
measurement will be performed only at Screening. 
Vital signs may be obtained more frequently if a condition that warrants additional monitoring 
develops. 


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8.2.4. 
Electrocardiograms 
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest at Screening, 
Day 1, Month 6, Month 12, and Follow-up or Early Termination (if applicable) Visits. 
8.2.5. 
Laboratory Tests 
Blood samples for laboratory testing from Screening and onward will be collected at study visits 
after at least an 8-hour overnight fast and prior to dosing. If the subject forgets to fast, the site 
will record it in the source document, continue to draw laboratory tests, and proceed with the 
visit. Additional details about sample collection, processing, and handling and laboratory 
determination techniques are provided in the laboratory manual. 
Laboratory tests will be collected at each study visit per the Schedule of Assessments (Table 1) 
and will include the following parameters (Appendix A). 
Biochemistry:  
ALP, AST, ALT, GGT, protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, 
5’-nucliotidase, aldolase, sodium, potassium, chloride, bicarbonate, blood urea nitrogen/urea, 
serum creatinine, eGFR, creatine kinase (CK), venous blood glucose, lactate dehydrogenase, 
triglycerides, total cholesterol, HDL-C, LDL-C, cystatin C, troponin I, lipase, and amylase. 
Hematology:  
Erythrocyte count, hemoglobin, hematocrit, leukocyte count (WBC), WBC differential (absolute 
and percentage), platelets, PT, and INR.  
PT and INR will also be performed locally at the Screening Visit, at the Run-in Visit, and during 
the Treatment Period if deemed necessary by the investigator. 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Other Testing: HBsAg, HCV RNA and HIV; vitamin A, vitamin D, vitamin E, and vitamin K; 
serum pregnancy testing (β-HCG) and urine pregnancy testing; and PK blood sample. 
Back-up Blood Sample:  
CCI
I 
I 
I 
I 


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Blood samples collected during the study will be archived as back-up samples. These samples 
can be stored for up to 5 years following completion of the study and can be used to measure 
drug level and future research purposes related to the study drug and/or cholestatic liver diseases.  
Urine Drug Screen:  
Amphetamine, THC (11-nor-9-carboxy-delta-9-THC), cocaine, opiates, and phencyclidine.  
Plasma concentrations testing: 
Subjects will be invited to participate in a PK sample collection to evaluate plasma 
concentrations of seladelpar and its metabolites. Subjects who consent to participate in this PK 
sample collection will provide 1 predose (-30 minutes prior to dosing) and 2 postdose samples at 
1 hour±30 minutes and 3 hours±30 minutes at Month 3 and Month 12, per the assigned schedule. 
For each sample collection timepoint, a total of 3 blood samples will be collected. 
Time of PK blood collection and time of dosing will be recorded in the source document. 
Sample collection, processing, and handling details are provided in the laboratory manual. 
8.2.6. 
Abdominal Ultrasound 
Abdominal ultrasound examination will be used to visualize the liver, gallbladder, common bile 
duct, portal vein, and spleen to detect anatomical structures and abnormalities. Ultrasound is a 
standard clinical procedure for subjects with liver diseases and uses transmission and reflection 
of ultrasound waves to visual internal organs through abdominal wall. Abdominal ultrasound 
will be used to determine changes in the examined organs over the study duration. 
Abdominal Ultrasound Examination Schedule and Timing: Subjects will undergo 3 abdominal 
ultrasound examinations as follows: at the Run-in and Month 12/EOT Visits or at the Early 
Termination Visit (if applicable). Clinical sites will determine the logistics of scheduling the 
abdominal ultrasound and will complete the examination within the study visit window. 
Abdominal Ultrasound Examination Instructions: Subjects will be instructed to fast for 8 or more 
hours (if possible) prior to the scheduled abdominal ultrasound examination but will be allowed 
to take necessary medications and small quantities of water. 
Abdominal Ultrasound Examination Analysis: Local reader will review and analyze the scans.  
8.2.7. 
Liver Elastography 
The FibroScan examination will be used to evaluate ELF through a noninvasive imaging 
technique. FibroScan is the most commonly used liver elastography method. It uses a modified 
ultrasound probe to measure the velocity of a shear wave. Cross-sectional elastogram images will 
be created, depicting the stiffness generated from the wave propagation information. FibroScan 
is considered a reliable, highly accurate, and precise method for assessing hepatic fibrosis. 
FibroScan Examination Schedule and Timing: Subjects will undergo 3 FibroScan examinations 
at sites when the test is available: Run-in, Month 6, Month 12, and Early Termination (if 
applicable) Visits. Clinical sites will determine the logistics of scheduling the FibroScan 
examination and will complete within the study visit window. Predose FibroScan examinations 
may be performed from the Run-In Visit (Week -2) to study drug dosing at Day 1. 


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FibroScan Examination Instructions: Subjects will be instructed to fast for 4 or more hours (if 
possible) prior to the scheduled FibroScan examination but will be allowed to take necessary 
medications and small quantities of water. 
FibroScan Examination Analysis: Local reader will review and analyze the scans. 
8.2.8. 
Liver Biopsy 
Liver biopsy will be collected in subjects who consent during Screening Period (any time 
between Screening and Day 1) but only after confirmation of eligibility and at Month 12 or Early 
Termination Visit for subjects who discontinue treatment, provided that they have had a liver 
biopsy performed at baseline and at least 6 months of treatment. All biopsies will be collected, 
processed, fully masked, and evaluated by the PRC as specified in the histopathology plan. 
Pathology evaluation will be done fully blinded with respect to study site, subject ID, treatment, 
timepoint, and other subject clinical and laboratory information. 
Consenting subjects who have had biopsy tissue collected within 6 months of screening may 
have that liver biopsy sample used instead of that from a screening period baseline biopsy 
provided it meets the quality requirements described in the Laboratory Manual. The medical 
monitor should be consulted to confirm the suitability of the sample. 
Liver biopsy will be used to determine PBC stage and activity, using appropriate central 
reporting. 
Pre-Liver Biopsy Instructions: The subject must have PT, INR, and platelets performed within 
2 weeks prior to liver biopsy. Subjects will be instructed, if possible, to fast 6 to 8 hours prior to 
the scheduled liver biopsy.  
Liver Biopsy Analysis: The PRC will review and analyze the biopsy samples in accordance with 
a histology plan (Section 16). 
8.2.9. 
Pruritus Numerical Rating Scale 
Pruritus NRS will be used as a key secondary measure to evaluate pruritus in subjects with PBC.  
The test will be performed based on data collected via e-diary on a daily basis from the Run-in 
(Week -2) Visit and for the first 6 months of study drug treatment. After 6 months of treatment, 
pruritus NRS will be evaluated for 7 consecutive days each month up to EOT. See Appendix D 
for details.  
Pruritus NRS data will be collected via e-diary. 
8.2.10. 
5-D Itch Scale 
The 5-D Itch scale will be used as a secondary measure for the multidimensional quantification 
of pruritus over time. The 5-D Itch scale is a measure of itching that has been validated in 
patients with chronic pruritus to detect changes over time. It is a brief, single-page, multiple 
choice or “check all boxes that apply” form (22). See Appendix E for details. 
The test will be performed based on data collected via e-diary on a biweekly basis from the 
Run-in Visit up until the Month 6 Visit and on a monthly basis from Month 6 until Month 12 or 
Early Termination Visit (if applicable).  


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The 5-D Itch data will be collected via e-diary. 
8.2.11. 
PBC-40 QoL 
The PBC-40 questionnaire will be used as a secondary measure to evaluate health-related QoL 
measures, specifically fatigue. PBC-40 is a disease-specific health-related QoL tool developed to 
measure specifically the psychometric profile of patients with PBC. It covers 6 domains relevant 
to PBC including cognitive, social, emotional function, fatigue, itch, and other symptoms (23). 
See Appendix F for details.  
It will be performed at Run-in, Day 1, and Month 1 visits, and every 3 months after initiation of 
treatment until the EOT Visit or Early Termination Visit (if applicable). The questionnaire will 
be evaluated by the site personnel, and the investigator will react to any evidence of 
deterioration.  
PBC-40 QoL data will be collected via e-diary. 
8.2.12. 
PGI-S and PGI-C 
The PGI-S and the PGI-C questionnaires will be used as an anchor scale to help interpret 
within-subject change in pruritus data collected via other pruritus questionnaires. The PGI-S 
evaluations will be performed at Run-in, Day 1, and Month 1 visits, and every 3 months after 
initiation of treatment until the EOT Visit or Early Termination Visit (if applicable). The PGI-C 
evaluations will be performed at Month 1 and every 3 months after initiation of treatment until 
the EOT Visit or Early Termination Visit (if applicable). See Appendix G and Appendix H for 
details. 
9. 
ADVERSE EVENTS 
9.1. 
Definition of Adverse Events 
An AE is any medical occurrence in a subject 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 the study treatment or (2) 
was present prior to initiation of the study treatment but worsened during study treatment. This 
would include any condition resulting from concomitant illnesses, reactions to concomitant 
medications, or progression of disease states. Pregnancy should be documented as an AE and 
should be immediately reported to the clinical monitor and to the sponsor upon learning of the 
event. Pregnancies will be followed up through delivery or termination of the pregnancy. 
A TEAE will be defined as any AE that newly appeared, increased in frequency, or worsened in 
severity after initiation of the study drug until up to 17 days after the last study medication 
administration. 


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9.2. 
Definition of Serious Adverse Events 
An SAE is any AE 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 important disability/incapacity, defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that, when based on appropriate medical judgment, 
may jeopardize the subject 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. 
9.3. 
Assessment of Adverse Events 
9.3.1. 
Severity 
The severity of an AE will be graded from 1 to 5 according to Appendix C and NCI CTCAE 
Version 5.0 criteria (27 November 2017). 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 5 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 important 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 
9.3.2. 
Outcome 
Subjects will be followed until AEs have resolved, have returned to baseline status, or are 
deemed stable or commensurate with ongoing disease processes, per the investigator’s clinical 
judgment. One of the 6 outcomes listed below must be recorded: 
Recovered/Resolved – The subject has fully recovered from the event with no residual effects 
observable or returned to baseline status. 


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Recovered/Resolved with sequelae – The subject has recovered from the event with some 
residual effect’s observable. 
Not Recovered/Not Resolved – The subject or event has not recovered or resolved or shown 
further improvement after an appropriate time of follow-up. 
Recovering/Resolving – The subject or event is still improving but has not fully recovered. 
Fatal – Death 
Unknown – Subject lost to follow-up 
9.3.3. 
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. 
Probable 
The AE is likely related to the study drug. 
Definite 
The AE is clearly related to the study drug. 
9.3.4. 
Action Taken With Study Medication 
As a consequence of an AE, the action taken with study drug (based on the NCI Thesaurus) can 
be as follows: 
• Dose not changed: An indication that a medication schedule was maintained 
• Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication 
• Drug interrupted: An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of medication 
• Dose reduced: An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength or amount 
• Not applicable: Determination of a value is not relevant in the current context 
• Unknown: Not known, not observed, not recorded, or refused 
9.4. 
Recording, Reporting, and Follow-up of Adverse Events 
9.4.1. 
Nonserious Adverse Events 
Details about the safety reporting process are presented in the safety reporting plan. 
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 will be 
captured until the last study visit.  


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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 will indicate the action taken. 
Abnormal laboratory findings will be determined by review of all laboratory data collected on 
the subjects. At each visit, the investigator is responsible for assuring that the subject is 
questioned regarding all potential AEs and concurrent illnesses. 
Any laboratory abnormality deemed clinically important by the investigator should be reported 
as an AE. A clinically important abnormality is a confirmed abnormality that is changed 
sufficiently from baseline, so that, in the clinical judgment of the investigator, a change in 
management is warranted. This alteration may include further monitoring the laboratory test, 
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 important 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. 
9.4.2. 
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 of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) guidelines E2A and E6 and per the US 21 Code of Federal Regulations 
§ 312.32. Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. Independent Ethics Committee (IEC) will be notified of any 
SAE according to applicable regulations. 
Any SAE, including death due to any cause, that occurred from the signing of ICF through the 
last study visit, 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 9.2. 
The outcome for the event will be listed on the SAE Report Form as defined in Section 9.3.2. 
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 
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SAEs must be collected and reported by the investigator for the whole period from the signing of 
ICF until the last study visit. If the event of death occurs after the last study visit, the death will 
not have to be reported as an SAE.  
The investigator will document all available information regarding the SAE on the SAE Report 
Form. The investigator should not wait to receive additional information to document fully the 
event before notifying the sponsor’s representative of an SAE. The initial notification should 
include, as a minimum, sufficient information to permit identification of the following: 
• Subject’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 counter-measures taken  
• Investigator’s opinion of the relationship of the event and the investigational product  
Follow-up report(s) should follow the initial report detailing relevant aspects of the AEs 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. 
9.4.3. 
Follow-up on Reported AEs 
SAEs recorded during the study should be followed by the investigator until resolution or 
stabilization. 
After the Follow-up Visit, nonserious AEs should be followed up until they resolve or stabilize, 
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.  
9.4.4. 
Distribution of Responsibilities 
Details about the distribution of safety responsibilities are presented in the safety reporting plan. 


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10. 
SAFETY MONITORING 
Enrolled subjects with the following laboratory 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 
events is observed. 
10.1.1. 
Liver Safety Monitoring 
Table 2 and Table 3 provide the algorithm that will be followed to assess potential drug-induced 
liver injury. 
Table 2: 
DILI Criteria for Participants With Normal Baseline ALT and AST 
 Baseline 
ALT or AST During 
Study Treatment 
Duration 
Other Concurrent Parameters 
Required During Study Treatment 
Duration 
Study Action 
NORMAL BASELINE ALT and AST 
ALT, AST, and total 
bilirubin <1.0× ULN 
ALT or AST >8× ULN 
-- 
Stop study 
drug 
permanentlyb 
ALT or AST >5× ULN for 
more than 2 weeks 
-- 
ALT or AST >3× ULN 
AND total bilirubin >2× ULN OR INR 
>1.5 
ALT or AST >3× ULN 
AND clinical symptomsa 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; DILI=drug-induced liver injury; 
INR=international normalized ratio; ULN=upper limit of normal. 
a Clinical symptoms associated with the study drug: appearance of fatigue, nausea, right upper quadrant pain or 
tenderness, fever, rash, jaundice, and/or eosinophilia (absolute count >1× ULN) 
b Repeat AST, ALT, total bilirubin, and PT/INR within 3 days and closely observe the subject (see Appendix B) 
Table 3: 
DILI Criteria for Participants With Abnormal Baseline ALT and AST 
Baseline 
ALT or AST During 
Study Treatment 
Duration 
Other Concurrent Parameters 
Required During Study Treatment 
Duration 
Study Action 
ABNORMAL BASELINE ALT and AST 
ALT or AST >1.0× 
ULN  
ALT or AST >2× BLM 
AND concomitant total bilirubin >2 × 
BLM OR INR increase by 0.2 
Stop study 
drug 
permanentlyb 
Regardless of ALT or 
AST levels 
Clinical symptomsa AND concomitant 
total bilirubin (>2 × BLM) 
ALT or AST <2× ULN  
ALT or AST >5× BLM 
-- 
Interrupt 
study drugb 
ALT or AST ≥2× ULN 
but <5× ULN 
ALT or AST >3× BLM 
ALT or AST ≥5× ULN 
ALT or AST >2× BLM 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BLM=baseline measurement; DILI=drug-induced liver injury; 
INR=international normalized ratio; ULN=upper limit of normal. 
a Clinical symptoms associated with the study drug: appearance of fatigue, nausea, right upper quadrant pain or tenderness, 
fever, rash, jaundice, and/or eosinophilia (absolute count >1× ULN). 
b Repeat AST, ALT, total bilirubin, and PT/INR within 3 days and closely observe the subject (see Appendix B) 


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• Interrupt study drug: Repeat AST, ALT, total bilirubin, and PT/INR within 3 days 
and closely observe the subject (see Appendix B). Study drug can be restarted at the 
same dose level only if a firm 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 bilirubin, and PT/INR 
within 3 days and closely observe the subject (see Appendix B). 
• If close observation of a participant is not possible, stop study drug permanently. 
10.1.2. 
Muscle Injury Safety Monitoring 
Table 4 provides the algorithm that will be followed to assess potential drug-induced muscle 
injury. 
Subjects with elevated CK levels >2.5× ULN should be initially queried for a possible clinical 
explanation (such as strenuous exercise, heavy labor, or traumatic injury), associated symptoms, 
and relationship to the study drug. Repeat CK level measurements within 3 days of initial CK 
elevation. 
Subjects may continue to take the study drug if (1) a clinical explanation is identified and/or (2) 
the event is considered unrelated to study drug.  
If no alternative clinical explanation is identified, the study drug will be interrupted, and the 
following algorithm should be followed to assess potential drug-induced muscle injury.  
Table 4: 
Muscle Injury Safety Criteria for Study Drug Interruption or Stopping Rules 
CK During Study 
Treatment 
Grade 3 
CTCAE 
Myalgia or 
Myopathy 
Repeat CK Test Results 
Study Action 
CK >2.5× ULN 
Not observed 
CK level is ≤2.5× ULN 
Study drug may be reinitiated at this time 
at the current dose level. 
CK >2.5× ULN 
Not observed 
CK level is >2.5× ULN 
Study drug should remain held and CK 
testing should be performed weekly until CK 
≤2.5× ULN. Study drug may then be 
reinitiated as outlined in Section 6.1.1 of 
the study protocol.  
CK >2.5× ULN 
Observed 
CK level is >2.5× ULN 
Study drug should remain held and CK 
testing should be performed weekly until CK 
≤2.5× ULN. Study drug may then be 
reinitiated at as outlined in Section 6.1.1 of 
the study protocol.  
If symptoms reappear after rechallenge and 
there is no clinical explanation, then the 
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. 
CK=creatine kinase; CTCAE=Common Terminology Criteria for Adverse Events; ULN=upper limit of normal. 


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10.1.3. 
Renal Safety Monitoring 
Table 5 provide the algorithm that should be applied to assess potential drug-induced renal 
injury. Repeat serum creatinine level measurements within 3 days of initial serum creatinine 
elevation. 
Table 5: 
Renal Safety Criteria for Study Drug Interruption or Stopping Rules 
sCr During Study Treatment 
Repeat sCr Test 
Results 
Alternative 
Etiology 
Identified? 
Study Action 
sCr >1.5× ULN but ≤2.0× ULN 
sCr <1.5× ULN 
N/A 
Continue study drug. 
sCr >1.5× ULN 
Yes 
Interrupt study drug.  
Participant should be monitored 
weekly until event resolution. 
Study drug may be reinitiated 
after serum creatinine returns to 
baseline levels. 
sCr >1.5× ULN 
No 
Interrupt study drug.  
Participant should be monitored 
weekly until event stabilization or 
resolution. Study drug may be 
reinitiated after serum creatinine 
returns to baseline levels. If serum 
creatinine increases after 
re-initiation of study drug, stop 
study drug permanently 
sCr >2.0× ULN 
sCr >2.0× ULN 
N/A 
Stop study drug permanently.  
Participant should be monitored 
weekly until event stabilization or 
resolution. 
N/A=not applicable; sCr=serum creatinine; ULN=upper limit of normal. 
10.1.4. 
Pancreatic Safety Monitoring 
As shown in Table 6, subjects with elevated amylase and/or lipase >3× ULN should be initially 
queried for symptoms of acute pancreatitis, possible clinical explanation (such as chronic 
pancreatitis), and relationship to study drug. Repeat amylase and lipase within 3 days of initial 
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Table 6: 
Pancreatic Safety Criteria for Study Drug Interruption or Stopping Rules 
Amylase or Lipase 
During Study 
Treatment 
Symptoms of 
Acute 
Pancreatitis? 
Repeat Amylase or 
Lipase Test Results 
Actions to Be Taken 
Amylase or lipase 
>3× ULN 
No 
Amylase or lipase   
≤ 3× ULN 
Continue study drug. 
No 
Amylase or lipase 
>3× ULN 
Interrupt study drug. 
Perform computed tomography or magnetic 
resonance imaging to rule out pancreatitis  
Monitor weekly until event resolution unless 
an alternative etiology is known. 
Study drug may be restarted if alternative 
etiology is identified as outlined in 
Section 6.1.1. 
Amylase or lipase 
>3× ULN 
Yes 
Amylase or lipase  
Interrupt study drug. 
Perform computed tomography or magnetic 
resonance imaging  
Monitor weekly until event resolution unless 
an alternative etiology is known (see Clinical 
practice guideline:  management of acute 
pancreatitis for suggested management 
guidelines) (25)  
Study drug may be restarted if alternative 
etiology is identified, episode is resolved, and 
amylase and lipase are normalized as outlined 
in Section 6.1.1. 
ULN=upper limit of normal. 
10.1.5. 
Additional Withdrawal Criteria and Replacement of Subjects 
Subjects may be discontinued from study drug intake for the following reasons. Subjects who 
discontinue study drug treatment anytime will be terminated from the study and will complete an 
Early Termination Visit. Subjects who discontinue from the study before Month 12 will be asked 
to be followed for PBC clinical outcomes on an annual basis unless occurrence of a PBC clinical 
outcome.  
• Enrolled into the study in violation of this protocol. 
• Required the use of a prohibited concomitant medication.  
• Subject experienced a PBC clinical outcome. 
• Grade 3 events and above not already described by the Safety Monitoring criteria and 
related to study drug: any subject will be discontinued from the study drug that 
experiences a CTCAE grade 3 or higher that is considered possibly or probably 
related to study drug. 
• Grade 4 events not already described by the Safety Monitoring and not related to 
study drug: any subject will be considered for discontinuation from the study drug. 
The Investigator, in consultation with the Sponsor’s medical monitor, may consider 


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specific medical nature of the event, the causality assessment, and possible outcome 
of the event.  An imminent resolution or improvement in the event, so that the subject 
would be suitable for the clinical study and it would be both safe and in their best 
interest to continue or restart study drug, the study drug may be continued. 
• The subject 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 subject from study participation. 
• Withdrawal of informed consent. 
• At the discretion of the investigator for medical reasons.  
• Female subjects who become pregnant.  
• At the discretion of the investigator or sponsor for noncompliance. 
11. 
PBC CLINICAL OUTCOMES 
Subjects will be assessed for the PBC clinical outcomes as outcomes during participation in the 
study. Subjects who met one of the PBC clinical outcomes will be discontinued from the study 
(i.e., will complete an Early Termination Visit). 
All subjects who discontinued study drug treatment for any reason other than a defined PBC 
clinical outcome and decline to stay in the study without study drug intake before Month 12, or 
who do not participate in the long-term study will be followed to collect information about PBC 
clinical outcomes on an annual basis per Section 8.1.7. 
PBC clinical outcomes will be defined as follows:  
a. Overall death 
b. Liver transplantation 
c. MELD score ≥15 for at least 2 consecutive visits.* For subjects who are on 
anticoagulation medication, the effect on INR as a secondary consequence of 
anticoagulation therapy will be taken into account for its impact on MELD score 
(both at baseline and on treatment) when determining if this Outcome has been 
met.  Subjects should be carefully monitored to ensure the adjusted INR on the 
anticoagulant therapy is maintained at a stable value. 
d. Ascites requiring treatment  
e. Hospitalization for new onset or recurrence of any of the following: 
i. 
Variceal bleeding 
ii. 
Hepatic encephalopathy (as defined by a West Haven score ≥2) 
iii. 
Spontaneous bacterial peritonitis (confirmed by culture from diagnostic 
paracentesis) 
*In subjects who reach a MELD score ≥ 15, repeat laboratory tests to assess serum 
creatinine, total bilirubin, INR, and sodium and recalculate the MELD score should be done 


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within 7 days to confirm the initial findings to evaluate for decompensation and determine if 
therapy should be discontinued. 
12. 
STUDY STOPPING CRITERIA 
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 
• Cancellation of seladelpar drug development 
The Data Safety Monitoring Board (DSMB, Section 14) will consider if the study should 
continue when any of the following occur:  
• Three subjects develop the same Grade 3 CTCAE attributed to study drug  
• Two subjects develop any Grade 4 CTCAE attributed to study drug 
• One subject develops a Grade 5 CTCAE 
13. 
PRECAUTIONS 
13.1. 
Pregnancy 
No specific human clinical studies have been performed to determine the reproductive and 
developmental toxicity of seladelpar. 
As a precaution, women of child-bearing potential receiving study drug must use 1 barrier 
contraceptive and a second effective birth control method during the study and for at least 
90 days after the last dose. Male subjects 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 is 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 study and the preferred and usual lifestyle of 
the subject. 
A second effective birth control method may include the following:  
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 


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− Oral 
− Injectable 
− Implantable 
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion  
• Vasectomized partner 
14. 
DATA SAFETY MONITORING BOARD 
An independent DSMB will be established in order to protect subjects’ welfare, preserve study 
integrity, and provide recommendations as needed regarding study conduct. The DSMB will be 
composed of 2 external liver disease clinical experts and a biostatistician. The DSMB will meet 
at predefined time points and on an as-needed basis based on enrollment, treatment milestones, 
and safety. The DSMB will also review all SAEs, liver-related safety events, and elevations in 
ALT/AST, serum creatinine, CK, and lipase that meet safety monitoring criteria. Formal minutes 
and recommendations will be provided by the DSMB to the sponsor regarding additional data 
requests and the continuation of the conduct of the study as outlined in the current protocol. The 
DSMB will operate under the guidance of an agreed upon charter. Details of the format, content, 
and frequency of these meetings will be described in a DSMB charter. 
The DSMB will consider if the study should continue when any of the following occur:  
• Three subjects develop the same Grade 3 CTCAE attributed to study drug,  
• Two subjects develop any Grade 4 CTCAE attributed to study drug 
• One subject develops a Grade 5 CTCAE 
15. 
CLINICAL EVENT REVIEW COMMITTEE 
A CERC will be established to act as an expert, independent capacity to review fatal events, 
hepatic events, and disease progression that occur during the course of the study (Section 11) to 
determine if events meet the prespecified event definitions. The members of the CERC will be 
composed of 3 independent hepatologists and/or gastroenterologists.  
A CERC charter will be developed to establish predefined critical event definitions and 
procedures that will be followed. The CERC members will evaluate whether critical event 
definitions are met during independent voting and will remain blinded to treatment assignment. 
16. 
PATHOLOGY REVIEW COMMITTEE 
The evaluation of liver biopsy tissue from subjects with PBC is intended to provide an important 
component of a comprehensive safety dataset to evaluate treatment effects of seladelpar in its 
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A PRC will be formed and will consist of at least 3 experienced hepatopathologists, who will 
serve as the blinded pathologists to read biopsies collected during the study. 
The PRC will be responsible for selecting the scoring system, approving the biopsy reading 
process, and establishing a framework for evaluating biopsies based on scoring that may guide 
selection of cases for adjudication, if necessary. Collectively, these will be translated to a 
histopathology plan that will also outline and standardize procedural recommendations for 
collection of the liver biopsy, the biopsy slide preparation, and staining. 
17. 
STUDY TERMINATION 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study if it becomes aware of 
information concerning the quality, safety of the study medication (based on recommendation 
from medical monitor), and other important information that may affect proper conduct of the 
study. Should the study be discontinued by the sponsor, then the investigator, IEC, and 
competent authorities will be notified by the sponsor or sponsor’s delegate, in accordance with 
applicable regulatory regulations. 
The study may be prematurely terminated by the principal investigator at his/her site, due to 
specific clinical observations relating to safety concerns. If the principal investigator intends to 
prematurely terminate the study at his/her site, he/she must immediately inform the sponsor on 
his/her intention and of the reasons why. 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study at any time for 
administrative reasons. 
18. 
DATA HANDLING CONSIDERATIONS 
18.1. 
Processing of Electronic Case Report Forms 
The study will be performed using electronic data capture. The investigator is responsible for 
prompt reporting of accurate, complete, and legible data in the eCRFs. Any change or correction 
to the eCRF after saving must be accompanied by a reason for the change. Corrections made 
after the investigator’s review and approval (by means of a password/electronic signature) will 
be reapproved by the investigator. The investigator should maintain a list of personnel authorized 
to enter data into the eCRF. The investigator will maintain a Site Delegation Personnel Log to 
document signatures and initials of all persons qualified and authorized by the investigator to 
make entries and/or corrections to the source documents. 
18.2. 
Database 
Data entry will be performed through username- and password-protected access to a secure 
database. All data will be entered using eCRFs. Internally developed programs for plausibility, 
consistency, and out-of-range data fields will supplement the review of the data. A manual 
review of AEs, drug accountability, and termination summary data will be performed by data 
management personnel. The Medical Dictionary for Regulatory Activities (MedDRA) coding 


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thesaurus will be used to classify AEs and medical history, and the World Health Organization 
Drug classification will be used to code medications. 
eCRFs will be available for review by the sponsor and sponsor’s designee after completion by 
the site. The eCRFs will be monitored remotely and/or onsite by the sponsor, Contract research 
organization (CRO), or other sponsor designee after documented training and in accordance with 
the monitoring plan. 
The completed eCRF must be electronically reviewed, signed, and dated by a qualified physician 
who is designated as principal or sub-investigator for the study. The investigator must retain the 
original source documents. A final pdf of the eCRFs will be provided to the study site by the 
CRO or designee at the end of the study for archival purposes.  
An electronic audit trail system will be maintained within the eCRF to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
18.3. 
Data Discrepancies 
After all subjects complete the study and data discrepancies are resolved, protocol deviations 
during both enrollment and study execution will be reviewed. Clinically important protocol 
deviations and procedural discrepancies will be discussed.  


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19. 
STATISTICAL ANALYSIS 
19.1. 
General Statistical Considerations 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using Statistical Analysis System Version 9.4 or higher. Unless specified 
otherwise, statistical tests will be conducted at the 2-sided 0.05 significance level (alpha), and all 
confidence intervals (CIs) will be reported as 2-sided 95%. 
Descriptive statistics will be displayed by treatment group to provide an overview of the study 
results. For categorical parameters, the number and percentage of subjects in each category will 
be presented in data summaries. The denominators for percentages will be based on the number 
of subjects (n) appropriate for analysis. Continuous variables will generally be summarized 
based on the following: n, mean, standard deviation, median, minimum, and maximum. 
Categorical data will be summarized using frequency tabulations (number and percentage of 
subjects). Time-to-event data will be summarized using counts and Kaplan-Meier estimates with 
standard errors, where appropriate. All data will be listed for all subjects. 
19.2. 
Determination of Sample Size 
For purposes of sample size estimation, the placebo group response rate is estimated as 20%. The 
seladelpar 10-mg dose group response rate is estimated as 55%. With the use of a 2-sided test of 
equality of binomial proportions based on Fisher’s exact test at the 0.05 level of significance, a 
sample size of 180 randomized subjects will provide >90% power to detect a difference between 
the 10-mg seladelpar group and the placebo group. 
The key secondary efficacy analysis of normalization of ALP is estimated to have a placebo 
response rate and a seladelpar response rate of 2.5% and 25.5%, respectively. A sample size of 
180 randomized subjects will provide >90% power to detect a difference between the seladelpar 
and placebo groups, based on a Fisher’s exact test at a 0.05 level of significance. 
The key secondary efficacy analysis of change from baseline in weekly averaged pruritus NRS at 
Month 6 sample size calculation is based on a 2-sample 2-sided t-test with a significance level of 
0.05. The standard deviation is estimated as 2. Under these assumptions, as well as a total of 48 
randomized subjects having a baseline NRS ≥4, this test provides >80% power to detect a 
treatment difference of ≥2 between 10-mg seladelpar and placebo groups. 
The stated power calculations are based on previous results from Study CB8025-31735 as well 
as an assumed dropout rate of approximately 10%. 
Randomization will be centralized to ensure adequate blinding of the study. 
19.3. 
Analysis Sets 
19.3.1. 
Safety Analysis Set 
The safety analysis set is defined as any subject who receives at least 1 dose of study drug. 
Subjects will be included in the group based on treatment received, if this should differ from the 
treatment assignment. All safety analyses will be completed using the safety analysis set. 


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19.3.2. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set is defined as any subject who is randomized into the study 
and receives at least 1 dose of study drug. The ITT analysis set will be the primary analysis set 
used for efficacy analyses, with the exception of secondary endpoints evaluated for subjects with 
moderate to severe pruritus.  
19.3.3. 
Modified Intent-to-Treat Biopsy Analysis Set 
The modified intent-to-treat biopsy (mITTb) analysis set includes any subject who is in ITT 
analysis set and has a baseline and Month 12/ET biopsy. The mITTb analysis set will be used to 
examine the histology changes or the lack thereof. 
19.3.4. 
Moderate to Severe Pruritus NRS Analysis Set 
The moderate to severe pruritus NRS (MSPN) analysis set includes any subjects who is in the 
ITT analysis set and has a baseline NRS value ≥4. The MSPN analysis set will be the primary 
analysis set for secondary endpoints based on NRS evaluations. 
Subjects in the ITT and MSPN analysis sets will be analyzed according to randomized treatment 
assignment. 
19.3.5. 
Per-Protocol Analysis Set 
The per-protocol (PP) analysis set includes any subject who is in the ITT analysis set, has at least 
1 postbaseline ALP and total bilirubin evaluation, and does not have a protocol violation that is 
deemed to impact the efficacy analysis. Selected analyses of efficacy will be conducted using the 
PP analysis set. 
19.3.6. 
Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set includes any subject who participates in the PK sample 
collection. 
19.4. 
Analysis Time Points 
Unless stated otherwise, baseline values will be based on the last non-missing assessment 
evaluated prior to the first administration of study drug. Baseline for chemistry and hematology 
measures will be calculated as the arithmetic mean of multiple pretreatment measurements 
(Screening, Run-in, Day 1, and unscheduled assessments) preceding the first administration of 
study drug. Baseline pruritus NRS is defined as the mean of all daily recorded scores during the 
Run-in Period.  
Unless otherwise noted, all references to Day 1 refer to the day of study drug initiation for 
analytical purpose.  
The final analysis will take place after the last subject visit at Month 12 (or Early Termination). 
19.5. 
Disposition, Demographics, and Baseline Characteristics 
The number of subjects screened, and the number and percentage of those subjects who were 
screen failures, broken down by primary reason for Screening failure will be presented.  


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Demographics and baseline characteristics (medical histories, physical examinations, and 
concomitant medications) will be summarized using descriptive statistics for continuous 
variables and frequency distributions for discrete variables.  
Study subjects who discontinue the study along with reasons for discontinuation will be 
summarized and listed. 
19.6. 
Efficacy Analysis 
All efficacy analyses will be conducted on the ITT analysis set. Analysis details for instances in 
which data present differently from testing assumptions will be provided in the SAP. Additional 
sensitivity and supplementary analyses will be performed for the primary and key secondary 
endpoints, as applicable. Subgroup analyses will be defined in the study SAP. Unless specified 
otherwise, data collected following treatment discontinuation will not be included in data 
summaries or inferential analyses.  
19.6.1. 
Primary Efficacy Analysis  
The primary efficacy analysis for the proportion of subjects who are considered responders will 
be based on the proportion of subjects achieving the following composite endpoint evaluated at 
12 months: 
• ALP <1.67× ULN 
• ALP decrease of ≥15% 
• Total bilirubin ≤1.0× ULN 
Any subject who does not provide an assessment at, or has discontinued treatment prior to, the 
specified time point for response evaluation or who otherwise has missing data will be 
considered a nonresponder. Analyses for the composite endpoint will be completed using a 
Cochran-Mantel-Haenszel (CMH) test. The CMH analysis will be stratified by the randomization 
stratum and will be conducted on the ITT analysis set. The risk difference and 95% CI using 
Miettinen and Nurminen will also be provided. Statistical significance of the difference between 
placebo and seladelpar will be defined as a 2-sided p≤0.05.  
19.6.2. 
Key Secondary Efficacy Endpoint Analysis  
The key secondary efficacy analysis for the proportion of subjects who achieve normalization of 
ALP at 12 months will be conducted in the ITT analysis set using the same approach specified 
for the primary efficacy analysis. 
Change from baseline in weekly averaged pruritus NRS at 6 months will be analyzed using a 
mixed-effect model for repeated measures (MMRM) for subjects in the MSPN analysis set. The 
model will include baseline NRS, randomization stratum, treatment group, week, and treatment-
by-week interaction term. Treatment by baseline interaction will be explored and added as a term 
if interaction is noted to be present. LS means for the change by treatment and the associated 
standard errors, the LS means for the difference between treatment groups, and the associated 
2-sided 95% CIs and 2-sided p-values, based on t-tests, will be derived from the MMRM model. 
Specifically, efficacy endpoints will be evaluated using the estimated treatment difference in 
mean change from baseline NRS for the week associated with their specified month. An 


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unstructured covariance matrix will be tried first. If the model fails to converge, compound 
symmetry will be used in place of an unstructured covariance. The Kenward-Roger correction 
for the denominator degrees of freedom will be applied. 
Type I error for the key secondary efficacy analyses will be maintained using a hierarchical 
fixed-sequence methodology. The fixed-sequence approach for the primary and key secondary 
analyses is as follows: 
10. If the primary efficacy analysis is positive for seladelpar 10 mg versus placebo at a 
2-sided 0.05 significance level, then the 2 key secondary endpoints will be analyzed 
hierarchically in the following order: 
11. Normalization of ALP at Month 12 (seladelpar 10 mg versus placebo): If negative at 
a 2-sided 0.05 significance level, no further inferential testing will be performed. 
Otherwise, if positive, then testing will proceed. 
12. Change from baseline to Month 6 in pruritus NRS (seladelpar 10 mg versus placebo) 
will be evaluated at a 2-sided 0.05 significance level. 
19.6.3. 
Other Secondary Efficacy Endpoint Analysis 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
.  
19.6.4. 
Exploratory Efficacy Endpoint Analysis  
 
 
19.6.5. 
Sensitivity Analysis for the Primary and Key Secondary Efficacy Endpoints 
Detailed descriptions of dropouts and missing data handling will be described in the SAP. All 
efforts will be made to prevent missing data from occurring.  
Sensitivity analyses will be performed on the primary and key secondary efficacy responder 
endpoints using observed data only. The robustness of the primary analysis will be explored 
using several sensitivity analyses on a variety of patient populations. 
CCI
CCI


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For efficacy endpoints that utilize MMRM, observed cases will serve as the primary analysis. 
The robustness of the primary and key secondary analyses will be explored using sensitivity 
analyses to assess the effect of missing data.  
The following sensitivity analyses will also be performed, where applicable: 
• Same as primary analysis except based on the PP analysis set. 
• Tipping point analysis and other sensitivity approaches will be performed in the 
primary and key secondary efficacy endpoint analyses and will be described in the 
SAP. 
19.7. 
Safety Analysis 
All safety analyses will be based on the safety analysis set.  
AEs will be coded based on the MedDRA. TEAE incidence will be summarized by MedDRA 
system organ class and preferred term by severity and by causal relationship to study drug. The 
severity of TEAEs will be graded based on NCI CTCAE Version 5.0. 
Safety laboratory parameters, liver fibrosis scores, vital signs, body weight, and body mass index 
values (absolute and change from baseline) will be summarized by treatment group using 
descriptive statistics at baseline and at each postbaseline visit.  
Further details of the safety analysis will be provided in the SAP. 
19.8. 
Pharmacokinetic Analysis 
Descriptive statistics will be provided for the concentrations-versus-time data per visit number 
for seladelpar and metabolites per visit. Further, pooling of the concentration data from this study 
with data from other studies will be done to facilitate development and/or updating of a 
population PK model and will be reported separately. 
20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
20.1. 
Study Monitoring 
20.1.1. 
Source Documents 
The investigators and institution(s) will permit study-related monitoring of the eCRF data by 
CymaBay Therapeutics, Inc. or their assignee by providing direct access to source data and/or 
documents. A study monitor will conduct onsite and/or remote monitoring visits, in accordance 
with the monitoring plan, to review the eCRF data against the source data/documents for 
completeness and accuracy. Remote access to source data will be provisioned only under 
approved country regulations and subject consent. Remote access to source data may include 
email, remote access to the electronic medical record (EMR), video calls, or teleconferences with 
the investigator/designee. 


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20.1.2. 
Case Report Forms 
Subjects who have signed the ICF will be assigned a subject number and will have study data 
entered into a CRF. CRF completion is important to the medical monitoring of the study and 
should be completed promptly after each subject visit. 
20.1.3. 
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 subject 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 protocol will be noted in the source documentation, in the eCRF, and in a 
complementary database. Protocol deviations related to missing protocol-specified information, 
missed visits or data collection, alternative visits, delays, etc., that occur in relation to COVID-19 
will be designated as such and captured in the source, eCRF, and complementary database. 
Administrative study guidance will outline how this information will be handled. The sponsor 
will assess any protocol deviation and decide whether any of these noncompliance’s should be 
reported to regulatory authorities as a serious breach of ICH Good Clinical Practice (GCP) and 
the protocol. 
20.2. 
Audits and Inspections 
20.2.1. 
Study Auditing 
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 onsite or remote 
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 subject-specific information is confidential and that no documentation 
that can link study information to the specific subject will be collected or retained by the 
sponsor. 
20.2.2. 
Study Monitoring 
A sponsor representative will visit the site at regular intervals and as managed under the 
risk-based monitoring approach, which is considerate of onsite source document verification and 
remote review (no source) options. Available medication dispensing and clinical drug supply 
records will be verified by the study monitor. It is understood that all subject-specific 
information is confidential and that no documentation that can link study information to the 
specific subject will be collected or retained by the sponsor. Remote source document 
verification may only occur in business critical situations when onsite source data verification 
cannot occur timely (e.g., database lock and subject safety) and only under approved country 
regulations and subject consent. Remote source document verification solutions may include 
encrypted email, remote access to the EMR, video calls, or teleconferences with the investigator. 


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20.3. 
Ethics Committees 
The investigators will provide IEC with all information impacting the risk profile of the drug. 
The study will not commence until written IEC approval for the protocol and ICF is received by 
the sponsor. The investigator has the responsibility to conform to all of the local requirements for 
periodic updates and notification to the committee. 
21. 
QUALITY CONTROL AND 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 AEs 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. 
22. 
ETHICS 
22.1. 
Ethics Review 
The protocols, ICFs, any information provided to the subject, recruitment advertisements, and 
any amendments to these items must be reviewed and approved by the IEC prior to their use in 
the study.  
The study will not start before written approval by IEC(s) has been obtained and compliance 
with the local regulatory requirements has been accomplished. 
The IEC must meet all the appropriate ICH requirements for composition, documentation, and 
operational procedures. 
22.2. 
Ethical Conduct of the Study 
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. 
22.3. 
Informed Consent 
Subjects must give consent to participate in the study only after having been fully informed by 
the investigator or a person designated by him/her of the nature, significance, and implications of 
the study, as well as the associated risks involved. Such meetings must be carried out on an 
individual basis and must be adapted to the educational background and previous knowledge of 
the subject. Participation in this meeting should be documented in the subject’s file. The subject 
must be allowed ample time to inquire about details and to decide whether to participate in the 
study. Informed consent will be obtained from all subjects enrolled in the study and before study-
related activities are performed on a subject. The process of obtaining informed consent will be 
documented in the source documents of the subject. Only ICFs approved by the IEC will be 
used. 


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The ICF must be dated and signed by both the investigator and the subject. Electronic signature 
may be provided if acceptable by local authorities. 
23. 
RETENTION OF RECORDS 
All study-related material, including source documents, eCRFs, competent authority and IEC 
correspondence and analyses, and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study or notification from the 
sponsor that the data can be destroyed, whichever comes first. 
24. 
PROTOCOL AMENDMENTS 
Any change or addition to this protocol will only be made when a protocol amendment has been 
written, approved, and signed by CymaBay Therapeutics, Inc. and the principal investigator 
before the change or addition can be considered effective. This amendment must also be 
submitted to the IEC for approval and, when necessary, competent authority approval before 
implementation. Protocol amendments may affect consent forms of current and future subjects. 
CymaBay Therapeutics, Inc. will clearly specify when a protocol amendment includes safety, 
procedural, and/or efficacy information that will require specific ICF text changes. 
25. 
DISCLOSURE OF INFORMATION AND PUBLICATION 
POLICY 
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 the 
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 prepublication manuscript prior to the submission of the 
manuscript to the publisher. 
 


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25. Greenberg JA, Hsu J, Bawazeer M, et al. Clinical practice guideline: management of 
acute pancreatitis. Can J Surg. 2016;59(2):128-140. doi:10.1503/cjs.015015 
 
 


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Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 88 of 100 
 
APPENDIX A. LABORATORY EVALUATIONS 
Biochemistry 
 
 
 
ALP 
AST 
ALT 
GGT 
Protein 
Albumin  
Total bilirubin  
5’-nucleotidase 
Direct bilirubin  
Indirect bilirubin 
Aldolase 
Sodium 
Potassium  
Chloride 
Cystatin C 
Bicarbonate 
BUN/urea  
Serum creatinine  
eGFR  
CK  
Venous blood glucose 
Troponin I 
LDH 
TG 
Total cholesterol 
HDL-C 
LDL-C 
Amylase 
Lipase 
Hematology 
 
Other Tests 
RBC 
Hemoglobin 
Hematocrit 
WBC 
WBC differentials 
(abs and %) 
Platelets 
PT/INR  
Serum pregnancy test  
Back-up sample  
HBsAg (Screening only) 
HCV RNA (Screening only) 
HIV (Screening only) 
PK blood sample  
Vitamin A (D1, M12, and ET only) 
Vitamin D (D1, M12, and ET only) 
Vitamin E (D1, M12, and ET only) 
Vitamin K (D1, M12, and ET only)  
Urine drug screen (Screening only) 
Urine pregnancy test  
CCI CCI


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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 89 of 100 
 
APPENDIX B. CLOSE OBSERVATION CRITERIA 
The “close observation” will be performed on subjects meeting liver safety monitoring criteria 
Section 10.1.1. If “close observation” is not feasible, study drug must be stopped. 
13. 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. 
14. Laboratory testing 
a. Repeat ALT, AST, bilirubin (total), and PT/INR within 3 days.  
b. Monitor the subject every 3 days until the laboratory abnormality stabilization. 
c. After laboratory abnormality is stabilized, monitor the subject once a week until 
the event resolution. 
15. 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. 


CymaBay Therapeutics, Inc. 
Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 90 of 100 
 
APPENDIX C. NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
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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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 91 of 100 
 
APPENDIX D. PRURITUS NRS 
Rate the intensity of the worst itching you experienced in the past 24 hours from no itching to 
worst possible itching by selecting a number. 
 
Itch Scale 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
No 
itching 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
itching 
 


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CymaBay Therapeutics, Inc. 
Protocol CB8025-32048 
 
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CCI


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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
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CCI


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CCI


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Protocol CB8025-32048 
 
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CONFIDENTIAL 
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APPENDIX G. PATIENT GLOBAL IMPRESSION OF SEVERITY 
Please choose the response below that best describes the severity of your pruritus over the past 
week. 
• None 
• Mild 
• Moderate 
• Severe 


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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 97 of 100 
 
APPENDIX H. PATIENT GLOBAL IMPRESSION OF CHANGE 
Please choose the response below that best describes the overall change in your pruritus since 
you started taking the study drug. 
• Very much better 
• Moderately better 
• A little bit better 
• No change 
• A little worse 
• Moderate worse 
• Very much worse 
 
 


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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 98 of 100 
 
APPENDIX I. CIRRHOSIS DETERMINATION 
For the study purposes, cirrhosis will be defined using the following criteria (one or more):  
• Historical liver biopsy demonstrating cirrhosis (e.g., Ludwig Stage 4 or Ishak 
Stage 5)  
• Current or prior history of decompensated liver disease, including ascites, hepatic 
encephalopathy, esophageal varices, or other clinical conditions consistent with liver 
cirrhosis and/or portal hypertension,  
• Liver stiffness >16.9 kPa by FibroScan at screening  
• Combination of platelets <140×10
3/μL with the following:  
− Serum albumin <3.5 g/dL 
− INR >1.3 (not due to antithrombotic agent use) 
− Total bilirubin >1.0×ULN 
• The presence of radiological evidence of cirrhosis (nodular liver) with concurrent 
splenomegaly) 
• Clinical determination by the investigator 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 99 of 100 
 
APPENDIX J. NORMAL RANGES FOR SAFETY LABORATORY 
PARAMETERS 
BIOCHEMISTRY 
Conventional Units 
SI Units 
ALP 
37-116 U/L 
37-116 U/L 
Albumin  
3.5-5.5 g/dL 
35-55 g/L 
ALT 
6-41 U/L 
6-41 U/L 
AST 
9-34 U/L 
9-34 U/L 
GGT 
Female : 7-38 U/L 
Male : 11-52 U/L 
Female : 7-38 U/L 
Male : 11-52 U/L 
Protein 
6.0-8.0 g/dL 
60-80 g/L 
Total Bilirubin 
0.10 – 1.10 mg/dL 
1.7-18.8 umol/L 
Direct Bilirubin 
0.00-0.20 mg/dL 
0.0-3.4 umol/L 
Indirect Bilirubin 
0.10- 1.00 mg/dL 
1.7-17.1 umol/L 
Aldolase 
<7.7 U/L 
<7.7 U/L 
Sodium 
134-144 mmol/L 
134-144 mmol/L 
Potassium 
3.5-5.1 mmol/L 
3.5-5.1 mmol/L 
Chloride 
95-110 mmol/L 
95-110 mmol/L 
Bicarbonate 
21-33 mmol/L 
21-33 mmol/L 
BUN/Urea  
5-22 mg/dL 
1.79-7.85 mmol/L 
Serum Creatinine 
Female : 0.49-1.12 mg/dL 
Male : 0.62-1.44 mg/dL 
Female : 43-99 umol/L 
Male : 55-127 umol/L 
CK 
Female : 26-192 U/L 
Male : 39-308 U/L 
Female : 26-192 U/L 
Male : 39-308 U/L 
Venous Glucose 
60-115 mg/dL 
3.3-6.4 mmol/L 
Troponin I 
<0.3 ng/mL 
<0.3 ug/L 
LDH 
113-226 U/L 
113-226 U/L 
TG 
50-150 mg/dL 
0.57-1.70 mmol/L 
Total Cholesterol 
100-200 mg/dL 
2.59-5.18 mmol/L 
HDL-C 
35-60 mg/dL 
0.91-1.55 mmol/L 
LDL-C 
50-130 mg/dL 
1.30-3.37 mmol/L 
Amylase 
22-123 U/L 
22-123U/L 
Lipase 
11-82 U/L 
11-82 U/L 
5’-nucleotidase 
0 - 15 U/L 
0 - 15 U/L 
Cystatin C 
0.49-1.19 mg/L 
0.49-1.19 mg/L 
eGFR 
18-49y : >60 mL/min/1.73m2 
>=50y : >=49 mL/min/1.73m2 
18-49y : >60 mL/min/1.73m2 
>=50y : >=49 mL/min/1.73m2 
HEMATOLOGY 
 
 
RBC 
Female : 3.90 – 5.40 106/uL 
Male :  4.30 – 6.00 106/uL 
Female : 3.90 – 5.40 1012/L 
Male :  4.30 – 6.00 1012/L 
Hemoglobin 
Female : 12.0-16.0 g/dL 
Male :  13.6-18.0 g/dL 
Female : 120-160 g/L 
Male :  136-180 g/L 
Hematocrit 
Female : 35-45% 
Male :  40-52% 
Female : 0.35-0.45 
Male : 0.4-0.52 
WBC 
3.5-11.0 103/uL 
3.5-11.0 109/L 
Neutrophils, abs 
1.0-8.0 103/uL 
1.0-8.0 109/L 
Lymphocytes, abs 
1.0-5.0 103/uL 
1.0-5.0 109/L 
Eosinophils, abs 
0.0-0.8 103/uL 
0.0-0.8 109/L 
Monocytes, abs 
0.0-1.0 103/uL 
0.0-1.0 10^9/L 
Neutrophils, % 
40.0-80.0 % 
40.0-80.0 % 
Lymphocytes, % 
15.0-45.0 % 
15.0-45.0 % 
Eosinophils, % 
0.0-10.0 % 
0.0-10.0 % 
Monocytes, % 
0.0-12.0 % 
0.0-12.0 % 
Platelets 
140-400 103/uL 
140-400 109/L 
PT 
Reagent specific ranges  
Reagent specific ranges 
INR 
0.8-1.2 
0.8-1.2 
OTHER 
 
 
Pregnancy test (β-HCG) 
Female : 0-5 IU/L 
Female : 0-5 IU/L 
Vitamin A 
24-128 ug/dL 
24-128 ug/dL 
Vitamin D 
30-80 ng/mL 
75.0-200.0 nmol/L 
Vitamin E 
0.51-2.88 mg/dL 
0.51-2.88 mg/dL 
Vitamin K 
0.22-4.88 nmol/L 
0.22-4.88 nmol/L 
HBsAg 
Non-reactive 
Non-reactive 
HCV RNA 
Not Detected 
Not Detected 
 


CymaBay Therapeutics, Inc. 
Protocol CB8025-32048 
 
Protocol Version 4.0, 09-FEB-2022 
CONFIDENTIAL 
Page 100 of 100 
 
APPENDIX K. INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
PROTOCOL TITLE: 
RESPONSE: A Placebo-controlled, Randomized, Phase 3 Study 
to Evaluate the Efficacy and Safety of Seladelpar in Patients with 
Primary Biliary Cholangitis (PBC) and an Inadequate Response to 
or an Intolerance to Ursodeoxycholic Acid (UDCA) 
PROTOCOL NUMBER: 
CB8025-32048 
VERSION NUMBER: 
4.0 
DATE OF PROTOCOL: 
09-February-2022 
SPONSOR: CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
United States of America 
I have read all pages of this clinical study protocol for which CymaBay Therapeutics, Inc. is the 
sponsor. I agree to conduct the study as outlined in the protocol and to comply with all the terms 
and conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and the provisions of Declaration of Helsinki. I will also ensure that  
sub-investigator(s) and other relevant members of my staff have access to copies of this protocol, 
and the ICH GCP guidelines and Declaration of Helsinki, to enable them to work in accordance 
with the provisions of these documents. 
Investigator: 
 
 
Printed Name: 
 
 
Signature: 
Date: 
 
 
 
 
 
 
 
Site Address: 
 
 
 
 
 
 
 

SAP_001.pdf: 
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DocuSign Envelope ID: 056E936E-990A-4E27-BEF1-O6872909798B 
Protocol Number: CB8025-32048 
SAP Version and Date: Version 1.0, 28-AUG-2023 
Approval Signature Page: CymaBay Therapeutics, Inc. 
Vice President of Biometrics 
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Page 2 of68 
30-Aug-2023110:41 PDT 
Date 
30-Aug-2023 I 11 :01 PDT 
Date 


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