Clinical trial NCT02955602
Conditions: Primary Biliary Cirrhosis
Keywords: PBC Primary Biliary Cholangitis (PBC)
Sponsor: Gilead Sciences
Start date: 2016-11-28; Completion date: 2019-07-08
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

Detailed description:
Primary:

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 8 weeks of treatment

Secondary:

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 12 and 26 weeks of treatment

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 52 weeks of treatment

To evaluate the pharmacokinetics (PK) of MBX-8025

Exploratory:

To evaluate the effect of MBX-8025 on bile acids, additional markers of inflammation and renal function

MBX-8025 doses of 1 mg and 15 mg may be evaluated if dose adjustment occurs

Arms: arm 1: MBX-8025 2 mg capsule once daily arm 2: MBX-8025 5 mg capsule once daily arm 3: MBX-8025 10 mg capsule once daily
Interventions: intervention 1: MBX-8025 2 mg Capsule intervention 2: MBX-8025 5 mg Capsule intervention 3: MBX-8025 10 mg Capsule
Intervention descriptions: intervention 1: Initial 8-week treatment:

• MBX-8025 2 mg

Extension:

The 2 mg group will be started after safety and efficacy review of the 5 mg and the 10 mg groups has been completed.

Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons. intervention 2: Initial 8-week treatment:

• MBX-8025 5 mg

Extension:

Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons. intervention 3: Initial 8-week treatment:

• MBX-8025 10 mg

Extension:

Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL  
 
Unique Protocol ID: CB8025-21629 
Official Title: An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week 
extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary 
Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA) 
 
NCT number: NCT02955602 
 
Protocol Version Number: Version 4.2 
 
Date Of Protocol: 20-JUL-2017 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-21629 
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CB8025-21629 
 
PROTOCOL TITLE: 
An 8-week, dose ranging, open label, randomized, Phase 2 study 
with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with 
Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic 
acid (UDCA) 
 
PROTOCOL VERSION NUMBER: Version 4.2 
 
 
 
DATE OF PROTOCOL: 
20-JUL-2017 
 
PROTOCOL NUMBER: 
CB8025-21629 
 
SPONSOR: 
CymaBay Therapeutics, Inc. 
7999 Gateway Blvd, Suite 130 
Newark, CA 94560 
United States of America 
 
SPONSOR CONTACT: 
 
 
 
EudraCT number: 
 
2016-002996-91 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information, which should not be disclosed, copied, referred 
to, released or published without written approval from CymaBay Therapeutics. Any supplemental 
information that may be added to this document is also confidential and proprietary to CymaBay 
Therapeutics and must be kept in confidence in the same manner as the contents of this document. 
 
 




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TABLE OF CONTENT 
1.
LIST OF ABBREVIATIONS ................................................................................................... 8
2.
LIST OF SPONSOR CONTACTS ......................................................................................... 11
3.
SYNOPSIS .............................................................................................................................. 12
Table 1: Schedule of Assessments ................................................................................................. 26 
4.
INTRODUCTION .................................................................................................................. 28
4.1 
Primary Biliary Cholangitis (PBC) .................................................................................. 28 
4.2 
MBX-8025 ....................................................................................................................... 29 
4.2.1 
Overview .................................................................................................................. 29 
4.2.2 
Mechanism of Action ............................................................................................... 29 
4.2.3 
MBX-8025 in PBC ................................................................................................... 29 
4.3 
NONCLINICAL INVESTIGATIONS WITH MBX-8025 ............................................. 32 
4.4 
HUMAN EXPERIENCE ................................................................................................. 32 
4.4.1 
Phase 1 studies ......................................................................................................... 32 
4.4.2 
Phase 2 studies ......................................................................................................... 33 
4.5 
RISK/BENEFIT ASSESSMENT .................................................................................... 34 
4.5.1 
Potential Benefits ..................................................................................................... 34 
4.5.2 
Potential Risks .......................................................................................................... 35 
4.5.2.1 
Non-clinical safety findings .............................................................................. 35 
4.5.2.2 
Human safety .................................................................................................... 35 
4.5.3 
Conclusions .............................................................................................................. 36 
4.6 
RATIONALE FOR DOSE SELECTION ....................................................................... 36 
5.
STUDY OBJECTIVES ........................................................................................................... 37
5.1 
PRIMARY OBJECTIVES .............................................................................................. 37 
5.2 
SECONDARY OBJECTIVES ........................................................................................ 37 
5.3 
EXPLORATORY OBJECTIVES ................................................................................... 37 
6.
STUDY POPULATION ......................................................................................................... 38
6.1 
SELECTION CRITERIA ................................................................................................ 38 
6.1.1 
Inclusion Criteria ...................................................................................................... 38 
6.1.2 
Exclusion Criteria ..................................................................................................... 38 
7.
STUDY DESIGN .................................................................................................................... 40
7.1 
TREATMENT AND ALLOCATION OF SUBJECTS .................................................. 41 


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7.2 
STUDY DURATION ...................................................................................................... 41 
7.3 
STUDY OUTCOME MEASUREMENTS ..................................................................... 41 
7.3.1 
Primary measures ..................................................................................................... 41 
7.3.2 
Secondary measures ................................................................................................. 42 
7.3.3 
Exploratory measures ............................................................................................... 42 
8. 
STUDY MEDICATIONS ....................................................................................................... 43 
8.1 
CLINICAL SUPPLIES .................................................................................................... 43 
8.1.1 
Investigational product, dosage and mode of administration ................................... 43 
8.1.2 
Packaging, Labeling and Shipping ........................................................................... 43 
8.1.2.1 
Dose Adjustment ............................................................................................... 43 
8.1.3 
Accountability of Clinical Supplies ......................................................................... 43 
8.1.4 
Replacement Study Medication ............................................................................... 43 
8.1.5 
Stability of Study Medication .................................................................................. 43 
8.2 
RANDOMIZATION ....................................................................................................... 43 
8.2.1. 
Randomization/Registration Procedure .................................................................... 43 
8.3 
METHOD OF ADMINISTRATION AND COMPLIANCE .......................................... 44 
8.4 
CONCOMITANT MEDICATIONS AND PROCEDURES .......................................... 44 
8.4.1 
Concomitant Medications ........................................................................................ 44 
8.4.1.1 
Allowed Concomitant Medication: ................................................................... 44 
8.4.1.2 
Prohibited Concomitant Medication ................................................................. 44 
8.4.2 
Concomitant Procedures .......................................................................................... 44 
9. 
STUDY PROCEDURES ........................................................................................................ 45 
9.1 
STUDY SCHEDULE ...................................................................................................... 45 
9.1.1 
Screening:  Visit 1 to Visit 2 (Week -2 to Day 1) .................................................... 45 
9.1.2 
Baseline:  Visit 2 (Day 1) ......................................................................................... 46 
9.1.3 
Initial Treatment:  Visit 3 (Week 1) to Visit 7 (Week 8) ......................................... 47 
9.1.4 
Extension:  Visit 8 (Week 12) to Visit 14 (Week 52) .............................................. 50 
9.1.5 
Follow-up Period: Visit 15 (Week 56) and Early Termination Visit ....................... 52 
9.2 
STUDY ASSESSMENTS ............................................................................................... 54 
9.2.1 
Medical History and Physical Examination ............................................................. 54 
9.2.2 
Vital Signs and Weight/Height ................................................................................ 55 
9.2.3 
Electrocardiograms ................................................................................................... 55 


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9.2.4 
Laboratory Tests ....................................................................................................... 55 
9.2.5 
PK Samples for MBX-8025 level ............................................................................ 56 
9.2.6 
5D-itch Scale ............................................................................................................ 57 
9.2.7 
Pruritus Visual Analog Score (VAS) ....................................................................... 57 
9.2.8 
PBC-40 QoL ............................................................................................................. 57 
10. 
ADVERSE EVENTS .......................................................................................................... 58 
10.1 GENERAL ....................................................................................................................... 58 
10.1.1 
Definition of Adverse Events (AEs) ........................................................................ 58 
10.1.2 
Definition of Serious AEs (SAEs) ........................................................................... 58 
10.1.3 
AE Severity .............................................................................................................. 58 
10.1.4 
Relationship to Treatment ........................................................................................ 58 
10.1.5 
Action Taken With Study Medication...................................................................... 59 
10.2 RECORDING, REPORTING AND FOLLOW-UP OF ADVERSE EVENTS .............. 59 
10.2.1 
SAE Reporting Process ............................................................................................ 60 
10.2.2 
Follow-up of Reported AEs ..................................................................................... 61 
10.3 DISTRIBUTION OF RESPONSIBILITIES ................................................................... 62 
10.4 SAFETY MONITORING CRITERIA, DOSE ADJUSTMENT, AND WITHDRAWAL 
CRITERIA, ................................................................................................................................. 62 
10.4.1 
Safety Monitoring and Dose Adjustment ................................................................. 62 
10.4.1.1. 
Liver Safety Monitoring ................................................................................... 62 
10.4.1.2. 
Muscle Safety Monitoring ................................................................................ 63 
10.4.1.3. 
Serum Creatinine Monitoring ........................................................................... 63 
10.4.1.4. 
Pancreatic Safety Monitoring............................................................................ 63 
10.4.2. 
Dose adjustment for extension periods ................................................................. 63 
10.4.3 
Additional Withdrawal Criteria and Replacement of Subjects ................................ 64 
10.5 DATA SAFETY AND MONITORING BOARD ........................................................... 64 
10.6 PRECAUTIONS .............................................................................................................. 64 
10.6.1 
Pregnancy ................................................................................................................. 64 
11. 
STUDY TERMINATION ................................................................................................... 66 
12. 
DATA MANAGEMENT AND STATISTICAL ANALYSES .......................................... 67 
12.1 DATA MANAGEMENT ................................................................................................ 67 
12.1.1 
Processing of Electronic Case Report Forms ........................................................... 67 
12.1.2 
Database ................................................................................................................... 67 


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12.1.3 
Data Discrepancies ................................................................................................... 67 
12.2 STATISTICAL ANALYSIS ........................................................................................... 67 
12.2.1 
Sample Size Estimation ............................................................................................ 67 
12.2.2 
Study Population ...................................................................................................... 67 
12.2.2.1 
Safety population .............................................................................................. 67 
12.2.2.2 
Modified intent to treat population (mITT) ...................................................... 68 
12.2.2.3 
Per-protocol population (PP) ............................................................................ 68 
12.2.3 
Demographics and Baseline Characteristics ............................................................ 68 
12.2.4 
Efficacy Analysis ..................................................................................................... 68 
12.2.4.1. Primary Efficacy Analysis ................................................................................... 68 
12.2.4.2. Secondary Efficacy Analysis ............................................................................... 68 
12.2.4.3. Exploratory Efficacy Analysis ............................................................................. 69 
12.2.5 
Pharmacokinetic Analyses ....................................................................................... 69 
12.2.6 
Safety Analysis ......................................................................................................... 69 
12.2.6.1 
Adverse Events ................................................................................................. 69 
12.2.6.2 
Vital Signs ......................................................................................................... 70 
12.2.6.3. 
Physical Examination ........................................................................................ 70 
12.2.6.3 
Laboratory Tests ............................................................................................... 70 
12.2.6.5 
Electrocardiograms ........................................................................................... 70 
12.2.6.5 
Concomitant Medications ................................................................................. 70 
12.2.7 
Timing of the Analysis ............................................................................................. 70 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................. 71 
13.1 STUDY MONITORING ................................................................................................. 71 
13.2 AUDITS AND INSPECTIONS ...................................................................................... 71 
13.3 ETHICS COMMITTEEs ................................................................................................. 71 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 72 
15. 
ETHICS ............................................................................................................................... 73 
15.1 ETHICS REVIEW ........................................................................................................... 73 
15.2 ETHICAL CONDUCT OF THE STUDY ....................................................................... 73 
15.3 WRITTEN INFORMED CONSENT .............................................................................. 73 
16. 
RETENTION OF RECORDS ............................................................................................. 74 
17. 
PROTOCOL AMENDMENTS ........................................................................................... 75 


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18. 
DISCLOSURE OF INFORMATION ................................................................................. 76 
19. 
REFERENCES .................................................................................................................... 77 
APPENDIX A – LABORATORY EVALUATIONS .................................................................... 79 
APPENDIX B – CLOSE OBSERVATION CRITERIA ............................................................... 80 
APPENDIX C – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS (NCI CTCAE) .................................................................................... 81 
APPENDIX D – 5D-ITCH SCALE ............................................................................................... 82 
APPENDIX E – PRURITUS VAS ................................................................................................ 83 
APPENDIX F – PBC-40 QoL ........................................................................................................ 84 
APPENDIX G – INVESTIGATOR’S PROTOCOL SIGNATURE PAGE .................................. 87 
 
List of Tables 
Table 1: Schedule of Assessments ................................................................................................. 26 
 
 


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1. 
LIST OF ABBREVIATIONS 
 
7α-HC 
7α-hydroxycholesterol 
7-DHC 
7-dehydrocholesterol 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMA 
Anti-Mitochondrial Antibodies 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline Phosphatase 
Apo B-100 
Apolipoprotein B-100 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATV 
Atorvastatin 
AUC 
Area Under the Curve 
β-SITO 
β-sitosterol 
BUN 
Blood Urea Nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one (bile acid precursor) 
CA 
Cholic Acid 
CAMP 
Campesterol 
CD-1 
Crl:CD1(ICR) Mice 
CDCA 
Chenodeoxycholic Acid 
CK 
Creatine Kinase 
CK-BB 
Creatine Kinase Brain Type 
CK-MB 
Creatine Kinase Heart Type 
CK-MM 
Creatine Kinase Muscle Type 
Cmax 
Maximum Plasma Concentration 
COPR 
Coprostanol 
CRO 
Contract Research Organization 
CSTN 
Cholestanol 
CTX 
C-terminal Telopeptide 
CYP 
Cytochrome P450 
DCA  
Deoxycholic Acid 
DESM 
Desmosterol  
DSMB 
Data Safety and Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
U.S. Food and Drug Administration 
FGF19 
Fibroblast Growth Factor 19 


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GCA 
Glycocholic Acid 
GCDCA 
Glycochenodeoxycholic Acid 
GCP 
Good Clinical Practice 
GDCA 
Glycodeoxycholic Acid 
GGT 
Gamma-glutamyl Transferase 
GLCA 
Glycolithocholic Acid 
GUDCA 
Glycoursodeoxycholic Acid 
HDL-C 
High Density Lipoprotein Cholesterol 
HoFH 
Homozygous Familial Hypercholesterolemia 
hs-CRP 
High sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IgM 
Immunoglobulin M 
IXRS 
Interactive Voice/Web Response System 
LANO 
Lanosterol  
LATH 
Lathosterol 
LCA 
Lithocholic Acid 
LDH 
Lactate Dehydrogenase 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOAEL 
Lowest Observed Adverse Effect Level 
LOCF 
Last Observation Carried Forward 
M 
MBX-8025 Metabolite 
MedRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OCA 
Obeticholic Acid, Ocaliva 
P1NP 
Procollagen Type 1 N-terminal Propeptide 
PBC 
Primary Biliary Cholangitis/Primary Biliary Cirrhosis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PPARδ 
Peroxisome Proliferator-activated Receptor Delta 
PV 
Pharmacovigilance 
q.d. 
Once Daily 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SQLN 
Squalene  
STIG 
Stigmasterol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 


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TC 
Total Cholesterol 
TCA 
Taurocholic Acid 
TCDCA 
Taurochenodeoxycholic Acid 
TDCA 
Taurodeoxycholic Acid 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLCA  
Taurolithocholic Acid 
Tmax 
Time to Cmax 
TUDCA 
Tauroursodeoxycholic Acid 
UDCA 
Ursodeoxycholic acid 
UK-PBC 
United Kingdom Primary Biliary Cirrhosis Score 
ULN 
Upper Limit of Normal 
UNS  
Unscheduled 
VAS 
Visual Analog Score 
VLDL-C 
Very Low Density Lipoprotein Cholesterol 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WHOCC 
World Health Organization Collaborating Centers 
 
 


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2. 
LIST OF SPONSOR CONTACTS  
 
 
 
Sponsor Contact 
 
 
 
CymaBay Therapeutics, Inc. 
7999 Gateway Blvd, Suite 130 
Newark, CA 94560 
United States of America  
 
 
 
 
 
 
 
The Sponsor will notify the Investigator(s) in writing with any change to the above information. 
 
 


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3. 
SYNOPSIS 
Study Number 
CB8025-21629  
Title 
An 8-week, dose ranging, open label, randomized, Phase 2 study with 
a 44-week extension, to evaluate the safety and efficacy of MBX-8025 
in subjects with Primary Biliary Cholangitis (PBC) and an inadequate 
response or intolerance to ursodeoxycholic acid (UDCA) 
Phase 
2 
Objectives 
Primary:  
To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 
10 mg over 8 weeks of treatment  
Secondary:  
To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 
10 mg over 12 and 26 weeks of treatment 
To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 
10 mg over 52 weeks of treatment 
To evaluate the pharmacokinetics (PK) of MBX-8025 
Exploratory: 
To evaluate the effect of MBX-8025 on bile acids, additional markers 
of inflammation and renal function 
MBX-8025 doses of 1 mg and 15 mg may be evaluated if dose 
adjustment occurs 
Study Outcome 
Measures 
Primary: 
Serum alkaline phosphatase (AP) 
Adverse events (AE) and Treatment Emergent Adverse Events 
(TEAEs), ECG, biochemistry, hematology, and urinalysis (NCI 
CTCAE Version 4.0) 
Secondary: 
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), 
Gamma-glutamyl transferase (GGT), 5’nucleotidase, Bilirubin (Total, 
Conjugated, Unconjugated), Bone-specific AP, Triglycerides (TG), 
Total Cholesterol (TC), High Density Lipoprotein Cholesterol 
(HDL- C), and Low Density Lipoprotein Cholesterol (LDL-C) 
Composite endpoint of AP and Total Bilirubin:  
• AP < 1.67 × upper limit of normal (ULN) 
• Total Bilirubin within normal limit  
• > 15% decrease in AP 
Published PBC response criteria (Barcelona, Paris I and II, Toronto I 
and II), UK- PBC risk score 


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5D-itch scale and pruritus Visual Analog Score (VAS) 
PBC-40 QoL 
PK of MBX-8025 and metabolites (at 0, 0.5, 1, 2, 4, 6 and 24 hours for 
Cmax, Tmax, T1/2 and AUC; trough level) 
Exploratory Measures: 
Anti-Mitochondrial Antibodies (AMA), C-terminal telopeptide 
(CTX), cystatin C, IgM, fibrinogen, fibroblast growth factor 19 
(FGF19), haptoglobin, high-sensitivity C-Reactive Protein (hs-CRP), 
homocysteine, microRNA-122, and procollagen type 1 N-terminal 
propeptide (P1NP);  
Bile acids: Primary Bile Acids and Salts: Cholic acid (CA), 
chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic 
acid 
(TCA), 
glycochenodeoxycholic 
acid 
(GCDCA), 
taurochenodeoxycholic acid (TCDCA); Secondary Bile Acids and 
Salts: 
Deoxycholic 
acid 
(DCA), 
lithocholic 
acid 
(LCA), 
glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), 
taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA); Other 
Bile Acids: ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid 
(GUDCA), tauroursodeoxycholic acid (TUDCA); 
Sterols: desmosterol (DESM), lanosterol (LANO), lathosterol 
(LATH), 7-dehydrocholesterol (7-DHC), cholestanol (CSTN), 
coprostanol (COPR), squalene (SQLN); β-sitosterol (β-SITO), 
campesterol (CAMP), stigmasterol (STIG) 7α-hydroxycholesterol (7 α 
HC); 
C4 (7α-hydroxy-4-cholesten-3-one);  
24-hour urinary excretion of MBX-8025 and metabolites 
Design 
Open label, randomized, uncontrolled, 8-week dose ranging parallel 
groups (2 mg, 5 mg, and 10 mg) 
Open label extension for a total of up to 52-week treatment 
Selected centers will perform PK (24-hour) testing 
 


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Treatment Groups 
Initial 8-week treatment: 
• MBX-8025 2 mg 
• MBX-8025 5 mg 
• MBX-8025 10 mg 
Extension: 
1mg, 2 mg, 5 mg, 10 mg, or 15 mg. Subjects will initially enter the 
extension on their assigned dose. The dose might be up- or down-
titrated after safety and efficacy data review of the first 8 weeks of 
treatment. During the extension, a subject’s dose might be re-adjusted 
for safety or efficacy reasons. Dose up-titration to 15 mg can be 
performed only within 26-week treatment period.  Beyond Week 26 
(Visit 11), the highest dose will be 10 mg.  
Number of Subjects 
Approximately 116 subjects  
• 2 mg treatment group: up to 18 subjects 
• 5 mg treatment group: approximately 49 subjects 
• 10 mg treatment group: approximately 49 subjects 
PK (24-hour):  up to 30 subjects 
• 2 mg treatment group: up to six subjects 
• 5 mg and 10mg treatment groups: up to twelve subjects per 
group 
Number of 
Investigational Sites 
Approximately 40  
Randomization  
MBX-8025 5 mg and MBX-8025 10 mg (1:1 ratio) 
Subjects in the MBX-8025 2 mg group will enter the study in 
chronological order 
Duration 
Screening: up to two weeks 
Initial Treatment: eight weeks  
Extension: 44 weeks 
Follow-up: four weeks 
Total Duration: up to 58 weeks 
Test Product  
Formulation/packaging  
Dose 
Frequency 
Administration Route   
MBX-8025  
1, 5, and 10mg capsules in bottle 
2, 5, and 10 mg; 1 and 15 mg through dose adjustment 
Once a day 
Oral 


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Population and Criteria 
for Eligibility 
Inclusion Criteria: 
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, by at least two of the 
following criteria: 
• History of AP above ULN for at least six months 
• Positive AMA titers (>1/40 on immunofluorescence or 
M2 positive by enzyme linked immunosorbent assay 
(ELISA) 
or 
positive 
PBC-specific 
antinuclear 
antibodies 
• Documented liver biopsy result consistent with PBC 
4. On a stable and recommended dose of UDCA for the past 
twelve months or intolerant to UDCA 
5. AP ≥ 1.67 × ULN 
6. Females of reproductive potential must use at least one 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: 
1. A medical condition, other than PBC, that in the investigator’s 
opinion would preclude full participation in the study or 
confound its results (e.g., cancer on active treatment) 
2. AST or ALT > 3 × ULN 
3. Total bilirubin > 2.0 mg/dL 
4. Total bilirubin > ULN AND albumin < LLN with the exception 
to subjects with Gilbert’s Syndrome. Subjects with Gilbert’s 
syndrome are excluded if Direct Bilirubin > ULN.  
5. Auto-immune hepatitis 
6. Primary sclerosing cholangitis 
7. Known history of alpha-1-Antitrypsin deficiency 
8. Known history of chronic viral hepatitis 
9. Creatine kinase above ULN 
10. Serum creatinine above ULN 
11. For females, pregnancy or breast-feeding 
12. Use of colchicine, methotrexate, azathioprine, or systemic 
steroids in the two months preceding screening 
13. Current use of fibrates or simvastatin  
14. Current use of obeticholic acid 
15. Use of an experimental or unapproved treatment for PBC 
16. Use of experimental or unapproved immunosuppressant 


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17. Adverse event leading to MBX-8025 discontinuation from 
CymaBay’s phase 2 PBC study (CB8025-21528) 
18. 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 
Procedures 
Initial 8-Week Treatment Period 
V1 Screening (Week -2): 
After signing an informed consent form (ICF), subjects will enter the 
screening period to confirm eligibility. A medical history will be taken, 
including PBC history, liver-related symptoms, detailed treatment 
history and a review of medications. A complete physical examination 
will be performed as well as a 12-lead Electrocardiogram (ECG). 
Liver-related symptoms will be evaluated. Vital signs will be collected. 
Height and weight will be collected for BMI calculation. A blood 
sample will be taken for hematology, biochemistry, and AMA. Women 
of child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. Subjects who will 
meet all inclusion criteria and do not meet any exclusion criteria will 
enter the study.  
Subjects in the 5 mg and 10 mg treatment groups will be randomized. 
Subjects in the 2 mg treatment group will be registered. 
Randomization/registration will occur ideally at least seven days prior 
to Visit 2 (Day 1). Subject-specific study drug supplies will be shipped 
to the site.  
V2 (Day 1) Baseline Visit: 
AEs since last visit will be evaluated. Medication history including 
medications since last visit will be reviewed. Vital signs and weight 
will be collected. A brief physical examination will be performed and 
liver-related symptoms will be evaluated. A blood sample will be taken 
for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols. A back-up serum sample will be collected. Women of 
child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. The subject will 
complete the 5D-itch scale, the pruritus VAS and the PBC-40 QoL. 
Subjects will be dispensed MBX-8025 to be taken orally once a day 
and immediately begin dosing. A 12-lead ECG will be performed 
approximately 60-90 minutes after dosing. 
Subjects participating in the PK analysis (selected centers):  
24-hour blood samples for PK and bile acids will be collected within 
30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after 
dosing. The subject will leave the site after the hour 6 blood draw and 
return to the site on the following day for the hour 24 blood draw. 


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For 24-hour urine collection, subjects will be instructed to empty their 
bladder before MBX-8025 administration. Urine will be collected over 
the following intervals: 0-6 hours and 6-24 hours.  
If a subject terminates study participation at any point after Day 1, an 
Early Termination visit will be completed. 
V3 (Week 1): 
TEAEs will be evaluated. Concomitant Medications history since last 
visit will be reviewed. Vital signs and weight will be collected. A brief 
physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, and bile acids/sterols. A back-
up serum sample will be collected. Spot urine sample will be collected 
for urinalysis. MBX-8025 will be administered. The subject will 
complete the 5D-itch scale and the pruritus VAS. A 12-lead ECG will 
be performed approximately 60- 90 minutes after dosing. Compliance 
to medication and drug accountability will be evaluated.  
V4 (Week 2): 
TEAEs will be evaluated. Concomitant Medications history since last 
visit will be reviewed. Vital signs and weight will be collected. A brief 
physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, bile acids/sterols, and PK 
trough level. A back-up serum sample will be collected. Spot urine 
sample will be collected for urinalysis. MBX-8025 will be 
administered. The subject will complete the 5D-itch scale and the 
pruritus VAS. A 12-lead ECG will be performed approximately 60-90 
minutes after dosing. Compliance to medication and drug 
accountability will be evaluated.  
V5 (Week 4): 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A brief physical examination 
will be performed and liver-related symptoms will be evaluated. A 
blood sample will be taken for hematology, biochemistry, exploratory 
biochemistry, and bile acids/sterols. Women of child-bearing potential 
will have a serum pregnancy test performed. A back-up serum sample 
will be collected. Spot urine sample will be collected for urinalysis. 
MBX-8025 will be administered. The subject will complete the 5D-
itch scale, the pruritus VAS, and the PBC-40 QoL. A 12-lead ECG will 
be performed approximately 60-90 minutes after dosing. Compliance 
to medication and drug accountability will be evaluated. MBX-8025 
will be dispensed. 
 


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V6 (Week 6): 
TEAEs will be evaluated. Concomitant Medications history since last 
visit will be reviewed. Vital signs and weight will be collected. A brief 
physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, and bile acids/sterols. A back-
up serum sample will be collected. Spot urine sample will be collected 
for urinalysis. MBX-8025 will be administered. The subject will 
complete the 5D-itch scale and the pruritus VAS. A 12-lead ECG will 
be performed approximately 60-90 minutes after dosing. Compliance 
to medication and drug accountability will be evaluated.  
V7 (Week 8) Completion of Initial Treatment/Initiation of Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A complete physical 
examination will be performed and liver-related symptoms will be 
evaluated. A blood sample will be taken for hematology, biochemistry, 
exploratory biochemistry, bile acids/sterols, and PK trough level. A 
back-up serum sample will be collected. Women of child-bearing 
potential will have a serum pregnancy test performed. Spot urine 
sample will be collected for urinalysis. MBX-8025 will be 
administered. The subject will complete the 5D-itch scale, the pruritus 
VAS, and the PBC-40 QoL. A 12-lead ECG will be performed 
approximately 60-90 minutes after dosing. Compliance to medication 
and drug accountability will be evaluated.  
At this visit, the subject will complete eight weeks of initial treatment 
with MBX-8025 and will be registered into the extension. Subjects will 
continue into the extension on their originally assigned dose unless 
otherwise specified. Subject’s safety and efficacy review will be 
performed by the Investigator in collaboration with Medical Monitor. 
Based on this individual subject review and the overall study safety 
and efficacy review, the dose might be up- or down-titrated for the 
extension part of the study. MBX-8025 will be dispensed. 
EXTENSION  
Post-Dose Adjustment Visit (for subjects with dose adjustment only) 
Subjects will return to the clinic in two weeks after dose adjustment 
occurs. If dose adjustment occurs approximately two weeks prior to the 
next scheduled visit, post-dose adjustment visit and the next planned 
visit can be combined. TEAEs will be evaluated. Concomitant 
medications will be reviewed. Vital signs and weight will be collected. 
A brief symptom-directed physical examination will be performed and 
liver-related symptoms will be evaluated. A blood sample will be taken 
for hematology, biochemistry, exploratory biochemistry, and bile 


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acids/sterols. A back-up serum sample will be collected. Spot urine 
sample will be collected for urinalysis. MBX-8025 will be 
administered. A 12-lead ECG will be performed approximately 60-90 
minutes after dosing. Compliance to medication and drug 
accountability will be evaluated. Additional assessments as determined 
by the Investigator. 
V8 (Week 12), Extension:  
TEAE since last visit will be evaluated. Medication history since last 
visit will be reviewed. Vital signs and weight will be collected. A brief 
symptom-directed physical examination will be performed and liver-
related symptoms will be evaluated. Blood sample will be taken for 
hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols. A back-up serum sample will be collected. Women of 
child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. MBX-8025 will be 
administered. The subject will complete the 5D-itch scale, the pruritus 
VAS and the PBC-40 QoL. A 12-lead ECG will be performed 
approximately 60-90 minutes after dosing. Compliance to medication 
and drug accountability will be evaluated. MBX-8025 will be 
dispensed. 
Subjects participating in the PK analysis (selected centers):  
24-hour blood samples for PK and bile acids will be collected within 
30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after 
dosing. The subject will leave the site after the hour 6 blood draw and 
return to the site on the following day for the hour 24 blood draw. 
For 24-hour urine collection, subjects will be instructed to empty their 
bladder before MBX-8025 administration. Urine will be collected over 
the following intervals: 0-6 hours and 6-24 hours. 
V9 (Week 16), Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A brief symptom directed 
physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, and bile acids/sterols. A back-
up serum sample will be collected. Women of child-bearing potential 
will have a serum pregnancy test performed. Spot urine sample will be 
collected for urinalysis. MBX-8025 will be administered. The subject 
will complete the 5D-itch scale, the pruritus VAS, and the PBC-40 
QoL. A 12-lead ECG will be performed approximately 60-90 minutes 
after dosing. Compliance to medication and drug accountability will be 
evaluated. MBX-8025 will be dispensed. 
 


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V10 (Week 20), Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A brief symptom directed 
physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, and bile acids/sterols. A back-
up serum sample will be collected. Women of child-bearing potential 
will have a serum pregnancy test performed. Spot urine sample will be 
collected for urinalysis. MBX-8025 will be administered. The subject 
will complete the 5D-itch scale, the pruritus VAS, and the PBC-40 
QoL. A 12-lead ECG will be performed approximately 60-90 minutes 
after dosing. Compliance to medication and drug accountability will be 
evaluated. MBX-8025 will be dispensed. 
V11 (Week 26), Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A complete physical 
examination will be performed and liver-related symptoms will be 
evaluated. A blood sample will be taken for hematology, biochemistry, 
exploratory biochemistry, and bile acids/sterols. A back-up serum 
sample will be collected. Women of child-bearing potential will have 
a serum pregnancy test performed. Spot urine sample will be collected 
for urinalysis. MBX-8025 will be administered. The subject will 
complete the 5D-itch scale, the pruritus VAS, and the PBC-40 QoL. A 
12-lead ECG will be performed approximately 60-90 minutes after 
dosing. Compliance to medication and drug accountability will be 
evaluated. MBX-8025 will be dispensed. 
V12 (Week 32), Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A brief symptom directed 
physical examination will be performed. A blood sample will be taken 
for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols. A back-up serum sample will be collected. Women of 
child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. MBX-8025 will be 
administered. The subject will complete the 5D-itch scale, the pruritus 
VAS, and the PBC-40 QoL. A 12-lead ECG will be performed 
approximately 60-90 minutes after dosing. Compliance to medication 
and drug accountability will be evaluated. MBX-8025 will be 
dispensed. 
V13 (Week 39), Extension: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A brief symptom directed 


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physical examination will be performed and liver-related symptoms 
will be evaluated. A blood sample will be taken for hematology, 
biochemistry, exploratory biochemistry, and bile acids/sterols. A back-
up serum sample will be collected. Women of child-bearing potential 
will have a serum pregnancy test performed. Spot urine sample will be 
collected for urinalysis. MBX-8025 will be administered. The subject 
will complete the 5D-itch scale, the pruritus VAS, and the PBC-40 
QoL. A 12-lead ECG will be performed approximately 60-90 minutes 
after dosing. Compliance to medication and drug accountability will be 
evaluated. MBX-8025 will be dispensed. 
V14 (Week 52), Completion of Extension/ End of Treatment: 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A complete physical 
examination will be performed and liver-related symptoms will be 
evaluated. A blood sample will be taken for hematology, biochemistry, 
exploratory biochemistry, and bile acids/sterols. A back-up serum 
sample will be collected. Women of child-bearing potential will have 
a serum pregnancy test performed. Spot urine sample will be collected 
for urinalysis. MBX-8025 will be administered. The subject will 
complete the 5D-itch scale, the pruritus VAS, and the PBC-40 QoL. A 
12-lead ECG will be performed approximately 60-90 minutes after 
dosing. Compliance to medication and drug accountability will be 
evaluated. MBX-8025 will be stopped and the subject will enter the 
four-week follow-up period. 
V15 (Week 56) Post-Treatment Follow-up/End of Study: 
Four weeks post-treatment, subjects will return to the clinic for a 
follow-up visit. This will be the subject’s last visit. 
TEAEs will be evaluated. Concomitant medications will be reviewed. 
Vital signs and weight will be collected. A complete physical 
examination will be performed, as well as a 12-lead ECG. Liver-related 
symptoms will be evaluated. A blood sample will be taken for 
hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols. A back-up serum sample will be collected. Women of 
child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. The subject will 
complete the 5D-itch scale, the pruritus VAS, and the PBC-40 QoL. 
Early Termination Visit 
TEAEs will be evaluated. Concomitant Medications will be reviewed. 
Vital signs and weight will be collected. A complete physical 
examination will be performed as well as a 12-lead ECG. Liver-related 
symptoms will be evaluated. A blood sample will be taken for 
hematology, biochemistry, exploratory biochemistry, and bile 


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acids/sterols. A back-up serum sample will be collected. Women of 
child-bearing potential will have a serum pregnancy test performed. 
Spot urine sample will be collected for urinalysis. The subject will 
complete the 5D-itch scale, the pruritus VAS, and the PBC-40 QoL. 
Compliance to medication and drug accountability will be evaluated.  
Unscheduled Visit (UNS) 
TEAEs will be evaluated. A brief symptom directed physical 
examination will be performed and liver-related symptoms will be 
evaluated. A blood sample will be taken for biochemistry, hematology. 
Spot urine sample will be collected for urinalysis. Compliance to 
medication and drug accountability will be evaluated. Additional 
assessments as determined by the Investigator. 
Concomitant Treatment UDCA will be continued approximately at the same dose during the 
study.  
During the extension, dose adjustment or interruption in UDCA is not 
recommended but acceptable. This must be documented. 
Subjects will be allowed to receive required medication to treat new or 
existing medical conditions. 
Prohibited Treatment 
Obeticholic acid 
Fibrates (e.g. fenofibrate, bezafibrate) 
Simvastatin 
Colchicine, methotrexate, azathioprine or long-term systemic steroids 
(>2 weeks)  
Dose adjustment for 
extension periods 
Unless otherwise specified, subjects will continue on their originally 
assigned dose. 
During the extension, the subject’s dose might be re-adjusted for safety 
or efficacy reasons. 
For individual subjects in the 2 mg, 5 mg and 10 mg treatment group, 
an ongoing safety and efficacy review will determine the dose to be 
used in the extension (1 mg, 2 mg, 5 mg, 10 mg, or 15 mg).  
Dose up-titration to 15 mg can be performed only within 26-week 
treatment period.  Beyond Week 26 (Visit 11), the highest dose will be 
10 mg. 
Safety 
Monitoring, 
Dose Adjustment, and 
Drug Interruption  
Liver Safety Monitoring 
 
I. Elevation of ALT/AST 
Normal ALT/AST at baseline  
• ALT/AST > 5 × ULN AND Total bilirubin is < 1.5 × ULN or 
< 2 mg/dL: interrupt MBX-8025. Repeat AST, ALT, total bilirubin, 
and INR within 3 days and closely follow the subject (see Appendix 


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B). Study medication can be restarted only if a firm competing 
etiology is identified and liver tests return to baseline. 
• ALT/AST > 5 × ULN AND Total bilirubin is ≥ 1.5 × ULN or ≥ 2 
mg/dL: stop MBX-8025. Repeat AST, ALT, total bilirubin, and INR 
within 3 days and closely follow the subject (see Appendix B). 
Elevated ALT/AST at baseline: 
• ALT/AST > 3 × baseline AND no liver-related symptoms (e.g., 
nausea, vomiting, right upper quadrant pain, loss of appetite, dark 
urine, or jaundice)/ INR < 1.5 × ULN: MBX-8025 can be 
continued. Repeat AST, ALT, total bilirubin, and INR within 3 
days. Closely follow the subject (see Appendix B) and discuss 
results with Medical Monitor to determine MBX-8025 intake. 
 
II. Symptoms of clinical hepatitis (e.g., nausea, vomiting, right upper 
quadrant pain, loss of appetite, dark urine, or jaundice) AND 
ALT/AST > 3 × baseline (irrespective of baseline levels): interrupt 
MBX-8025. Repeat AST, ALT, total bilirubin, and INR within 3 
days. Closely follow the subject (see Appendix B). Study 
medication can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline. 
 
III. Elevation of total bilirubin (> 2 × ULN or > 1.5 × baseline), 
regardless of ALT or AST levels, indicators of immunological 
reaction (e.g., rash, eosinophilia > 5%), or symptom of clinical 
hepatitis (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice): interrupt MBX-8025. Repeat 
AST, ALT, total bilirubin, and INR within 3 days and closely follow 
the subject (see Appendix B). Study medication can be restarted 
only if a firm competing etiology is identified and liver tests return 
to baseline. 
 
IV. Hepatic decompensation (eg., progression to cirrhosis, gastro-
esophageal variceal bleeding, ascites) during the trial: stop  
MBX-8025.   
V. Close monitoring of a subject is not possible: stop MBX-8025 (see 
Appendix B for more details). 
Muscle Safety Monitoring 
I. CK > 5 × ULN with musculoskeletal symptoms: stop MBX- 8025. 
Repeat the test within 3 days. Follow the subject weekly until 
resolution or stabilization.  
II. CK > 5 × ULN without musculoskeletal symptoms: repeat the test 
within 3 days. If on repeat test CK is > 2.5 × ULN, stop MBX-8025. 
Follow the subject weekly until the event resolution or stabilization.  
III. CK > 2.5 × ULN and ≤ 5 × ULN with musculoskeletal symptoms: 
interrupt MBX-8025. Repeat the test within 3 days. Follow the 


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subject weekly until the event resolution or stabilization. MBX-
8025 might be resumed at a decreased dose after event resolution.  
IV. CK > 2.5 × ULN and ≤ 5 × ULN without musculoskeletal 
symptoms: repeat the test within 3 days. If the test is confirmed, 
MBX-8025 will be continued at a decreased dose.  
Serum Creatinine Monitoring 
I. Serum Creatinine > 2.0 × ULN: stop MBX-8025. The subject should 
be monitored weekly until resolution or stabilization.  
II. Serum Creatinine > 1.5 × ULN and ≤ 2.0 × ULN: interrupt 
MBX- 8025. Repeat the test within 3 days. If the test is confirmed 
and no alternative etiology is identified, stop MBX-8025. If 
alternative etiology is identified, MBX-8025 may be restarted after 
serum creatinine returns to baseline values. The subject should be 
monitored weekly until event resolution or stabilization.  
Pancreatic Safety Monitoring 
I. Amylase > 3 × ULN and/or lipase > 3 × ULN without clinical 
symptoms of acute pancreatitis: repeat the test within 3 days. If the 
test confirms suspicion, interrupt MBX-8025. Abdominal imaging 
is to be performed to exclude an alternative cause for the event. 
MBX-8025 might be restarted only if a firm competing etiology of 
acute pancreatitis is identified. 
II. Amylase > 3 × ULN and/or lipase > 3 × ULN with clinical 
symptoms of acute pancreatitis: interrupt MBX-8025. Abdominal 
imaging is to be performed to exclude an alternative cause for the 
event and repeat amylase/lipase within 3 days. MBX-8025 might 
be restarted only if a firm competing etiology of acute pancreatitis 
is identified. 
Statistics 
Population: 
Safety: Any subject who receives at least one dose of medication 
Modified intent to treat (mITT): Any subject who receives at least one 
dose of medication and has at least one post baseline AP evaluation on 
treatment 
Per-protocol (PP): Any subject who receives at least one dose of 
medication, has at least one post baseline AP evaluation, and does not 
have a protocol violation that is deemed to impact the efficacy analysis 
Analysis: 
Safety analysis will be conducted on the safety population. Efficacy 
analysis will be conducted on the mITT population and the PP 
population. The mITT population will be used for the primary efficacy 
analysis.  


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Baseline will be defined as the mean between V1 and V2 (Week-2 and 
Day 1, baseline 1) for the primary analysis and composite endpoint, 
and as V2 (Day 1, baseline 2) values for other analyses. 
Descriptive statistics such as means, medians and measures of 
dispersion will be presented. 
The last observation carried forward (LOCF) approach will be used for 
missing laboratory data. 
The primary efficacy analysis will compare the mean percentage 
change from baseline to end of 8-week treatment in AP levels. This 
analysis will be conducted using an analysis of covariance (ANCOVA) 
model with treatment group as a factor and the baseline AP as a 
covariate.   
Other analyses will be secondary. 
Sample Size and Power: 
It is assumed that the 5 mg and 10 mg treatment groups will have at 
least 10% difference in the mean AP percent change with a 15 % 
standard deviation.  Based on this assumption, and on the use of two-
sided, two-sample t-test at the alpha =0.05 level of significance, a study 
sample size of 49 subjects per group will have a 90% power to detect 
a 10% mean difference between 5 mg and 10 mg treatment groups.  
There is no formal sample size justification for 2 mg treatment group. 
 




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1. Randomization will occur only for 5 mg and 10 mg treatment groups. Subjects in the 2 treatment group will be registered for the study. Randomization/registration will occur ideally at least 7 
days prior to Visit 2 (Baseline). Study drug kits will be shipped from the drug depot facility to the site on a subject-by-subject basis. 
2. Including PBC history 
3. Liver-related symptoms will be evaluated as part of physical exam. UNS visit might be scheduled, if needed per PI judgment.  
4. Symptoms-directed (brief) physical examination 
5. ECG will be performed approximately 60-90 minutes after dosing (Visit 2 through Visit 11) 
6. Blood will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject forgets to fast, the site will continue to draw labs 
7. If at Visit 1 (Screening) an unexpected abnormal CK level is observed, re-test the subject to confirm eligibility 
8. At Visit 1 (Screening) only AMA is to be performed 
9. The 24-hour blood sample (selected centers) will be collected at the following time points: within 30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hours after the dosing 
10. The 24-hour urine sample (selected centers) will be collected over the following intervals: 0-6 hours and 6-24 hours. 
11. Safety and efficacy data review will be performed after a subject completes the initial 8-week treatment period. The review will be done by the Investigator in collaboration with Medical Monitor. 
Based on this review, the dose might be up- or down-titrated for the extension period. 
12. Applicable only for subjects who had dose adjustment at any time during extension. The visit will occur in two weeks after initiation of the extension dose. If dose adjustment occurs approximately 
two weeks prior to the next scheduled visit, post-dose adjustment visit and the next planned visit can be combined. 
 


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4. 
INTRODUCTION  
4.1 
Primary Biliary Cholangitis (PBC) 
Primary Biliary Cholangitis (PBC, formerly known as Primary Biliary Cirrhosis) is a serious and 
potentially life threatening autoimmune disease of the liver characterized by impaired bile flow 
(cholestasis) and accumulation of toxic bile acids. The hallmarks of PBC is cholestasis with 
accompanying elevation in serum markers including AP, GGT and, depending on the severity of 
the disease, bilirubin and liver transaminases.  
Serologically, PBC is characterized by the presence of anti-mitochondrial antibodies, which are 
present in nearly all patients and are often detectable years before the appearance of clinical signs 
(Selmi et al., 2010). Histopathologically, PBC is characterized by portal inflammation and 
immune-mediated destruction of intrahepatic bile ducts. The loss of bile duct function leads to 
decreased bile secretion and the retention of toxic substances within the liver, resulting in further 
hepatic damage, fibrosis, cirrhosis and eventually, liver failure (Kaplan et al., 2005; Lindor et al., 
2007; Kumagi et al., 2008). It is a long-term debilitating disease whose progression is associated 
with an increased risk of hepatocellular carcinoma and liver related mortality (Kaplan et al., 2005; 
Lindor et al., 2007; Kumagi et al., 2008). 
Its peak incidence occurs in the fifth decade of life, and it is uncommon in persons under 25 years 
of age (Kaplan et al., 2005). The diagnosis of PBC in a patient often occurs at an early stage when 
following up on abnormal liver tests (especially elevated AP) that suggest the presence of 
cholestasis. Fifty to 60% of patients are asymptomatic at diagnosis (Kaplan, et al 2005). Fatigue 
and pruritus are the most common presenting symptoms (Kaplan et al., 2005). Fatigue has been 
noted in up to 78% of patients and can be a significant cause of disability (Kaplan et al., 2005). 
Pruritus, whose cause is uncertain, occurs in 20 to 70% of patients and can be extremely distressing 
(Rishe et al., 2008). Other common findings of PBC include jaundice, hyperlipidemia (notably 
hypercholesterolemia), hypothyroidism, osteopenia and osteoporosis and coexisting autoimmune 
diseases (Kaplan et al., 2005; Kumagi et al., 2008). Portal hypertension is a late complication of 
the disease, as is malabsorption, deficiencies of fat-soluble vitamins, and steatorrhea. Rarely, 
patients present with ascites, hepatic encephalopathy, or hemorrhage from esophageal varices 
(Kaplan et al., 2005). 
The long standing Food and Drug Administration (FDA)-approved treatment for PBC is UDCA, 
also known as ursodiol (Ursodiol Package Insert, 2005; Tsochatzis et al., 2009). UDCA acts as a 
choleretic agent and at a dose of 12 to 15 mg per kilogram of body weight per day, decreases serum 
levels of AP, GGT, bilirubin, ALT, AST, TC, and IgM, all of which are elevated in patients with 
PBC and can serve as biochemical markers of the disease (Heathcote et al., 1994; Kaplan, et al., 
2005). A recent systematic review, however, did not substantiate any significant benefit of Ursodiol 
on all-cause mortality, liver transplantation, pruritus, or fatigue in patients with PBC (Rudic, et al., 
2012). It is also known that up to 50% of PBC patients fail to respond to Ursodiol (Rudic, et al., 
2012). 


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In May of 2016, obeticholic acid (OCA, Ocaliva) was conditionally approved by the FDA as second 
line therapy for PBC patients with an inadequate response to UDCA (Ocaliva Prescribing 
Information). At 12 months, 48 and 46% of the patients on the 10 mg and 5 mg titrated to 10 mg 
groups, respectively (Ocaliva Prescribing Information) met the composite endpoint of biochemical 
response (AP < 1.67 x ULN plus a decrease of AP of at least 15% plus normal TB levels). A 
majority of patients treated with OCA continued to be above the biochemical response criterion of 
AP < 1.67 x ULN. OCA was associated with dose-dependent pruritus as an adverse event and was 
also associated with dose-dependent reductions in HDL (Ocaliva Prescribing Information).  
A number of studies have been conducted with fibrates (peroxisome proliferator-activated receptor 
(PPAR)- and dual PPAR/ agonists) documenting biochemical improvements in patients with 
PBC, sometimes in combination with UDCA. Fenofibrate (Ghonem et al., 2013) and bezafibrate 
(Ghonem et al., 2013; Honda et al., 2013, Lens et al., 2014, and Hosonuma et al.,2015) have limited 
data from randomized clinical trials and are not currently approved for treatment of PBC.  
Unapproved 
therapies, 
such 
as 
colchicine, 
methotrexate, 
prednisone 
and 
multiple 
immunosuppressive regimens have been attempted. However, their efficacy is controversial, 
limited, or unproven, and they are associated with multiple side-effects impacting tolerance and 
safety (Kumagi, et al., 2008). 
In summary, despite the previously mentioned therapeutic interventions and recent approval of 
OCA, it is evident that many PBC patients do not respond adequately to therapy and continues to 
have a progression of their disease (Kaplan, et al., 2005; Kumagi, et al., 2008, Momah, et al., 2014) 
and additional treatments are needed. 
4.2 
MBX-8025 
4.2.1 Overview 
MBX-8025 is a potent and selective PPAR agonist being developed for the treatment of PBC in 
subjects who are inadequate responders to UDCA or intolerant to UDCA and for the treatment of 
HoFH. 
4.2.2 Mechanism of Action 
MBX-8025 is a selective agonist of human PPARδ. PPARδ agonists have been shown to affect the 
transport, storage and metabolism of lipids (Barish, et al., 2006). The precise linkage between 
PPARδ agonism to improve cholestasis is not fully elucidated, a situation somewhat similar to the 
mechanism of action of bile acids and bile acid derivatives in PBC (Lindor et al., 2007).  The results 
from non-clinical studies with MBX-8025 as well as with other PPARδ agonists suggest that 
PPARδ agonism by MBX-8025 has the potential to decrease cholestasis (increases bile flow) while 
mitigating its consequences (inflammation, fibrosis and survival). For more detailed information, 
see the Investigator’s Brochure (IB). 
4.2.3 MBX-8025 in PBC 
CymaBay conducted a 12-week dose ranging (50 or 200 mg daily), placebo-controlled Phase 2 
study (NCT02609048) of MBX-8025 in subjects with PBC who had an inadequate response to 
UDCA (enrollment target of 75). The study was stopped early by the decision of the sponsor 




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proportion difference p <0.0001 and p = 0.0036 for the MBX-8025 200 mg and MBX-8025 50 mg 
groups, respectively, compared to placebo). Additional biochemical markers of cholestasis were 
also reduced by MBX-8025. Both MBX-8025 treatment groups showed significantly greater 
LSmean percentage reductions in GGT and total bilirubin levels at the end of treatment than did 
the placebo group. The MBX-8025 200 mg group had an LSmean reduction in GGT of 47.17% 
(SE 9.084) and the MBX-8025 50 mg group had an LSmean reduction of 42.60% (SE 7.796) 
compared with a mean reduction of 1.83% (SE 7.889) in the placebo group (LSmean difference 
40.78%, p = 0.0007 and LSmean difference 40.78%, p = 0.0008 for the MBX-8025 200 mg and 
MBX-8025 50 mg groups, respectively, compared to the placebo group). At the end of treatment, 
the MBX-8025 200 mg group had an LSmean increase in total bilirubin of 1.40% (SE 6.384), the 
MBX-8025 50 mg group had an LSmean reduction of 16.79% (SE 5.586), and the placebo group 
had an LSmean reduction of 4.79% (SE 5.793). The LSmean percentage change in total bilirubin 
in the MBX-8025 200 mg group was comparable to that in the placebo group. Although the 
LSmean percentage change in the MBX-8025 50 mg group was numerically greater than the 
placebo group, the between-group difference in total bilirubin did not achieve statistical 
significance (LSmean difference 12.00%, p = 0.1459). 
MBX-8025 also produced potentially beneficial metabolic and anti-inflammatory effects. Hs-CRP 
levels were reduced in response to MBX-8025 treatment. Median percentage changes at the end of 
treatment were an increase of 0.39% in the placebo group and decreases of 47.83%, and 4.26% in 
the MBX-08025 50 mg and MBX-8025 200 mg groups, respectively. Both MBX-8025 treatment 
groups showed greater LSmean percentage reductions in LDL-C levels at the end of treatment than 
did the placebo group. The MBX-8025 200 mg group had an LSmean reduction of 17.63% (SE 
4.372) and the MBX-8025 50 mg group had an LSmean reduction of 12.83% (SE 3.763) compared 
with a mean reduction of 2.78% (SE 3.958) in the placebo group.  
The two bile acid precursor oxysterols (7- hydroxycholesterol and C4), potential bile acid 
synthesis biomarkers, were decreased by MBX-8025 treatment. Median percentage changes from 
Baseline 2 in C4 at the last observation on treatment were an increase of 29.46% and decreases of 
54.85% and 77.02% in the placebo, MBX-8025 50 mg and MBX-8025 200 mg groups, 
respectively. Changes in the MBX-8025 50 mg group and the MBX-8025 200 mg group were 
substantially different from placebo. The C4 decreases in the MBX-8025 groups were associated 
with decreases in 7-α-hydroxycholesterol (median decreases of 54.26% and 43.04% in the 
MBX-8025 50 mg and 200 mg groups, respectively, at the last observation on treatment compared 
with a median increase of 11.89% in the placebo group).  
Three subjects developed a CTCAE grade 3 ALT and AST elevation (ALT and AST > 5.0-20.0 x 
ULN) and discontinued treatment. Of these subjects, two were receiving MBX-8025 200 mg (one 
case was considered drug related and the other possibly drug related) and one was receiving MBX-
8025 50 mg (considered possibly drug related). For these three subjects, the clinical picture was 
similar. The transaminase elevations were documented at the first active treatment planned protocol 
visit, after two weeks of treatment. The transaminase elevations were asymptomatic, not associated 
with an abnormal increase in bilirubin, and fully reversible upon treatment discontinuation. Of 
note, the transaminase elevations were associated with a decrease in biochemical markers of 
cholestasis (AP and GGT).  


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Although, the number of subjects enrolled in this study was small, there was no indication MBX-
8025 caused or worsen pruritus.  
MBX-8025 has also exhibited reductions in biochemical markers of cholestasis in prior clinical 
studies. MBX-8025 has been studied in a Phase 2 study in overweight subjects with mixed 
dyslipidemia. The study was a randomized, double-blind, placebo-controlled, parallel group proof-
of-concept study in 181 men and women (Bays, et al., 2011). Subjects were administered once 
daily placebo, atorvastatin (ATV) 20 mg, MBX-8025 at 50 or 100 mg alone or combined with ATV 
20 mg for eight weeks. MBX-8025 has also been studied in a Phase 2 study in patients with HoFH. 
This study had an open-label, single-arm, dose-escalating (50, 100, and 200 mg/day) design with 
3 consecutive 4-week treatment periods. In both studies, the AP decrease was rapid (onset within 
4 days), consistent, sustained, and reversible upon MBX-8025 discontinuation (within a week or 
two). AP did not decrease below the lower limit of normal and was associated with a concomitant 
decrease in GGT of similar amplitude. A transaminase signal was not previously observed in other 
populations that received multiple MBX-8025 at doses of up to 100 mg in subjects with mixed 
dyslipidemia and up to 200 mg in healthy volunteers and subjects with HoFH. 
In conclusion, MBX-8025 has demonstrated potent and rapid decreases in biochemical markers of 
cholestasis (AP, GGT, and total bilirubin), decreases in a marker of inflammation (hs-CRP) and 
decrease in LDL-C in PBC subjects who had an inadequate response to UDCA. The transaminase 
elevations signal appears to be dose-related with more elevation at 200 mg than at 50 mg. Because 
of the frequency, the timing of the transaminase elevations (within 2-4 weeks) and the absence of 
sign of hypersensitivity (clinical or biological) a toxic mechanism is favored rather than an 
idiosyncratic one. Recent data from a mass balance study in rodents indicate that MBX-8025 and 
its metabolites are largely cleared by the bile and consequently MBX-8025 and its metabolites 
might be accumulating within the liver tissues in subjects affected with a cholestatic syndrome 
(such as PBC subjects). No clear transaminase elevation signal was seen in subject not affected 
with a cholestatic syndrome (healthy volunteers, mixed dyslipidemia and HoFH) despite using the 
same doses of MBX-8025. It is hypothesized that MBX-8025 liver exposure is higher in subjects 
with PBC who have impaired bile excretion. This would have potentially resulted in toxic 
accumulation of MBX-8025 in hepatocytes or too rapid intra-cellular changes in bile acids. 
4.3 
NONCLINICAL INVESTIGATIONS WITH MBX-8025 
Please see the IB for details on the nonclinical studies conducted with MBX-8025. 
4.4 
HUMAN EXPERIENCE 
To date, MBX-8025 has been investigated in five Phase 1 clinical studies in healthy volunteers and 
in three Phase 2 studies. Phase 2 studies were conducted on dyslipidemic, overweight subjects 
treated with and without ATV; on subjects with HoFH, and on subjects with PBC and an inadequate 
response to UDCA.  
4.4.1 Phase 1 studies  
Five Phase 1 clinical studies have been conducted in healthy male subjects. The aims of these 
studies were to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of MBX-8025. 
A total of 117 healthy male subjects have been dosed with either MBX-8025, MBX-8025 in 


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combination with other agents, or placebo in the five completed clinical studies. One hundred and 
seven subjects received at least one dose of MBX-8025 (alone or in combination), and 27 subjects 
received at least one dose of placebo. MBX-8025 was administered as a solution in sterile water, 
or as a hard gelatin capsule. In the five Phase 1 clinical studies MBX-8025 was generally well 
tolerated. There were no deaths or serious adverse events (SAEs) recorded. All AEs were mild or 
moderate in severity. The type and incidence of AEs were generally similar across the various 
MBX-8025 and placebo dose groups. Please see the Investigator’s Brochure (IB) for more 
complete details on the Phase 1 studies conducted with MBX-8025. 
4.4.2 Phase 2 studies 
Study M8025-20711 was a multicenter randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, PK and efficacy of MBX-8025 in moderately obese hyperlipidemic 
subjects with or without concomitant ATV (Bays, et al., 2011; Choi, et al., 2012). This study 
evaluated 181 overweight men and women with mixed dyslipidemia. Subjects were administered 
once daily placebo, ATV 20 mg, or MBX-8025 at 50 or 100 mg alone or combined with ATV. The 
treatment duration was eight weeks. There were no significant gender differences in the PK 
parameters of MBX-8025 or its metabolites, M1, M2 and M3 PK (Tmax, Cmax and AUC(0-8h)). 
Compared to placebo, MBX-8025 alone and in combination with ATV significantly reduced Apo 
B-100 20-38%, LDL-C 18-43%, TG 26-30%, non-HDL-C 18-41%, FFA 16-28%, and hs-CRP 43-
72%. MBX-8025 raised HDL-C 1-12% and also reduced the number of subjects with a metabolic 
syndrome and a preponderance of small LDL particles.  MBX-8025 was safe and generally well-
tolerated. Three subjects experienced a total of 6 SAEs, none of which was deemed “related” to 
the study drug. The most frequently related AEs were increase in CK and headache. As previously 
noted, MBX-8025 also reduced transaminases, AP and GGT levels (Bays et al., 2011).  
Study CB8025-21427 was the pilot study of MBX-8025 in the treatment of HoFH. The study was 
a 12-week, open label, multicenter, non-controlled, monthly dose escalation study (MBX-8025: 
50, 100, and 200 mg; p.o. daily) in adults with genetically confirmed HoFH. A total of 13 subjects 
were enrolled, received treatment, and completed this study; 8 subjects were on concomitant LDL-
C apheresis group. All of the subjects were on stable lipid-lowering therapy and were receiving 
maximum dose of statins and ezetimibe. During the study, five subjects (42%), had a ≥ 20% LDL-
C decrease from baseline (including one LDL-R null mutation) of which three (25%) had a ≥ 30% 
LDL-C decrease. Five subjects had a decrease of <15%. Overall, the mean decrease in LDL-C was 
10% with no clear dose response. Mean PCSK9 was elevated at baseline (543.9 +/- 132.7 ng/mL) 
and increased during treatment (mean +43%). A total of 13 subjects were evaluated for safety; of 
these, 13 (100%) subjects were exposed to MBX-8025 50 mg; 13 were exposed to MBX-8025 100 
mg; and 10 (77%) subjects were exposed to MBX-8025 200 mg. The overall incidences of AEs 
were similar between study drug doses. There were 3 SAEs, none drug related, and three 
discontinuations for AEs possibly related to MBX-8025. The investigators considered the TEAEs 
leading to study drug discontinuation (angina pectoris, arthralgia, and musculoskeletal pain) to be 
mild or moderate in severity and the relationship to study drug possible. The most commonly 
reported TEAE was nasopharyngitis. In conclusion, MBX-8025 showed meaningful lipid lowering 
effect in a number of subjects and was generally well tolerated.  


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Study CB8025-21628 was a 12-week dose ranging (50 or 200 mg daily), placebo-controlled Phase 
2 study (NCT02609048) of MBX-8025 in subjects with PBC who had an inadequate response to 
UDCA. The study was conducted in North America, UK, Germany and Poland. The enrollment 
target was approximately 75 subjects (25 per treatment group). The study was stopped early by the 
decision of the sponsor because of a transaminase elevation signal and because the proof of concept 
that MBX-8025 was active in PBC subjects was demonstrated. At the time of study was stopped 
41 subjects had been randomized. Of these 41, ten had completed the study and 31 were at different 
time points in the study, mostly in the immediate post randomization period. Treatments with 
MBX-8025 at doses of 50 mg daily and 200 mg were associated with profound, rapid, and sustained 
decreases in biochemical markers of cholestasis (AP, GGT, 5’nucleotidase and total bilirubin) and 
marker of inflammation (hs-CRP). Three subjects developed a CTCAE grade 3 ALT and AST 
elevation (ALT and AST > 3.0-20.0 x ULN) and discontinued treatment. Two of these subjects 
were receiving MBX-8025 200 mg and one was receiving MBX-8025 50 mg. For these three 
subjects, the clinical picture was similar. The transaminase elevations were documented at the first 
active treatment planned protocol visit, after two weeks of treatment. The transaminase elevations 
were asymptomatic, not associated with an abnormal increase in bilirubin, and fully reversible upon 
treatment discontinuation. One subject discontinued treatment because of an adverse event of 
myopathy. The subject was taking MBX-8025 200 mg. The adverse event was reversible upon 
treatment discontinuation and was considered possibly related to treatment. One additional subject 
discontinued the study before starting blinded treatment because of upper gastro-intestinal bleeding 
associated with previously undiagnosed esophageal varices. One subject, who did develop grade 3 
transaminase elevations and was on MBX-8025 200 mg, had a concomitant increase in serum 
creatinine from 0.93 mg/dL at baseline (normal range 0.49-1.12 mg/dL) to 1.49 mg/dL. The serum 
creatinine returned to normal upon treatment discontinuation. The investigator considered this 
elevation as an adverse event of acute kidney injury that was possibly related to treatment. There 
was no serious adverse event during the treatment phase of the study or the two-week follow up 
period. For more details about this study, please refer to the IB.  
4.5 
RISK/BENEFIT ASSESSMENT   
The study being proposed is an 8-week, open-label, randomized, uncontrolled, Phase 2 study with 
a 44-week extension to evaluate the effects of MBX-8025 in PBC subjects who have inadequate 
response or intolerance to UDCA. 
4.5.1 Potential Benefits 
Patients selected for this study do not respond adequately to UDCA. A potential benefit is to 
demonstrate that the addition of MBX-8025 to UDCA will improve cholestasis-related biochemical 
markers as well as the PBC-associated inflammation.  
In previous PBC study, subjects receiving placebo showed no relevant change, while all subjects 
receiving MBX-8025 exhibited a pronounced decrease in AP, already evident over the first 2 
weeks. Subjects who received MBX-8025 beyond 2 weeks showed a consistent and continually 
progressive decrease. Additional biochemical markers of cholestasis such as GGT and 5’ 


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nucleotidase were also reduced by MBX-8025. MBX-8025 also produced potentially beneficial 
metabolic and anti-inflammatory effects. 
4.5.2 Potential Risks 
4.5.2.1 Non-clinical safety findings  
Please see the IB for more complete details on the nonclinical studies conducted with MBX-8025. 
4.5.2.2 Human safety 
Currently, MBX-8025 has been used for a maximum of 21 days in healthy volunteers at a 
maximum dose of 200 mg per day; in overweight subjects with mixed dyslipidemia, with and 
without atorvastatin, for a maximum of eight weeks and with a maximum dose of 100 mg per 
day; in subjects with HoFH, on concomitant ezetimibe and maximum statin therapy (+/- LDL-C 
apheresis), with dose escalation from 50 mg to a maximum of 200 mg per day; and in subjects 
with PBC on concomitant UDCA, for a maximum of 12 weeks and with a maximum dose of 
200 mg per day. 
MBX-8025 has been associated with increases in transaminases (AST and ALT), particularly in 
subjects with PBC. The increases were seen at 50 mg per day and 200 mg per day and appears to 
be dose dependent and population dependent. The increases were fully reversible upon treatment 
discontinuation. In rodents, MBX-8025 and its metabolites are almost exclusively cleared by the 
bile and consequently MBX-8025 and its metabolites might be accumulating within the liver 
tissues in subjects affected with a cholestatic syndrome (such as PBC subjects). No clear 
transaminase elevation signal was seen in subject not affected with a cholestatic syndrome 
(healthy volunteers, mixed dyslipidemia and HoFH) despite using the same doses of MBX-8025. 
MBX-8025 has been associated with a pre-clinical muscle toxicity signal. One PBC subject 
taking 200 mg per day discontinued drug for acute muscle pain associated with increased muscle 
enzymes. The adverse event was reversible upon treatment discontinuation and was considered 
possibly related to treatment. 
MBX-8025 has been associated with increase in serum creatinine. These increases are generally 
mild (in the 10% range) and serum creatinine shifts are within the normal range. Similar 
increases have been observed with drugs of the PPAR-α class or the mixed PPAR-α/δ class. In 
the short term, these increases in serum creatinine have not been associated with relevant 
decreases in measured glomerular filtration rate. In the long run, data from controlled clinical 
trials do not support that PPAR-α or mixed PPAR-α/δ are associated with a degradation of renal 
function. It is hypothesized that the increase in serum creatinine is of muscle origin (with an 
increase in creatine synthesis which is later metabolized into creatinine). However, caution must 
be exercised. One subject with HoFH and a chronic renal insufficiency, treated with MBX-8025 
100 mg and one subject with PBC treated with MBX-8025 200 mg had serum creatinine 
elevation above the normal range that were reversible upon treatment discontinuation and 
considered possibly related to MBX-8025. 


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4.5.3 Conclusions 
In conclusion, MBX-8025 demonstrated the potent and rapid decrease in biochemical markers of 
cholestasis (AP, GGT, and total bilirubin), decrease a marker of inflammation (hs-CRP) and 
decrease LDL-C in PBC subjects who had an inadequate response to UDCA. However, the clinical 
experience with MBX-8025 is still limited. Precautions should be exercised particularly towards 
transaminase elevations, potential muscle-related toxicities and potential increases in serum 
creatinine. 
4.6 
RATIONALE FOR DOSE SELECTION 
Available clinical data suggest that MBX-8025 at daily dose of up to 100 mg for up to eight weeks 
in obese males and females with mixed dyslipidemia (Bays, et al., 2011) and at daily dose of 
200 mg for up to three weeks in healthy volunteers are well tolerated and generally safe. In subjects 
with HoFH, with dose escalation from 50 mg daily to up to 200 mg daily, no consistent safety 
signal was elicited. However, few HoFH subjects were studied (N=13) and most of them were 
affected with multiple co-morbidities and were on multiple concomitant therapies (e.g. ezetimibe, 
maximum statin therapy, LDL-C apheresis, etc.) which makes the interpretation of safety data 
difficult.  
In subjects with PBC, who were inadequately responding to UDCA, treatments with MBX-8025 
at doses of 50 mg daily and 200 mg were associated with profound, rapid, and sustained decreases 
in biochemical markers of cholestasis (AP, GGT, 5’nucleotidase and total bilirubin) and marker of 
inflammation (hs-CRP). However, at these doses, MBX-8025 was associated with an increase in 
transaminases levels. As, in rodents, MBX-8025 is largely excreted through the bile, it is 
hypothesized that MBX-8025 exposure to liver tissues is higher in subjects with cholestasis than 
in subjects with normal biliary function. Indeed, no transaminase elevations signal has been seen 
in normal healthy volunteers, subjects with dyslipidemia or HoFH at doses up to 200 mg daily. 
Because of the timing of transaminase elevations (early on in exposure) and the absence of any 
clinical or biological signs of allergic reactions, it is hypothesized that the mechanism is a direct 
toxicity rather than an idiosyncratic reaction. Also, it appears that in PBC subjects more 
transaminases elevations were seen at 200 mg daily compared to 50 mg daily, supporting a dose 
response toxicity-based mechanism. Hence, lower doses of MBX-8025 should be tested in subjects 
with PBC who are inadequately responding, or intolerant to UDCA, to test whether the activity of 
MBX-8025 is retained without eliciting a transaminases elevation signal. 
Doses of 5 mg and 10 mg have been initially selected to be tested in subjects with PBC because 
they are 10- and 5-fold lower than the dose previously used doses while having the potential to 
retain pharmacodynamics activities. Dose of 2 mg daily will also be tested.  
 
 


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5. 
STUDY OBJECTIVES 
5.1 
PRIMARY OBJECTIVES 
The primary objective of this study is to evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, 
and 10 mg over 8 weeks of treatment. 
5.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
- To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 12 and 26 weeks 
of treatment 
 - To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 52 weeks of 
treatment 
- To evaluate the pharmacokinetics of MBX-8025 
5.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are to evaluate the effect of MBX-8025 on bile acids, 
additional markers of inflammation and renal function 
MBX-8025 doses of 1 mg and 15 mg may be evaluated if dose adjustment occurs.  
 
 


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6. 
STUDY POPULATION 
Approximately 116 subjects with PBC who have inadequate response or intolerance to UDCA will 
be recruited. 
6.1 
SELECTION CRITERIA  
6.1.1 Inclusion Criteria 
For inclusion into the study, subjects must fulfill all of the following criteria: 
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 by at least two of the following criteria: 
• History of AP above ULN for at least six months 
• Positive AMA (Anti-Mitochondrial Antibodies) titers (>1/40 on immunofluorescence or 
M2 positive by ELISA) or positive PBC-specific antinuclear antibodies 
• Documented liver biopsy result consistent with PBC 
4. On a stable and recommended dose of UDCA for the past twelve months or intolerant to UDCA 
5. AP ≥ 1.67 × ULN 
6. Females of reproductive potential must use at least one 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  
6.1.2 Exclusion Criteria 
1. A medical condition, other than PBC, that in the investigator’s opinion would preclude full 
participation in the study or confound its results (e.g., cancer on active treatment) 
2. AST or ALT > 3 × ULN 
3. Total bilirubin > 2.0 mg/dL 
4. Total bilirubin > ULN AND albumin < LLN with the exception to subjects with Gilbert’s 
Syndrome. Subjects with Gilbert’s syndrome are excluded if Direct Bilirubin > ULN. 
5. Auto-immune hepatitis 
6. Primary sclerosing cholangitis 
7. Known history of alpha-1-Antitrypsin deficiency 
8. Known history of chronic viral hepatitis 
9. Creatine kinase above ULN  
10. Serum creatinine above ULN 
11. For females, pregnancy or breast-feeding 
12. Use of colchicine, methotrexate, azathioprine or systemic steroids in the two months preceding 
screening 
13. Current use of fibrates or simvastatin  
14. Current use of obeticholic acid 


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15. Use of an experimental or unapproved treatment for PBC 
16. Use of experimental or unapproved immunosuppressant 
17. Adverse event leading to MBX-8025 discontinuation from CymaBay’s phase 2 PBC study 
(CB8025-21528) 
18. 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  
 


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7. 
STUDY DESIGN  
This will be an international, multicenter study in males and females with PBC who have 
inadequate response or intolerance to UDCA. 
The study will utilize an open-label, randomized, uncontrolled, 8-week dose ranging parallel 
groups (2 mg, 5 mg, and 10 mg) design with an open-label extension for a total of up to 52 weeks 
of treatment. 
After signing an ICF, subjects will enter a screening period (up to two weeks). Subjects in 5 mg 
and 10 mg treatment groups will enter the 8-week initial treatment period study in parallel. Subjects 
in the 2 mg groups will enter the 8-week initial treatment period in chronological order.  
Randomization will occur only for 5 mg and 10 mg treatment groups; subjects in the 2 mg treatment 
group will be registered for the study. Randomization/registration will occur ideally at least 7 days 
prior to first dose of MBX-8025 (study drug). A subject will be considered formally entered in the 
trial at randomization/registration. Study drug kits will be shipped from the drug deposit facility to 
the site on a subject-by-subject basis. Subject-specific study drug supplies (MBX-8025) will be 
taken orally once a day, for a period of eight weeks. To confirm study drug compliance, MBX-
8025 trough level will be measured after two and eight weeks of treatment. 
After completion of the 8-week initial treatment period, subjects will enter the open-label extension 
for a total of up to 52 weeks of treatment. Subjects will initially enter the extension on their assigned 
dose. Based on this individual subject review and the overall study safety and efficacy review, the 
dose might be up- or down-titrated for the extension part of the study. During the extension, the 
subject’s dose might be re-adjusted for safety or efficacy reasons. For individual subjects in the 2 
mg, 5 mg and 10 mg treatment groups, an ongoing safety and efficacy review will determine the 
dose to be used (1 mg, 2 mg, 5 mg, 10 mg, or 15 mg). Dose up-titration to 15 mg can be performed 
only within 26-week treatment period.  Beyond Week 26 (Visit 11), the highest dose will be 10 mg. 
Subject’s safety and efficacy review will be performed by the Investigator in collaboration with 
Medical Monitor. During the extension period, subject-specific study drug supplies (MBX-8025) 
will be taken orally once a day, for a total maximum duration of up to 52 weeks. 
After the end of treatment, subjects will enter a four-week follow-up period. 
At selected centers, subjects will participate in 24-hour PK testing. 24-hour PK testing will be 
performed at the time of initiation of study treatment and after twelve of treatment. Subjects 
participating in 24-hour PK testing will have PK blood and urine samples, and bile acids samples 
collected multiple times within 24 hours. 


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7.1 
TREATMENT AND ALLOCATION OF SUBJECTS 
Each new subject will receive a unique subject number assigned by IXRS (interactive voice/web 
response) system.  
Approximately 116 subjects will participate in the study:  
• 2 mg treatment group: up to 18 subjects 
• 5 mg treatment group: approximately 49 subjects 
• 10 mg treatment group: approximately 49 subjects 
PK (24-hour):  up to 30 subjects 
• 2 mg treatment group: up to six subjects 
• 5 mg, and 10mg treatment groups: up to twelve subjects per group 
7.2 
STUDY DURATION  
The screening period will be a maximum of two weeks (14 days) in duration (Week -2 to Day 1).  
The 8-week initial treatment period will be eight weeks (56 days) in duration (Day 1 to Week 8). 
The extension period will be 44 weeks (308 days). The follow-up period will be four weeks 
(28 days) in duration (Week 52 to Week 56). The follow-up period concludes the study. In total, 
the duration of study per subject will be 406 days (58 weeks). 
7.3 
STUDY OUTCOME MEASUREMENTS 
7.3.1 Primary measures 
• Serum AP levels 
• Adverse events (AE) and Treatment Emergent Adverse Events (TEAEs), ECG, 
biochemistry, hematology, and urinalysis (NCI CTCAE Version 4.0) 


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7.3.2 Secondary measures  
• Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma-glutamyl 
transferase (GGT), 5’nucleotidase, Bilirubin (Total, Conjugated, Unconjugated), 
Bone- specific AP, Triglycerides (TG), Total Cholesterol (TC), High Density Lipoprotein 
Cholesterol (HDL-C), and Low Density Lipoprotein Cholesterol (LDL-C) 
• Composite endpoint of AP and Total Bilirubin:  
✓ AP < 1.67 × upper limit of normal (ULN) and 
✓ Total Bilirubin within normal limit and 
✓ > 15% decrease in AP 
• Published PBC response criteria (Barcelona, Paris I and II, Toronto I and II), UK-PBC risk 
score 
• 5D-itch scale and pruritus Visual Analog Score (VAS) 
• PBC-40 QoL 
• PK of MBX-8025 and metabolites (at 0, 0.5, 1, 2, 4, 6 and 24 hours for Cmax, Tmax, T1/2 and 
AUC; trough level) 
7.3.3 Exploratory measures 
• Anti-Mitochondrial Antibodies (AMA), C-terminal telopeptide (CTX), cystatin C, IgM, 
fibrinogen, fibroblast growth factor 19 (FGF19), haptoglobin, high-sensitivity C-Reactive 
Protein (hs-CRP), homocysteine, microRNA-122, and N-terminal propeptide of type 1 
procollagen (P1NP);  
• Bile acids: Primary Bile Acids and Salts: Cholic acid (CA), chenodeoxycholic acid 
(CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid 
(GCDCA), taurochenodeoxycholic acid (TCDCA); Secondary Bile Acids and Salts: 
Deoxycholic acid (DCA), lithocholic acid (LCA), glycodeoxycholic acid (GDCA), 
glycolithocholic acid (GLCA), taurodeoxycholic acid (TDCA), taurolithocholic acid 
(TLCA); Other Bile Acids: ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid 
(GUDCA), tauroursodeoxycholic acid (TUDCA); 
• Sterols: 
desmosterol 
(DESM), 
lanosterol 
(LANO), 
lathosterol 
(LATH), 
7- dehydrocholesterol (7-DHC), cholestanol (CSTN), coprostanol (COPR), squalene 
(SQLN); β-sitosterol (β-SITO), campesterol (CAMP), stigmasterol (STIG) 7α-
hydroxycholesterol (7 α HC); 
• C4 (7α-hydroxy-4-cholesten-3-one); 
• 24-hour urinary excretion of MBX-8025 and metabolites 
 
 


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8. 
STUDY MEDICATIONS 
8.1 
CLINICAL SUPPLIES 
8.1.1 Investigational product, dosage and mode of administration 
MBX-8025 will be supplied as 1 mg, 5 mg, and 10 mg capsules. The study drug will be 
administered orally, once daily in doses of 2 mg, 5 mg, and 10 mg as described in the protocol. If 
dose adjustment occurs, the study drug might be administered at doses of 1 mg and 15 mg. 15 mg 
dose can be administered only within 26-week treatment period. Beyond Week 26 (Visit 11), the 
highest administered dose will be 10 mg.  
8.1.2 Packaging, Labeling and Shipping 
The Sponsor will provide the Investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. Following randomization, subject-specific study drug 
supplies will be shipped to the site. Study drug kits will be shipped from the drug depot facility to 
the site on a subject-by-subject basis. 
8.1.2.1 Dose Adjustment 
For the subjects who meet the criteria for dose adjustment (per Section 10.5), a new study drug kit 
will be shipped to the site.  
8.1.3 Accountability of Clinical Supplies  
The Investigator or a designee will keep a record of the dates and amounts of study medication 
received, the amount dispensed to study subjects, and the amount unused. 
8.1.4 Replacement Study Medication 
Additional replacement study medication will be available as required. All replacement shipments 
must be accounted for in the same manner as the initial medication supply. 
8.1.5 Stability of Study Medication 
All supplies of medication must be stored as defined on the primary packaging to ensure quality. 
8.2 
RANDOMIZATION 
Subjects on 5 mg and 10 mg treatment group will be centrally randomized in a 1:1 ratio to receive 
MBX-8025 5 mg or MBX-8025 10 mg. Subjects in 2 mg treatment group will be registered to the 
study.  
8.2.1. 
Randomization/Registration Procedure 
Once all laboratory evaluations are available and the subject has been confirmed to meet all of 
the inclusion and none of the exclusion criteria, the clinical site will centrally randomize/register 
an eligible subject via IXRS. The subject will then return to the clinic as soon as possible (ideally 
within seven days) to receive study drug supplies and begin dosing (the first day of dosing will be 
Day 1). 


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8.3 
METHOD OF ADMINISTRATION AND COMPLIANCE  
MBX-8025 will be dispensed on study Visit 2 (Day 1), Visit 5 (Week 4), Visit 7 (Week 8), Visit 8 
(Week 12), Visit 9 (Week 16), Visit 10 (Week 20), Visit 11 (Week 26), Visit 12 (Week 32) and 
Visit 13 (Week 39) to be taken orally once a day, according to the study schedule. 
Compliance to medication and drug accountability will be evaluated on all study visits during the 
treatment period, between Visit 3 (Week 1) and Visit 14 (Week 52).   
Compliance and accountability will also be performed at the Early Termination Visit. 
8.4 
CONCOMITANT MEDICATIONS AND PROCEDURES  
The use of concomitant medications or procedures (defined below), 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. 
8.4.1 Concomitant Medications  
A concomitant medication is any drug of substance other than MBX-8025, including over-the-
counter medications, herbal medications and vitamin supplements, administered during subjects’ 
participation in this trial.  
UDCA will be continued at approximately the same dose during the study. During the extension, 
dose adjustment or interruption in UDCA is not recommended but acceptable. This must be 
documented. 
All subjects will be instructed to remain on their current diet and lifestyle, including drinking 
habits, specifically alcoholic beverages, throughout the entire study. 
8.4.1.1 Allowed Concomitant Medication:  
Subjects will be allowed to receive required medication to treat new or existing medical conditions. 
8.4.1.2 Prohibited Concomitant Medication 
Use of obeticholic acid, fibrates (e.g. fenofibrate, bezafibrate), simvastatin, colchicine, 
methotrexate, azathioprine or long term systemic steroids (>2 weeks) will be prohibited during the 
study. 
8.4.2 Concomitant Procedures  
A concomitant procedure is any therapeutic intervention (e.g. surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g. blood gas measurement, bacterial cultures) performed during subjects’ 
participation in this trial. Subjects will be allowed to receive required procedures to treat new or 
existing medical conditions. 
 
 


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9. 
STUDY PROCEDURES  
9.1 
STUDY SCHEDULE 
The schedule of study procedures is presented in Table 1. 
The study for an individual subject consists of the following periods: 
• Screening (up to two-weeks):  Visit 1 to Visit 2 (Week -2 to Day 1) 
• Initial treatment (eight-weeks):  Visit 2 to Visit 7 (Day 1 to Week 8)  
• Extension (forty-four-weeks): Visit 7 to Visit 14 (Week 8 to Week 52) 
• Follow-up (four-weeks):  Visit 14 to Visit 15 (Week 52 to Week 56) 
Visits, which occur within +/- three days of the calculated date during the initial treatment period 
and within +/- seven days of the calculated date during the extension period will not be considered 
protocol violations. 
Additional visits may be scheduled to evaluate an abnormal laboratory value or reported AE. 
9.1.1 Screening:  Visit 1 to Visit 2 (Week -2 to Day 1) 
All subjects will review and sign the ICF prior to any screening procedures.  
Screening evaluations (Visit 1 or Week -2) will be performed within two weeks prior to entering 
the initial treatment period at baseline randomization (Visit 2 or Day 1).  
The evaluations will consist of: 
• Assessment of all inclusion and exclusion criteria 
• Review of medical history including PBC history and liver-related symptoms (e.g., nausea, 
vomiting, right upper quadrant pain, loss of appetite, dark urine, or jaundice) 
• Documentation of prior and concomitant medications (including supplements and vitamins) 
• Vital signs (as described in Section 9.2.2) This will include temperature, heart rate, 
respiration rate and blood pressure 
• Height and weight measurement 
• Complete physical examination (as described in Section 9.2.1)  
• This will include a full review of the following systems: general, skin, eyes, nose/sinuses, 
ears, mouth/throat, neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary, musculoskeletal, neurologic, mental health, endocrine and 
hematologic and evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper 
quadrant pain, loss of appetite, dark urine, or jaundice) 
• 12-lead ECG after at least 5 minutes rest 
• Blood drawn for hematology, biochemistry, and AMA (exploratory biochemistry) as 
outlined in Section 9.2.4 and Appendix A  
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis. 


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If unexpected abnormal CK level is observed at Screening (Visit 1), the subject can be re-tested to 
confirm his/her eligibility. 
Subjects who meet all inclusion criteria and do not meet any exclusion criteria will enter the study. 
Subjects in the 5 mg and 10 mg treatment groups will be randomized and subjects in the 2 mg 
treatment group will be registered into the study using IXRS system. Randomization/registration 
will occur ideally at least seven days prior to Visit 2 (Day 1). Subject-specific study drug supplies 
will be shipped to the site.  
Untoward event occurred any time after ICF is signed will be recorded as AE. Any laboratory 
abnormality deemed clinically significant 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 
• To continue UDCA at approximately the same dose 
• Not to use prohibited concomitant medications 
• Females of reproductive potential will be reminded to use at least one 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 to use a second effective 
birth control method during the study and for at least 90 days after the last dose 
9.1.2 Baseline:  Visit 2 (Day 1)  
Subjects who have been deemed eligible during the screening period will return for Visit 2 (Day 1) 
and the following evaluations will be performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of medication (including supplements and vitamins) since the last visit 
• Vital signs and weight (as described at Section 9.2.2)  
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols as outlined in Appendix A  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis  
• 5D-itch scale, Pruritus VAS, and PBC-40 QoL 
• MBX-8025 administration 
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 


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• The subjects will be dispensed four weeks’ worth of MBX-8025 to be taken once daily. 
Subjects participating in the PK analysis (selected centers) only: 
• 24-hour blood samples for PK and bile acids/sterols will be collected within 30 minutes 
prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after dosing. The subject will leave the site 
after the hour 6 blood draw and return to the site on the following day for the hour 24 blood 
draw. 
• For 24-hour urine collection, subjects will be instructed to empty their bladder before 
MBX- 8025 administration. Urine will be collected over the following intervals: 0-6 hours 
and 6-24 hours. 
If a subject terminates study participation at any point after Day 1, an Early Termination visit will 
be completed. 
9.1.3 Initial Treatment:  Visit 3 (Week 1) to Visit 7 (Week 8)  
Visit 3 (Week 1)  
At Visit 3 (Week 1) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols as outlined in Appendix A  
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 
• 5D-itch scale and pruritus VAS  
• MBX-8025 administration 
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
Visit 4 (Week 2) 
At Visit 4 (Week 2) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 


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• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• MBX-8025 trough level (only for non-PK subjects) 
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale and Pruritus VAS  
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
Visit 5 (Week 4) 
At Visit 5 (Week 4) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL  
• 12-lead ECG after at least 5 minutes rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
• Dispense of MBX-8025 (four weeks’ worth) to be taken once daily. 
Visit 6 (Week 6) 
At Visit 6 (Week 6) the following evaluations will be performed: 


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• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale and Pruritus VAS  
• 12-lead ECG after at least 5 minutes rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability. 
Visit 7 (Week 8), Completion of Initial Treatment/Initiation of Extension: 
At Visit 7 (Week 8) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described in Section 9.2.1)  
This will include a full review of the following systems: general, skin, eyes, nose/sinuses, 
ears, mouth/throat, neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary, musculoskeletal, neurologic, mental health, endocrine and 
hematologic and evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper 
quadrant pain, loss of appetite, dark urine, or jaundice). UNS visit might be scheduled if 
needed per PI judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• MBX-8025 trough level 
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed (performed  
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL  


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• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
• Dispense of MBX-8025 (four weeks’ worth) to be taken once daily. Subjects will continue 
into the extension on their originally assigned dose unless otherwise specified. 
• Subject’s safety and efficacy review. This review will be performed by the Investigator in 
collaboration with Medical Monitor. Based on this individual subject review and the overall 
study safety and efficacy review, the dose might be up- or down-titrated for the extension 
part of the study 
9.1.4 Extension:  Visit 8 (Week 12) to Visit 14 (Week 52)  
Post-Dose Adjustment Visit  
Subjects who had dose adjustment at any time during the extension will return to the clinic in two 
weeks after initiation of the extension dose. If dose adjustment occurs approximately two weeks 
prior to the next scheduled visit, post-dose adjustment visit and the next planned visit can be 
combined.  The following will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
• Additional assessments as determined by the Investigator. 
Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20), Visit 12 (Week 32) and Visit 13 (Week 
39) 
At Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20) and Visit 13 (Week 39) the following 
evaluations will be performed: 


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• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL  
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
• Dispense of MBX-8025 (four weeks’ worth for Visit 8 and Visit 9, six weeks’ worth for 
Visit 10, and thirteen weeks’ worth for Visit 12) to be taken once daily. 
At Week 8 (week 12) subjects participating in the PK analysis (selected centers) only: 
• 24-hour blood samples for PK blood and bile acids/sterols will be collected within 30 
minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after dosing. The subject will 
leave the site after the hour 6 blood draw and return to the site on the following day for the 
hour 24 blood draw. 
• For 24-hour urine collection, subjects will be instructed to empty their bladder before MBX-
8025 administration. Urine will be collected over the following intervals: 0-6 hours and 
6- 24 hours. 
Visit 11 (Week 26): 
At Visit 11 (Week 26) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement  
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  


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• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL 
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
• Dispense of MBX-8025 (thirteen weeks’ worth) to be taken once daily. 
Visit 14 (Week 52), Completion of Extension/End of Treatment (EOT): 
At Visit 14 (Week 52) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described in Section 9.2.1)  
• This will include a full review of the following systems: general, skin, eyes, nose/sinuses, 
ears, mouth/throat, neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary, musculoskeletal, neurologic, mental health, endocrine and 
hematologic and evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper 
quadrant pain, loss of appetite, dark urine, or jaundice). UNS visit might be scheduled if 
needed per PI judgement 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Spot urine sample will be collected for urinalysis 
• MBX-8025 administration 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL 
• 12-lead ECG after at least 5 minutes’ rest and approximately 60-90 minutes after dosing 
• Compliance to study medication and drug accountability 
MBX-8025 will be stopped and the subject will enter the four-week follow-up period. 
9.1.5 Follow-up Period: Visit 15 (Week 56) and Early Termination Visit  
Visit 15 (Week 56), Post-Treatment Follow-up/End of Study (EOS) 
The subject will return to the clinic for a follow-up visit in approximately four weeks after the last 
dose was taken. This will be the subject’s last visit. 


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At Visit 15 (Week 56) the following evaluations will be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described in Section 9.2.1)  
• This will include a full review of the following systems: general, skin, eyes, nose/sinuses, 
ears, mouth/throat, neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary, musculoskeletal, neurologic, mental health, endocrine and 
hematologic and evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper 
quadrant pain, loss of appetite, dark urine, or jaundice). UNS visit might be scheduled if 
needed per PI judgement 
• 12-lead ECG after at least 5 minutes rest 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols (as outlined in Appendix A)  
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 
• Women of child-bearing potential will have a serum pregnancy test performed 
• 5D-itch scale, Pruritus VAS, and the PBC-40 QoL 
Visit 15 (Week 56) concludes the follow-up period and defines the end of the study. Any clinically 
significant abnormalities should be followed up by the Investigator, until resolution, or stabilization 
of those abnormalities.  
Early Termination Visit  
Subjects who discontinue participation in the study prematurely should return for an Early 
Termination Visit and the following evaluations should be performed: 
• Documentation of TEAEs that occurred since the signing of the ICF  
• Review and documentation of concomitant medication (including supplements and 
vitamins) 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described at Section 9.2.1) and evaluation of liver-
related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, dark 
urine, or jaundice). UNS visit might be scheduled if needed per PI judgement 
• 12-lead ECG after at least 5 minutes rest 
• Blood drawn for hematology, biochemistry, exploratory biochemistry, and bile 
acids/sterols as outlined in Appendix A  
• Back-up blood sample will be collected 
• Spot urine sample will be collected for urinalysis 


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• 5D-itch scale, Pruritus VAS, and PBC-40 QoL 
• Compliance to study medication and drug accountability 
• Women of reproductive status will have the serum pregnancy test performed. 
Any clinically significant abnormalities should be followed up by the Investigator until resolution 
or stabilization of those abnormalities. 
Unscheduled Visit 
At Unscheduled Visit the following evaluations will be performed:  
• Documentation of TEAEs that occurred since the signing of the ICF 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) and 
evaluation of liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss 
of appetite, dark urine, or jaundice). UNS visit might be scheduled if needed per PI 
judgement 
• Blood drawn for biochemistry and hematology  
• Spot urine sample will be collected for urinalysis 
• Compliance to study medication and drug accountability 
• Additional assessments as determined by the Investigator  
9.2 
STUDY ASSESSMENTS 
9.2.1 Medical History and Physical Examination  
A detailed medical history (including PBC history and detailed treatment history) will be taken at 
screening (Visit 1 or Week -2).  
Complete physical examinations will be performed at screening (Visit 1 or Week -2), Visit 7 
(Week 8), Visit 11 (Week 26), Visit 14 (Week 52) and Visit 15 (Week 56), and ET visit (of 
applicable). These will include a full review of the following systems: general, skin, eyes, 
nose/sinuses, ears, mouth/throat, neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary, musculoskeletal, neurologic, mental health, endocrine and hematologic. 
Symptom-directed (brief) examinations will be performed at Visit 2 (Day 1) through Visit 6 (Week 
6) and from Visit 8 (Week 12) though Visit 10 (Week 20), Visit 12 (Week 32), Visit 13 (Week 39) 
and UNS. Brief physical exam will be performed for a condition that warrants the exam as 
determined by the PI. Subjects with platelet level above 500 × 103 µL on hematology panel will be 
evaluated for thrombolytic events.  
Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, dark 
urine, or jaundice) will be evaluated at each visit from Screening (Visit 1) till Week 15 (Week 56). 
UNS visit might be scheduled if needed per PI judgement. 
Any clinically significant change in physical examination findings that occur after signing the ICF 
at screening (Visit 1 or Week -2) will be recorded as an AE.  


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9.2.2 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 rest.  
Vital signs and weight will be assessed on all visits, i.e. Visit 1 (Week -2) through Visit 15 
(Week 56), and ET Visit (if applicable). Height measurement will be performed only on Visit 1 
(Week -2). 
Vital signs may be obtained more frequently if a condition develops that warrants additional 
monitoring. 
9.2.3 Electrocardiograms 
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest at Visit 1 
(Week - 2) through Visit 15 (Week 56), and ET Visit (if applicable). At Visit 2 (Day 1) through 
Visit 14 (Week 52) ECG will be performed approximately 60-90 minutes after dosing. 
9.2.4 Laboratory Tests  
Laboratory testing (as described below) will be carried out at Visit 1 (Week -2) through Visit 15 
(Week 56) or ET Visit.  
Blood samples will be collected after at least an 8-hour overnight fast and prior to dosing. If the 
subject forgets to fast, the site will continue to draw labs. 
Hematology will be assessed at all visits. 
Biochemistry will be assessed at all visits. Exploratory biochemistry will be assessed at Visit 1 
(Week -2) (AMA only), and Visit 2 (Day 1) through Visit 15 (Week 56), and ET Visit. 
Bile acids/sterols will be assessed from Visit 2 (Day 1) through Visit 15 (Week 56), and ET Visit 
(if applicable).  
Women of child-bearing potential will have a serum pregnancy test performed at Visit 1 
(Week - 2), Visit 2 (Day 1), Visit 5 (Week 4), and Visit 7 (Week 8) through Visit 15 
(Week 56)/EOS, and ET visit (if applicable).  
Urinalysis (spot) will be assessed at Visit 1 (Week -2), Visit 2 (Day 1) through Visit 15 (Week 56), 
and ET and UNS visits (if applicable). 
For subjects participating in 24-hour PK testing: 
Samples for bile acids/sterols will be collected at the same time points as 24-hour PK blood samples 
- within 30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after the dosing at Visit 2 
(Day 1) and Visit 8 (Week 12). 
Samples for the 24-hour urine collection will be collected over two intervals, 0 to 6 hours and 6 to 
24 hours at Visit 2 (Day 1) and Visit 8 (Week 12).  
Laboratory testing will be obtained as follows: 


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a) Biochemistry:  
AP, AST, ALT, GGT, 5’ nucleotidase, Protein, Albumin, Total Bilirubin, Conjugated Bilirubin, 
Unconjugated Bilirubin, Bone-specific AP, aldolase, Sodium, Potassium, Chloride, Bicarbonate, 
BUN/Urea, Creatinine, eGFR, CK (if above upper limit of normal, CK-MM, CK-MB, and CK-BB 
will be measured), venous blood glucose, LDH, TG, TC, HDL-C, and LDL-C, Troponin I, 
Aldolase, Lipase  
b) Hematology:  
Erythrocyte Count (RBC), Hemoglobin, Hematocrit, Leukocyte Count (WBC), WBC Differential 
(absolute and percentage), Platelets, PT/INR 
c) Exploratory biochemistry: 
AMA, CTX, Cyctacin C, IgM, Fibrinogen, Fibroblast growth factor 19 (FGF19), Haptoglobin, 
hs- CRP, homocysteine, P1NP 
d) Bile Acids and Sterols:  
- 
Bile Acids: CA, CDCA, GCA, TCA, GCDCA, TCDCA, DCA, LCA, GDCA, GLCA, 
TDCA, TLCA, UDCA, GUDCA, TUDCA 
- 
Sterols: DESM, LANO, LATH, 7-DHC, CSTN, COPR, SQLN; β-SITO, CAMP, STIG,  
- 
C4 (7α-hydroxy-4-cholesten-3-one) 
e) Back-Up Serum Sample:  
From Visit 2 (Day 1) through Visit 15 (Week 56) or ET visit (if applicable), one of the blood 
samples collected at each study visit will be archived as a back-up sample. These samples can be 
stored for up to two years following completion of the study and used to measure drug level, 
potential new biochemical markers, and/or to replace any missing or discarded samples.  
f) Urinalysis 
Spot sample will be analyzed via dip stick. Blood, Glucose, Ketones, Leukocyte Esterase, Nitrites, 
pH, and Protein will be measured. If positive, microscopic examination of sediments will be 
performed. Urine myoglobin will be measured if muscle injury is suspected.  
24-hour urine collection will be analyzed for urine creatinine and creatinine clearance will be 
calculated. Additional details about sample collection, processing, handling and laboratory 
determination techniques are provided in the Laboratory Manual. 
9.2.5 PK Samples for MBX-8025 level 
24-hour plasma and urine concentration determination of MBX-8025 and its metabolites (M1, M2 
and M3) will be performed on subjects participating in 24-hour PK testing. 24-hour blood samples 
will be collected at Visits 2 (Day 1) and Visit 8 (Week 12). Blood samples will be collected within 
30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hrs after dosing.  


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24-hour urine sample will be collected over two intervals 0-6 hours and 6-24 hours.  
PK trough level: Plasma concentration determination of MBX-8025 and its metabolites (M1, M2 
and M3) will be collected pre-dose at Visits 4 (Week 2) and Visit 7 (Week 8).  
Sample collection, processing and handling details are provided in the Laboratory Manual. 
9.2.6 5D-itch Scale 
The 5-D-itch scale will be used as a secondary measure for the multidimensional quantification of 
pruritus over time. The 5D-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 (Elman, et al., 2015). See Appendix D for details. 
The test will be performed at Visit 2 (Week 0) through Visit 15 (Week 56), and Early Termination 
Visit (if applicable). 
9.2.7 Pruritus Visual Analog Score (VAS)  
VAS will be used as a secondary measure to evaluate pruritus in subjects with PBC.   
The test will be performed at Visit 2 (Week 0) through Visit 15 (Week 56), and Early Termination 
Visit (if applicable). See Appendix E for details.  
9.2.8 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 quality of life tool 
developed to specifically measure the psychometric profile of PBC patients.  It covers six domains 
relevant to PBC including cognitive, social, emotional function, fatigue, itch, and other symptoms 
(Jacoby, et al., 2005). See Appendix F for details.  
It will be performed at Visit 2 (Day 1), Visit 5 (Week 4), and Visit 7 (Week 8) though Visit 15 
(Week 56), and ET Visit (if applicable). The questionnaire will be evaluated by the site personnel 
and the investigator will react to any evidence of deterioration. 
 
 


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10. 
ADVERSE EVENTS 
10.1 
GENERAL 
10.1.1 Definition of Adverse Events (AEs) 
An adverse event (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 study treatment, or 2) was 
present prior to 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 adverse event and should be 
reported to the clinical monitor and to the Sponsor immediately upon learning of the event. 
Pregnancies will be followed up through delivery or termination of the pregnancy. 
10.1.2 Definition of Serious AEs (SAEs) 
A serious adverse event (SAE) is any medical occurrence that: 
• Results in death 
• Is life-threatening (was at risk of death) at the time of the event  
• Requires in-patient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity defined as a substantial 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 upon 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 
10.1.3 AE Severity  
The severity of an AE will be graded from 1 to 5 according to the CTCAE version 4.0 criteria 
(v4.03, June 14, 2010) and appendix F. 
10.1.4 Relationship to Treatment  
The relationship or association of the AE to a study treatment will be characterized as “unrelated”, 
“unlikely/remote,” “possible,” or “related”. 


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• Unrelated: indicates that the AE can be explained by known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject or it does not follow a 
reasonable temporal sequence from administration of the study treatment 
• Unlikely/Remote: an event for which an alternative explanation is more likely (e.g. 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
study drug administration and/or exposure suggests that a causal relationship is unlikely 
• Possible: the event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and study drug administration 
• Related: there is clear evidence that the event is related to the use of the study treatment 
(e.g. confirmation by positive re-challenge test) 
10.1.5 Action Taken With Study Medication  
As a consequence of an AE, the action taken with the MBX-8025 can be: 
• None: no changes were made to MBX-8025 administration or dose 
• Permanently discontinued: MBX-8025 was stopped and not restarted 
• Temporarily interrupted, restarted at the same dose: dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose 
• Temporarily interrupted, restarted at a decreased dose: dosing was temporarily interrupted 
or delayed due to the AE and restarted at a decreased dose 
• Not applicable: e.g. in case the AE occurred after signing the ICF but before the 
administration of MBX-8025 was commenced 
• Specific subject withdrawal criteria and dose adjustments are mentioned in Section 10.5. 
10.2 
RECORDING, REPORTING AND FOLLOW-UP OF 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 CRF, regardless of association with the use of 
the study treatment. An AE will be recorded any time after the time of signed ICF and captured 
until the end-of-study Visit. To avoid colloquial expressions, the AE should be reported in standard 
medical terminology. Whenever possible, the AE should be evaluated and reported as a diagnosis 
rather than as individual signs or symptoms. If a definitive diagnosis is not possible, the individual 
signs and symptoms should be recorded.  
For each AE, the Investigator or an adequately qualified designee will evaluate and report the onset, 
duration, severity, seriousness, and relationship to (association with) the study treatment, and 
indicate the action taken. 
Abnormal laboratory findings will be determined by review of all laboratory data collected on the 
subjects. At each visit, the Investigator is responsible for assuring that the subject is questioned 
regarding all potential AE and intercurrent illnesses. 


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Any laboratory abnormalities deemed clinically significant by the Investigator should be reported 
as an AE. A clinically significant abnormality is a confirmed abnormality that is changed 
sufficiently from baseline, so that in the judgment of the Investigator, a change in management is 
warranted. This alteration may include: monitoring the laboratory test further, initiating other 
diagnostic tests or procedures, or administering treatment. Whenever possible, the etiology of the 
abnormal findings will be documented in the CRF. Repeated, additional tests and/or other 
evaluations required to establish the significance and etiology of an abnormal result should be 
obtained when clinically indicated. 
Any clinically significant laboratory abnormalities that are either unexplained or considered 
treatment-related should be promptly reported to the Sponsor. Any additional relevant laboratory 
results obtained by the Investigator during the course of this study will be supplied to the Sponsor 
and recorded in the CRF. 
If the event is a non-serious AE, then the event’s outcome is characterized by one of the following:  
• AE Persists: Subject terminates from the trial and the AE continues  
• Recovered: Subject recovered completely from the AE  
• Became Serious: The event became serious (the date that the event became serious should 
be recorded as the Resolution Date of that AE and the Onset Date of the corresponding 
SAE)  
• Change in Severity (if applicable): AE severity changed  
10.2.1 SAE Reporting Process 
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 Conference on Harmonization (ICH) guidelines E2A and ICH E6, and per the 
United States Code of Federal Regulations (CFR); 21 CFR § 312.32. Country specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Independent Ethics Committees 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 to the 
end-of-study evaluation, regardless of relationship to the study treatment, must be reported 
immediately (no later than 24 hours) by the Investigator to the Sponsor’s representative (Contract 
Research Organization (CRO)) 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 follows: 
• Hospitalization or prolongation of hospitalization 
• Life threatening 
• Death 
• Persistent or significant disability/incapacity  
• Congenital anomaly 


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• Other important medical event 
All criteria, which are applicable for same subject, should be entered. The outcome for the event 
will be listed on the SAE Report Form as follows: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown 
If additional information regarding a previously submitted SAE is obtained, a follow-up SAE must 
be sent to the Sponsor’s representative (CRO). 
The Sponsor and/or its designee will identify and report to regulatory authorities within the required 
timeframes, all serious and unexpected suspected adverse reactions (SUSARs) and clinically 
important increases in rate of serious suspected adverse reactions. 
SAEs must be collected and reported by the Investigator for the whole period from the signing of 
ICF until the end-of-study. If the event of death occurs after the end-of-study, the death will not 
have to be reported as a Serious Adverse Event.  
The Investigator will document all available information regarding the SAE on the SAE form. The 
Investigator should not wait to receive additional information to fully document the event before 
notifying the Sponsor’s representative of an SAE. The initial notification should include, as a 
minimum, sufficient information to permit identification of: 
• Subject’s study number  
• Time and date of MBX-8025 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, using the SAE form in CRF detailing relevant 
aspects of the adverse events in question. Where applicable, information from relevant hospital 
case records and autopsy reports should be obtained. All source information provided to the 
Sponsor must be appropriately anonymized. 
10.2.2 Follow-up of Reported AEs  
SAEs recorded during the study will be followed by the Investigator until resolution or 
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After EOS Visit (Visit 12), non-serious AEs should be followed up until they resolve or have failed 
to resolve, for a duration determined by the Investigator.  
Follow-up procedures will be determined by the nature of the event and the judgment of the 
Investigator. 
10.3 
DISTRIBUTION OF RESPONSIBILITIES 
Details about the distribution of safety responsibilities are presented in the Safety Reporting Plan. 
10.4 
SAFETY 
MONITORING 
CRITERIA, 
DOSE 
ADJUSTMENT, 
AND 
WITHDRAWAL CRITERIA,  
10.4.1 Safety Monitoring and Dose Adjustment 
Enrolled subjects with the following lab abnormalities should be monitored closely and may be 
discontinued from MBX-8025 or go through MBX-8025 dose adjustment if criteria are met: 
10.4.1.1. 
Liver Safety Monitoring 
I. 
Elevation of ALT/AST 
Normal ALT/AST at baseline  
• ALT/AST > 5× ULN AND Total bilirubin is < 1.5 × ULN or < 2 mg/dL: interrupt MBX-
8025. Repeat AST, ALT, total bilirubin, and INR within 3 days and closely follow the 
subject (see Appendix B). Study medication can be restarted only if a firm competing 
etiology is identified and liver tests return to baseline. 
• ALT/AST > 5 × ULN AND Total bilirubin is ≥ 1.5 × ULN or ≥ 2 mg/dL: stop MBX-8025. 
Repeat AST, ALT, total bilirubin, and INR within 3 days and closely follow the subject 
(see Appendix B). 
Elevated ALT/AST at baseline: 
• ALT/AST > 3 × baseline AND no liver-related symptoms (e.g., nausea, vomiting, right 
upper quadrant pain, loss of appetite, dark urine, or jaundice)/ INR < 1.5 × ULN: 
MBX- 8025 can be continued. Repeat AST, ALT, total bilirubin, and INR within 3 days. 
Closely follow the subject (see Appendix B) and discuss results with Medical Monitor to 
determine MBX-8025 intake. 
II. 
Symptoms of clinical hepatitis (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice) AND ALT/AST > 3 × baseline (irrespective of baseline 
levels): interrupt MBX-8025. Repeat AST, ALT, total bilirubin, and INR within 3 days. 
Closely follow the subject (see Appendix B). Study medication can be restarted only if a 
firm competing etiology is identified and liver tests return to baseline. 
III. 
Elevation of total bilirubin (> 2 × ULN or > 1.5 × baseline), regardless of ALT or AST 
levels, and indicators of immunological reaction (e.g., rash, eosinophilia > 5%), or 
symptom of clinical hepatitis (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice): interrupt MBX-8025. Repeat AST, ALT, total bilirubin, 
and INR within 3 days and closely follow the subject (see Appendix B). Study medication 


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can be restarted only if a firm competing etiology is identified and liver tests return to 
baseline. 
IV. 
Hepatic decompensation (eg., progression to cirrhosis, gastro-esophageal variceal bleeding, 
ascites) during the trial: stop MBX-8025.   
V. 
Close monitoring of a subject is not possible: stop MBX-8025 (see Appendix B for more 
details). 
10.4.1.2. Muscle Safety Monitoring 
I. 
CK > 5 × ULN with musculoskeletal symptoms: stopped MBX-8025. Repeat the test within 
3 days. Follow the subject weekly until resolution or stabilization.  
II. 
CK > 5 × ULN without musculoskeletal symptoms: repeat the test within 3 days. If on 
repeat test CK is > 2.5 × ULN, stop MBX-8025. Follow the subject weekly until the event 
resolution or stabilization.  
III. 
CK > 2.5 × ULN and ≤ 5 × ULN with musculoskeletal symptoms: interrupt MBX-8025. 
Repeat the test within 3 days. Follow the subject weekly until the event resolution or 
stabilization. MBX-8025 might be resumed at a decreased dose after event resolution.  
IV. 
CK > 2.5 × ULN and ≤ 5 × ULN without musculoskeletal symptoms: repeat the test within 
3 days. If the test is confirmed, MBX-8025 will be continued at a decreased dose.  
10.4.1.3. Serum Creatinine Monitoring 
I. 
Serum creatinine > 2.0 × ULN: stop MBX-8025. The subject should be monitored weekly 
until resolution or stabilization.  
II. 
Serum Creatinine > 1.5 × ULN and ≤ 2.0 × ULN: interrupt MBX-8025. Repeat the test 
within 72 hours. If the test is confirmed and no alternative etiology is identified, stop 
MBX- 8025. If alternative etiology is identified, MBX-8025 may be restarted after serum 
creatinine returns to baseline values. The subject should be monitored weekly until event 
resolution.  
10.4.1.4. Pancreatic Safety Monitoring 
I. 
Amylase > 3 × ULN and/or lipase > 3 × ULN without clinical symptoms of acute 
pancreatitis: repeat the test within 3 days. If the test confirms suspicion, interrupt 
MBX- 8025. Abdominal imaging is to be performed to exclude an alternative cause for the 
event. MBX-8025 might be restarted only if a firm competing etiology of acute pancreatitis 
is identified. 
II. 
Amylase > 3 × ULN and/or lipase > 3 × ULN with clinical symptoms of acute pancreatitis: 
interrupt MBX-8025. Abdominal imaging is to be performed to exclude an alternative cause 
for the event and repeat amylase/lipase within 3 days. MBX-8025 might be restarted only 
if a firm competing etiology of acute pancreatitis is identified. 
10.4.2. Dose adjustment for extension periods 
• Unless otherwise specified, subjects will continue into the extension on their originally 
assigned dose. 
• During the extension, the subject’s dose might be re-adjusted for safety or efficacy reasons. 


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• For individual subjects in the 2 mg, 5 mg, and 10 mg treatment groups, an ongoing safety 
and efficacy review will determine the dose to be used (1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 
or 20 mg). 
• Dose up-titration to 15 mg can be performed only within 26-week treatment period.   
Beyond Week 26 (Visit 11), the highest dose will be 10 mg.  
10.4.3 Additional Withdrawal Criteria and Replacement of Subjects 
Subjects must be discontinued from the study for the following reasons: 
• Entered the study in violation of this protocol 
• Required the use of a prohibited concomitant medication  
• 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  
• Significant protocol deviation  
• Administrative decision by the Investigator or Sponsor or designee  
• Lost to follow-up 
The date the subject is withdrawn and the reason for discontinuation will be recorded in the eCRF.  
Subjects will not be considered to have completed the study if, for any reason, they do not 
successfully complete the end-of-study Visit 12 (Week 30).  
If a subject withdraws from the study, he/she may be replaced.  
10.5 
DATA SAFETY AND MONITORING BOARD  
There is no DSMB in the study. It is an open label study. The Investigator, the subject and the 
Sponsor will know the study drug assessment. The Sponsor will be reviewing safety and efficacy 
data in the ongoing manner to determine if the individual subject dose needs to be adjusted.   
10.6 
PRECAUTIONS 
10.6.1 Pregnancy 
No specific studies have been performed to determine the reproductive and developmental toxicity 
of MBX-8025. As a precaution, women of child bearing potential receiving MBX-8025 must use 
one 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.   
Acceptable methods of birth control include consistent use of an approved oral contraceptive (birth 
control pill), an implantable contraceptive (such as Norplant), an injectable contraceptive (Depo-
Provera), a double-barrier method (diaphragm with spermicide, condom with spermicide), or 


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abstinence.  Oral, implantable, or injectable contraceptives are only considered effective if used 
properly and started at least 60-90 days prior to the screening visit.   
 
 
 


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11. 
STUDY TERMINATION 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study if it becomes aware of 
information concerning the quality, safety of the trial medication (based on recommendation from 
Medical Monitor), as well as other important information that may affect proper conduct of the 
trial. Should the study be discontinued by the Sponsor, then the Investigator, EC, and competent 
authorities should 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, due to specific clinical 
observations relating to safety concerns. If the Investigator intends to prematurely terminate the 
trial at his/her site, he/she must immediately inform the Sponsor on his/her intention as well as of 
the reasons why. 
 
 


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12. 
DATA MANAGEMENT AND STATISTICAL ANALYSES 
12.1 
DATA MANAGEMENT  
12.1.1 Processing of Electronic Case Report Forms  
Electronic CRFs will be completed for all study subjects enrolled in the study. At scheduled 
monitoring visits, eCRFs will be 100% verified against source documentation. Upon completion 
of this review, finalized eCRFs will be submitted to the Sponsor’s designated CRO. Any 
subsequent changes to the eCRFs will be performed in accordance with the CRO’s Standard 
Operating Procedures (SOP) for editing and clarifying CRFs. 
12.1.2 Database  
Data entry will be performed through username and password protected access to a secure database. 
All data will be entered using electronic Case Report Form (eCRFs). Internally developed programs 
for plausibility, consistency, and out-of-range data fields will supplement the review of the data. A 
100% manual review of AEs, drug accountability and termination summary data, will be performed 
by Data Management personnel. The MedDRA coding thesaurus will be used to classify AEs and 
Medical History, and the WHO Drug classification will be used to code medications. 
12.1.3 Data Discrepancies 
After all subjects complete the study and data discrepancies are resolved, protocol deviations 
during both enrollment and study execution will be reviewed. Significant protocol deviations and 
procedural discrepancies will be discussed. All data will be included in the safety analyses. 
12.2 
STATISTICAL ANALYSIS 
12.2.1 Sample Size Estimation  
It is assumed that the 5 mg and 10 mg treatment groups will have at least 10% difference in the 
mean AP percent change with a 15 % standard deviation.  Based on this assumption, and on the 
use of two-sided, two-sample t-test at the alpha =0.05 level of significance, a study sample size of 
49 subjects per group will have a 90% power to detect a 10% mean difference between 5 mg and 
10 mg treatment groups.  
There is no formal sample size justification for 2 mg treatment group.  
12.2.2 Study Population 
Approximately 116 subjects from 18 to 75 (inclusive) old will receive MBX-8025 according to the 
protocol.  
12.2.2.1 
Safety population  
The safety population is defined by any subject who receives at least one dose of medication.  
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 population. 


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12.2.2.2 
Modified intent to treat population (mITT)  
The mITT population is defined as any subject who receives at least one dose of medication and 
has at least one post baseline AP evaluation on treatment. The mITT population is the primary 
analysis population for all efficacy analyses. Subjects will be included in the treatment group to 
which they were assigned.  
12.2.2.3 
Per-protocol population (PP)  
The PP population is defined as any subject who receives at least one dose of medication, has at 
least one post baseline AP evaluation, and does not have a protocol violation that is deemed to 
impact the efficacy analysis. Supportive efficacy analyses will be completed using the PP 
population. 
12.2.3 Demographics and Baseline Characteristics  
Demographic 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. 
12.2.4 Efficacy Analysis 
12.2.4.1. Primary Efficacy Analysis  
Efficacy analysis will be conducted on the mITT population and the PP population.  The mITT 
population will be used for the primary efficacy analysis.  
Descriptive statistics such as means, medians and measures of dispersion will be presented. 
Baseline will be defined as the mean assessments between V1 and V2 (Week-2 and Day 1, baseline 
1) for the primary analysis and composite endpoint, and as V2 (Day 1, baseline 2) values for other 
analyses. 
The last observation carried forward (LOCF) approach will be used for missing laboratory data. 
The primary efficacy analysis will compare the mean percentage change from baseline to end of 8-
week treatment in AP levels. The primary efficacy analysis will compare the mean percentage 
change to end-of treatment with AP levels using an analysis of covariance (ANCOVA) model with 
treatment group as the factor and the baseline AP level as a covariate. Pairwise comparisons 
between the MBX-8025 2 mg, 5 mg, and 10 mg treatment groups will be tested. 
12.2.4.2. Secondary Efficacy Analysis 
The secondary efficacy analysis will compare the mean percentage change in AP levels from 
baseline to Week 12, from baseline to Week 26, and from baseline to the end of extension (52-
week treatment). An additional secondary analysis will use the absolute AP change from baseline 
to end of 8-week treatment, from baseline to end of 12-week treatment, from baseline to end of 26-
week treatment, and from baseline to end of extension (52-week treatment). These analyses will be 
completed using the same type of ANCOVA model as described for the primary analysis. Pairwise 
comparisons between the MBX-8025 2 mg, 5 mg, and 10 mg treatment groups will again be tested. 


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The secondary efficacy analysis will analyze the responder rate with a composite endpoint of AP 
and Total Bilirubin (AP < 1.67 × upper limit of normal (ULN), Total Bilirubin within normal limit, 
and at least 15% decrease in AP). 
Published PBC response criteria (Barcelona, Paris I and II; Toronto I and II), UK-PBC risk score, 
5D-itch scale, pruritus VAS, and PBC-40 QoL will be used as secondary measures to assess 
subject’s treatment response. In order to determine the biochemical response, parameters available 
from biochemistry (i.e. AP, AST, ALT, albumin, total bilirubin) and hematology (i.e. platelet 
count) will be used (Carbone, et al., 2015; Hirschfield, et al., 2014).  
Primary and secondary analyses will be carried out using two-sided tests at the alpha=0.05 level of 
significance.  
12.2.4.3. Exploratory Efficacy Analysis 
The exploratory efficacy analysis will be performed on bile acids, sterols, C4, and additional 
biochemistry measurements (AMA, CTX, cystatin C, IgM, fibrinogen, FGF19, haptoglobin, 
hs- CRP, homocysteine, microRNA-122, and P1NP). Descriptive summaries will be used for this 
analysis.  
Please see the Statistical Analysis Plan (SAP) for more details. 
12.2.5 Pharmacokinetic Analyses 
PK parameters for MBX-8025 and metabolites (M1, M2 and M3) will be summarized using 
descriptive statistics. Pharmacokinetic modeling may also be performed on the data generated from 
the study. Dose proportionality may be examined using graphical methods. 24-hour urinary 
excretion of MBX-8025 and metabolites will be analyzed. Other statistical analyses will be added 
in the SAP.  
12.2.6 Safety Analysis  
Safety analysis will be conducted on the safety population.  
The safety measures will be incidence rate of adverse events (AE) and Treatment Emergent 
Adverse Events (TEAEs), ECG, biochemistry, hematology, and urinalysis (NCI CTCAE Version 
4.0) 
Safety data will be summarized by dose level. Baseline values for laboratory tests, vital signs, and 
electrocardiograms will be defined as the last evaluation performed prior to administration of 
MBX-8025. 
12.2.6.1 
Adverse Events 
The subset of AEs occurred after the first dose of MBX-8025 will be considered to be TEAEs. The 
incidence of AEs and TEAEs will be tabulated. 


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12.2.6.2 
Vital Signs 
Descriptive statistics and mean or median change from baseline will be determined for vital signs 
(temperature, heart rate, respiratory rate, blood pressure) at each assessment time.  Vital signs 
collected at all study time points will be recorded in the eCRF and analyzed. 
12.2.6.3. 
Physical Examination 
Clinically significant abnormalities on physical examination will be recorded as AEs in the eCRF. 
12.2.6.3 
Laboratory Tests 
Descriptive statistics and mean or median change from baseline will be determined for each 
measure of laboratory tests, at each assessment time. Abnormal laboratory values will be graded 
by the investigator as: “clinically significant” or “not clinically significant”, where available, and 
all laboratory values will be reported. Clinically significant abnormal laboratory values will be 
reported as AEs, after study treatment has been initiated. Investigators may repeat laboratory tests 
for any parameter that is abnormal and/or clinically significant. 
The last observation carried forward (LOCF) will be used for missing laboratory data. 
12.2.6.5 
Electrocardiograms 
Clinically significant abnormalities on ECGs will be recorded as AEs in the eCRF. 
12.2.6.5 
Concomitant Medications 
Concomitant medications will be listed and summarized by WHOCC (World Health Organization 
Collaborating Centre for Drug Statistics Methodology), ATC (Anatomical Therapeutic Chemical) 
system class, generic term, and treatment group. 
12.2.7 Timing of the Analysis 
After the 24th subject in the 5 mg and 10 mg treatment groups was enrolled, a safety and efficacy 
data review was performed.   


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1 
STUDY MONITORING 
The Investigators and institution(s) will permit trial-related monitoring of the eCase Report Form 
data by CymaBay Therapeutics Inc. or their assignee by providing direct access to source data 
and/or documents. The study monitor will verify the CRFs 100% against the source documentation. 
Deviations from the protocol with regard to subject enrollment or study conduct will also be noted 
in the source documentation, in the eCRF and a complementary database. A Sponsor representative 
will visit the site to initiate the study, prior to the first treatment of the first subject, and at agreed 
upon times throughout the study, including at the end of the study. Medication dispensing and 
clinical drug supply records will be 100% verified at the study site by the study monitor. It is 
understood that all subject specific information is confidential and no documentation that can link 
study information to the specific subject will be collected or retained by the Sponsor. 
13.2 
AUDITS AND INSPECTIONS 
Regulatory authorities, the Ethics Committee (EC), and/or CymaBay Therapeutics Inc. or its 
designee(s) may request access to all source documents, electronic Case Report Form data, and 
other study documentation for on-site audit or inspection. Direct access to these documents must 
be guaranteed by the Investigator, who must provide support at all times for these activities. 
It is understood that all subject specific information is confidential and no documentation that can 
link study information to the specific subject will be collected or retained by the Sponsor. 
13.3 
ETHICS COMMITTEEs 
The Investigators will provide ECs with all information impacting the risk profile of the drug. The 
trial will not commence until written EC 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. 
 
 


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14. 
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 primary efficacy analyses and adverse events will be source 
documents verified by the monitors. Additionally, the Sponsor will conduct audit reviews of 
monitored eCRFs. 
A final audit of the electronic database against the final eCRF will be done. 
 
 


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15. 
ETHICS 
15.1 
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 EC prior to their use in the trial.  
The study will not start before written approval by EC(s) has been obtained and the local regulatory 
requirements have been complied with. 
The EC must meet all the appropriate ICH requirements for composition, documentation, and 
operational procedures.  
15.2 
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in strict accordance with the Declaration of Helsinki, ICH Good 
Clinical Practice (GCP) guidelines, applicable laws and regulations, and the procedures outlined in 
EC approved version of this protocol.  
15.3 
WRITTEN INFORMED CONSENT 
The subject must give consent to participate in the trial, only after having been fully informed by 
the Investigator or a person designated by him/her of the nature, significance, and implications of 
the trial, as well as to the associated risks involved. Such meetings must be carried out on an 
individual basis, and 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 or not to participate in the study. 
Written informed consent will be obtained for all subjects enrolled in the trial and before study 
related activities are performed on a subject. The process of obtaining written informed consent 
will be documented in the source documents of the subject. Only ICFs approved by the EC will be 
used. 
The ICF must be personally dated and signed by both the Investigator and the subject. The original 
will be retained by the Investigator and filed in the Investigator’s Site File. A copy of the original 
must be provided to the study subject. 
 
 


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16. 
RETENTION OF RECORDS 
All study related material, including source documents, eCRFs, competent authority, and EC 
correspondence and analyses, and any other documentation required by applicable laws and 
regulations will be maintained for fifteen (15) years after completion of the study, or notification 
from the Sponsor that the data can be destroyed, whichever comes first. 
 
 


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17. 
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 
EC 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. 
 
 


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18. 
DISCLOSURE OF INFORMATION 
Information concerning the investigational medication and patent application processes, scientific 
data or other pertinent information is confidential and remains the property of CymaBay 
Therapeutics, Inc. The Investigator may use this information for the purposes of the study only. It 
is understood by the Investigator that CymaBay Therapeutics, Inc. will use information developed 
in this clinical study in connection with the development of the investigational medication and, 
therefore, may disclose it as required to other clinical investigators and to regulatory agencies. In 
order to allow the use of the information derived from this clinical study, the Investigator 
understands that he/she has an obligation to provide complete test results and all data developed 
during this study to the Sponsor.  
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from CymaBay Therapeutics, Inc. CymaBay Therapeutics, Inc. 
agrees that, before it publishes any results of the study, it shall provide the Investigator with at least 
30 days for review of the pre-publication manuscript prior to the submission of the manuscript, to 
the publisher. 
 
 


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19. 
REFERENCES 
Bays HE, et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other 
metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin 
Endocrinol Metab. 2011; 96(9):2889-97. 
Barish, G.D., Narkar, V.A., Evans, R.M. (2006). "PPAR delta: a dagger in the heart of the 
metabolic syndrome." J Clin Invest. 116(3):590-7. 
Choi YJ, et al. Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia. 
Atherosclerosis. 2012; 220(2):470-6. 
Carbone N, et al. The UK-PBC Risk Score: derivation and validation of a risk score to predict the 
need for LT in patients with PBC.  2015. Manuscript in Preparation. 
Elman S, et al. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010; 162(3): 587–
593.   
Ghonem, N. S. and J. L. Boyer (2013). "Fibrates as adjuvant therapy for chronic cholestatic liver 
disease: its time has come." Hepatology 57(5): 1691-1693. 
Heathcote E, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of 
Ursodeoxycholic Acid in Primary Biliary Cirrhosis. Hepatology. 1994. 19(5): 1149-1156.   
Hirschfield GM, et al. Efficacy of Obeticholic Acid in Patients with Primary Biliary Cirrhosis and 
Inadequate Response to Ursodeoxycholic Acid. Gastroenterology. 2014. Manuscript submitted.  
Honda, A., et al. (2013). "Anticholestatic effects of bezafibrate in patients with primary biliary 
cirrhosis treated with ursodeoxycholic acid." Hepatology 57(5): 1931-1941. 
Hosonuma, K., et al. (2015). "A prospective randomized controlled study of long-term combination 
therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and 
dyslipidemia." Am J Gastroenterol 110(3): 423-431. 
Jacoby A, et al. Development, validation, and evaluation of the PBC-40, a disease specific health 
related quality of life measure for primary biliary cirrhosis. Gut. 2005; 54: 1622-1629. 
Kaplan MM, et al. Primary Biliary Cirrhosis. N Engl J Med. 2005; 353(12): 1261-1273.  
Kumagi, T et al. Primary biliary cirrhosis. Orphanet Journal of Rare Diseases. 2008; 3: 1-17. 
Lens, S., et al. (2014). "Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis 
patients with incomplete response to ursodeoxycholic acid." Liver Int 34(2): 197-203. 
Lindor K. Ursodeoxycholic Acid for the Treatment of Primary Biliary Cirrhosis, N Engl J Med. 
2007; 357(15): 1524-1529.  
Lammers WJ, et al. Levels of Alkaline Phosphatase and Bilirubin Are Surrogate End Points of 
Outcomes of Patients With Primary Biliary Cirrhosis: An International Follow-up Study. 
Gastroenterology. 2014. 147:1338–1349. 


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Momah N, et al. Primary biliary cirrhosis in adults.  Expert 2014. Expert Rev Gastroenterol 
Hepatol.Expert Rev Gastroenterol Hepatol. 2014; 8(4):427-433. 
Neuberger J. Liver transplantation for primary biliary cirrhosis: indications and risk of recurrence. 
J Hepatology. 2003; 39: 142–148 
Ocaliva Prescribing Information, Intercept Pharmaceuticals 2016 
Poupon R. Ursodeoxycholic acid and bile- acid mimetics as therapeutic agents for cholestatic liver 
diseases: An overview of their mechanisms of action. Clinics and Research in Hepatology and 
Gastroenterology. 2012; 36:  S3—S12 
Rishe E, et al. Itch in Primary Biliary Cirrhosis: A Patients’ Perspective. Acta Derm Venereol. 
2008; 88: 34–37.  
Rudic JS, et al. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev. 
2012; 12: CD000551. 
Selmi C, et al. Immune-mediated bile duct injury: The case of primary biliary cirrhosis. World J 
Gastrointest Pathophysiol. 2010; 1(4): 118-128 
Tsochatzis EA, et al.  Ursodeoxycholic acid and primary biliary cirrhosis: EASL and AASLD 
guidelines. J Hepatol. 2009; 51:1084-1085. 
Ursodiol oral suspension.  US Package Insert, 2005. 
 


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APPENDIX A – LABORATORY EVALUATIONS 
Biochemistry 
 
 
AP 
AST 
ALT 
GGT 
5’ nucleotidase 
Protein 
Albumin 
Total Bilirubin 
Conjugated Bilirubin 
Troponin I 
Unconjugated Bilirubin 
Bone-specific AP 
Aldolase 
Sodium 
Potassium 
Chloride 
Bicarbonate 
BUN/Urea 
Serum Creatinine  
eGFR  
CK 
(if 
ULN, 
CK-MM,   
CK-MB, and CK-BB) 
Venous Glucose 
LDH 
TG 
Total Cholesterol 
HDL-C 
LDL-C 
Amylase 
Lipase 
Hematology 
Exploratory 
Biochemistry 
Urinalysis 
Other Tests 
RBC 
Hemoglobin 
Hematocrit 
WBC 
WBC differentials (abs 
and %) 
Platelets 
PT/INR  
 
AMA 
CTX 
Cystatin C 
IgM 
Fibrinogen 
FGF19 
Haptoglobin  
hs-CRP 
Homocysteine  
P1NP 
microRNA-122 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
pH  
Protein 
Microscopic examination of 
sediments (if positive) 
Urine Myoglobin (if muscle 
injury is suspected) 
Serum Pregnancy Test  
24 hour PK Blood Samples 
24-hour PK Urine Samples 
PK trough level  
24-hour Urine Creatinine 
Creatinine Clearance 
Back-up Sample 
Bile Acids and Sterols 
 
Bile Acids: CA, CDCA, GCA, TCA, GCDCA, TCDCA DCA, LCA, GDCA, GLCA, TDCA, TLCA UDCA, GUDCA, 
TUDCA TC 
Sterols: DESM, LANO, LATH, 7-DHC, CSTN, COPR, SQLN β-SITO, CAMP, STIG 7 α HC C4 
 
 
 


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APPENDIX B – CLOSE OBSERVATION CRITERIA 
The “close observation” will be performed on subjects meeting liver safety monitoring criteria per 
Section 10.4.1.1. If “close observation” is not feasible, MBX-8025 must be stopped. 
1. Comprehensive Medical History and Health Status Review
a.
Provide detailed history of current liver-related symptoms (eg., right upper quadrant
pain or tenderness, nausea, vomiting, fatigue, loss of appetite, dark urine, or
jaundice)
b. Provide all current diagnoses, diseases, procedures, and symptoms
c.
Provide comprehensive medical history including prior diagnoses, procedures and
symptoms
d. Provide concomitant drug use, including: prescription medications, nonprescription
medications, herbal supplements, dietary supplements, alcohol use, recreational
drug use, special diets and exposure to environmental chemical agents
e.
Provide comprehensive medication and drug use history, including: nonprescription
medications, herbal supplements, dietary supplements, alcohol use, recreational
drug use, special diets and exposure to environmental chemical agents
2. Laboratory Testing
a.
Repeat ALT, AST, Bilirubin (total), and INR within 3 days
b. Monitor the subject every 3 days until the lab abnormality stabilization
c.
After lab abnormality is stabilized, monitor the subject once a week until the event
resolution
3. Rule out the following diagnoses:
a.
Acute viral hepatitis types A, B, C, D and E
b. Autoimmune or alcoholic hepatitis
c.
NASH
d. Hypoxic/ischemic hepatopathy
e.
Biliary Tract Disease besides PBC


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APPENDIX C – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) 
 
The NCI CTCAE will be used to assess an AE severity.  
The NCI CTCAE will be provided as a separate document with the study protocol.  
The NCI CTCAE may also be accessed here:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 












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APPENDIX G – INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
 
CB8025-21629 
An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to 
evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) 
and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA) 
 
PROTOCOL VERSION NUMBER:  Version 4.2 
DATE OF PROTOCOL: 
 
20-JUL-2017 
 
 
SPONSOR:  CymaBay Therapeutics, Inc. 
7999 Gateway Blvd, Suite 130 
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 (DD/MMM/YYYY):   
Site Address: 
  
 
  
 
  
 
 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
Unique Protocol ID: CB8025-21629 
Official Title: An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week 
extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary 
Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA) 
 
NCT number: NCT02955602 
 
Version Number: Version 4.1 
 
Date Of SAP: 26-Nov-2019 




 
 
Sponsor: CymaBay Therapeutics, Inc. 
Statistical Analysis Plan 
Protocol no: CB8025-21629 
26 November, 2019 Final Version 2.2 
 
Page 2 of 35 
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved. 
Table of Contents 
 
Approvals .................................................................................................................................................................................... 1 
Table of Contents ..................................................................................................................................................................... 2 
1.0 Introduction ....................................................................................................................................................................... 4 
2.0 Study Objectives ............................................................................................................................................................... 4 
2.1 Primary Objective ....................................................................................................................................................... 4 
2.2 Secondary Objectives ................................................................................................................................................. 4 
2.3 Exploratory Objective ................................................................................................................................................ 4 
3.0 Study Design ....................................................................................................................................................................... 4 
3.1 Sample Size Considerations .................................................................................................................................... 8 
3.2 Randomization ............................................................................................................................................................. 8 
4.0 Study Variables and Covariates .................................................................................................................................. 8 
4.1 Efficacy ............................................................................................................................................................................. 8 
4.1.1 Primary Variable ................................................................................................................................................. 8 
4.1.2 Secondary Variables .......................................................................................................................................... 8 
4.1.3 Exploratory Variables ....................................................................................................................................... 9 
4.2 Pharmacokinetics (PK) ............................................................................................................................................. 9 
4.2.1 General Methods ................................................................................................................................................. 9 
4.2.2 Bioanalysis ............................................................................................................................................................. 9 
4.2.3 Handling of Missing Data for PK Analyses ................................................................................................ 9 
4.2.4 Plasma Concentrations ................................................................................................................................... 10 
4.2.5 Pharmacokinetic Data Analysis Methods................................................................................................ 10 
4.3 Safety .............................................................................................................................................................................. 12 
4.3.1 Primary Variables ............................................................................................................................................. 12 
4.3.2 Secondary Variables ........................................................................................................................................ 12 
4.4 Predetermined Covariates and Prognostic Factors .................................................................................... 12 
5.0 Definitions ......................................................................................................................................................................... 12 
5.1 General ........................................................................................................................................................................... 12 
5.2 Efficacy ........................................................................................................................................................................... 15 
5.3 Safety .............................................................................................................................................................................. 17 
6.0 Analysis Sets ..................................................................................................................................................................... 17 
6.1 Safety Population ...................................................................................................................................................... 17 
6.2 Intention-to-Treat Population (ITT) ................................................................................................................. 17 
6.3 Modified intention-to-Treat Population (ITT) .............................................................................................. 17 
6.4 Per Protocol Population (PP) ............................................................................................................................... 17 
6.5 Pharmacokinetic Population (PK) ...................................................................................................................... 17 
7.0 Interim and Final Analyses ........................................................................................................................................ 17 
7.1 Interim Analyses ........................................................................................................................................................ 18 
7.1.1 24 Subjects at 8 Weeks ................................................................................................................................... 18 
7.1.2 24 Subjects at 12 Weeks ................................................................................................................................ 18 
7.1.3 45 Subjects at 26 Weeks ................................................................................................................................ 18 
7.1.4 Subjects at 52 Weeks ....................................................................................................................................... 18 
8.0 Data Review ...................................................................................................................................................................... 18 
8.1 Data Handling and Transfer .................................................................................................................................. 18 
8.2 Data Screening ............................................................................................................................................................ 18 
9.0 Statistical Methods ........................................................................................................................................................ 18 
9.1 Subject Disposition ................................................................................................................................................... 19 
9.2 Protocol Deviations .................................................................................................................................................. 19 


 
 
Sponsor: CymaBay Therapeutics, Inc. 
Statistical Analysis Plan 
Protocol no: CB8025-21629 
26 November, 2019 Final Version 2.2 
 
Page 3 of 35 
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved. 
9.3 Treatments ................................................................................................................................................................... 19 
9.3.1 Extent of Study Drug Exposure ................................................................................................................... 19 
9.3.2 Prior and Concomitant Medications/Procedures ............................................................................... 20 
9.4 Demographic and Baseline Characteristics .................................................................................................... 20 
9.5 Efficacy Analyses ....................................................................................................................................................... 20 
9.5.1 Primary Variable ............................................................................................................................................... 20 
9.5.2 Methods for Handling Dropouts and Missing Data ............................................................................. 22 
9.5.3 Multiplicity........................................................................................................................................................... 23 
9.5.4 Pooling of Sites ................................................................................................................................................... 23 
9.5.5 Secondary Variables ........................................................................................................................................ 23 
9.6 Safety Analyses ........................................................................................................................................................... 25 
9.6.1 Adverse Events .................................................................................................................................................. 25 
9.6.2 Deaths and Serious Adverse Events .......................................................................................................... 26 
9.6.3 Laboratory Data................................................................................................................................................. 26 
9.6.4 Vital Signs ............................................................................................................................................................. 27 
9.6.5 Physical Examinations and Electrocardiogram (ECGs) .................................................................... 27 
9.7 Exploratory Analyses ............................................................................................................................................... 28 
9.8 Subgroup Analyses ................................................................................................................................................... 28 
10.0 Planned Differences from Protocol ...................................................................................................................... 28 
10.1 Timing of Interim Analyses ................................................................................................................................ 28 
10.2 Clinical Laboratory Analysis Baseline ............................................................................................................ 28 
10.3 Study Completer ...................................................................................................................................................... 28 
10.4 Analysis Treatment Group .................................................................................................................................. 28 
10.5 Study Populations ................................................................................................................................................... 28 
11.0 Validation ........................................................................................................................................................................ 28 
12.0 References ...................................................................................................................................................................... 29 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 30 
Appendix 2 List of Inferential Analysis Supportive SAS Output Appendices ............................................... 33 
Appendix 3 Document History ......................................................................................................................................... 34 
 


 
 
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Statistical Analysis Plan 
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1.0 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under CymaBay Therapeutics, Inc. Protocol CB8025-21629, titled “An 8-week, 
dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and 
efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or 
intolerance to ursodeoxycholic acid (UDCA)”. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using protocol versions 4.0 (United Kingdom version), 4.1 (German version), 
4.2 (United States version), and 4.3 (Canadian version) dated 20 July 2017 and CRF version 4.1 dated 19 
Dec 2017. Any further changes to the protocols or CRF may necessitate updates to the SAP. Changes 
following the approval of the SAP will be tracked in the SAP Change Log and a final version of the SAP will 
be issued for sponsor approval prior to database lock. 
2.0 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 
10 mg over 8 weeks of treatment. 
2.2 Secondary Objectives 
The secondary objectives for this study are: 
• 
To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 12 and 26 weeks 
of treatment 
• 
To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 52 weeks of 
treatment 
• 
To evaluate the pharmacokinetics of MBX-8025 
2.3 Exploratory Objective 
The exploratory objectives of this study are to evaluate the effect of MBX-8025 on bile acids, additional 
markers of inflammation and renal function. 
3.0 Study Design 
This will be an international, multicenter study in males and females with PBC who have inadequate 
response or intolerance to UDCA. 
The study will utilize an open-label, partially randomized, uncontrolled, 8-week dose ranging parallel groups 
(2 mg, 5 mg, and 10 mg) design with an open-label extension for a total of up to 52-weeks of treatment. 
After signing an informed consent form (ICF), subjects will enter a screening period (up to 2 weeks). 
Subjects in the 5 mg and 10 mg treatment groups will enter the 8-week initial treatment period study in 
parallel. Subjects in the 2 mg group will enter the 8-week initial treatment period in chronological order. 
Randomization will occur only for 5 mg and 10 mg treatment groups; subjects in the 2 mg treatment group 
will be registered for the study. Randomization/registration will occur ideally at least 7 days prior to first 
dose of MBX-8025 (study drug). A subject will be considered formally entered in the trial at 
randomization/registration. Study drug kits will be shipped from the drug deposit facility to the site on a 
subject-by-subject basis. Subject-specific study drug supplies (MBX-8025) will be taken orally once a day, 
for a period of 8 weeks. To confirm study drug compliance, MBX-8025 trough level will be measured after 
2 and 8 weeks of treatment. 
After completion of the 8-week initial treatment period, subjects will enter the open-label extension for a 
total of up to 52 weeks of treatment. Subjects will initially enter the extension on their assigned dose. Based 






 
 
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1. 
Randomization will occur only for 5 mg and 10 mg treatment groups. Subjects in the 2 mg treatment group will be registered for the study. Randomization/registration will 
occur ideally at least 7 days prior to Visit 2 (Baseline). Study drug kits will be shipped from the drug depot facility to the site on a subject-by-subject basis. 
2. 
Including PBC history 
3. 
Liver-related symptoms will be evaluated as part of physical exam. UNS visit might be scheduled, if needed per PI judgment.  
4. 
Symptoms-directed (brief) physical examination 
5. 
ECG will be performed approximately 60-90 minutes after dosing (Visit 2 through Visit 11) 
6. 
Blood will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject forgets to fast, the site will continue to draw labs 
7. 
If at Visit 1 (Screening) an unexpected abnormal CK level is observed, re-test the subject to confirm eligibility 
8. 
At Visit 1 (Screening) only AMA is to be performed 
9. 
The 24-hour blood sample (selected centers) will be collected at the following time points: within 30 minutes prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hours after the 
dosing 
10. The 24-hour urine sample (selected centers) will be collected over the following intervals: 0-6 hours and 6-24 hours. 
11. Safety and efficacy data review will be performed after a subject completes the initial 8-week treatment period. The review will be done by the Investigator in collaboration 
with Medical Monitor. Based on this review, the dose might be up- or down-titrated for the extension period. 
12. Applicable only for subjects who had dose adjustment at any time during extension. The visit will occur in two weeks after initiation of the extension dose. If dose adjustment 
occurs approximately two weeks prior to the next scheduled visit, post-dose adjustment visit and the next planned visit can be combined. 
 
 


 
 
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3.1 Sample Size Considerations 
Approximately 116 subjects will participate in the study:  
• 
2 mg treatment group: up to 18 subjects 
• 
5 mg treatment group: approximately 49 subjects 
• 
10 mg treatment group: approximately 49 subjects 
PK (24-hour):  up to 30 subjects 
• 
2 mg treatment group: up to 6 subjects 
• 
5 mg, and 10 mg treatment group: up to 12 subjects per group. 
It is assumed that the 5 mg and 10 mg treatment groups will have at least 10% difference in the mean AP 
percent change with a 15 % standard deviation. Based on this assumption, and on the use of two-sided, 
two-sample t-test at the alpha =0.05 level of significance, a study sample size of 49 subjects per group 
will have a 90% power to detect a 10% mean difference between 5 mg and 10 mg treatment groups. 
There is no formal sample size justification for 2 mg treatment group. 
3.2 Randomization 
Subjects in the 5 mg and 10 mg treatment groups will be centrally randomized in a 1:1 ratio to receive MBX-
8025 5 mg or MBX-8025 10 mg. Subjects in the 2 mg treatment group will be registered to the study. 
4.0 Study Variables and Covariates 
4.1 Efficacy 
4.1.1 Primary Variable 
• 
Percent change from baseline to end of 8-week treatment in AP level. 
4.1.2 Secondary Variables 
• 
Change from baseline to 12 weeks and 52 weeks of treatment in AP level. 
• 
Percent change from baseline to 12 weeks and 52 weeks of treatment in AP level. 
• 
Composite responder endpoint of AP and total bilirubin: 
o 
AP < 1.67 × upper limit of normal (ULN) and 
o 
Total Bilirubin within normal limit and 
o 
> 15% decrease in AP 
• 
Change and percent change from baseline to 12 weeks and 52 weeks of treatment in the following 
parameters: 
• 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), 5’nucleotidase, bilirubin (total, conjugated, unconjugated), bone-specific 
AP, Triglycerides (TG), total cholesterol (TC), high density lipoprotein Cholesterol (HDL-C), and 
low density lipoprotein cholesterol (LDL-C), PBC response criteria (Barcelona, Paris I and II, 
Toronto I and II) 
• 
UK-PBC risk score 
• 
5D-itch scale 


 
 
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• 
Pruritus Visual Analog Score (VAS) 
• 
PBC-40 QoL 
• 
Model for End-Stage Liver Disease (MELD) scores 
• 
GLOBE score 
4.1.3 Exploratory Variables 
• 
Exploratory biochemistry:  Anti-Mitochondrial Antibodies (AMA), C-terminal telopeptide (CTX), 
cystatin C, IgM, fibrinogen, fibroblast growth factor 19 (FGF19), haptoglobin, high-sensitivity C-
Reactive Protein (hs-CRP), homocysteine, microRNA-122, and N-terminal propeptide of type 1 
procollagen (P1NP);  
• 
Bile acids: Primary Bile Acids and Salts: Cholic acid (CA), chenodeoxycholic acid (CDCA), 
glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), 
taurochenodeoxycholic acid (TCDCA); Secondary Bile Acids and Salts: Deoxycholic acid (DCA), 
lithocholic 
acid 
(LCA), 
glycodeoxycholic 
acid 
(GDCA), 
glycolithocholic 
acid 
(GLCA), 
taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA); Other Bile Acids: ursodeoxycholic acid 
(UDCA), glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA);   
• 
Sterols: desmosterol (DESM), lanosterol (LANO), lathosterol (LATH), 7- dehydrocholesterol (7-
DHC), cholestanol (CSTN), coprostanol (COPR), squalene (SQLN); β-sitosterol (β-SITO), 
campesterol (CAMP), stigmasterol (STIG), 7α-hydroxycholesterol (7 α-HC); 
• 
Bile acid precursor:  C4 (7α-hydroxy-4-cholesten-3-one); 
4.2 Pharmacokinetics (PK) 
4.2.1 General Methods  
24-hour plasma and urine concentration determination of MBX-8025 and its metabolites (M1, M2 and M3) 
will be performed on subjects participating in 24-hour PK testing. 24-hour blood samples will be collected 
at Visit 2 (Day 1) and Visit 4 (Week 2) or 8 (Week 12). Blood samples will be collected within 30 minutes 
prior to dosing, and 30 min, 1, 2, 4, 6 and 24 hours after dosing. 
24-hour urine sample will be collected over two intervals 0-6 hours and 6-24 hours. 
PK trough level: Plasma concentration determination of MBX-8025 and its metabolites (M1, M2 and M3) 
will be collected from non-PK subjects only pre-dose at Visits 4 (Week 2) and Visit 7 (Week 8). 
Sample collection, processing and handling details are provided in the Laboratory Manual. 
4.2.2 Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility designated by 
the sponsor. 
Concentrations of MBX-8025 and its metabolites (M1, M2, and M3) will be assayed using validated 
analytical methods. 
4.2.3 Handling of Missing Data for PK Analyses 
No data exclusions or imputations are planned. Exclusions or imputations may be made in the case of 
implausible or outlier data. Such cases will be adjudicated by a trained pharmacokineticist and reported 
with justification. In cases where imputations or exclusions may affect the conclusions or interpretation of 
the results significantly, an assessment of such impact may be conducted, at the discretion of the 
pharmacokineticist, by comparing the results with and without such actions. All imputations and 








 
 
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• 
5/10 mg titration: This group will consist of all subjects randomized to the 5 mg treatment group 
who uptitrated to 10 mg at any time during the study. 
 
Age at PBC diagnosis 
Age at PBC diagnosis is calculated as: (Onset date of PBC in medical history CRF page - the birth 
date+1)/365.25. See imputation of partial missing dates in Section 9.5.2 Methods for Handling Dropouts 
and Missing Data. 
Baseline 
Baseline is defined as the mean between all assessments at and between Visit 1 (Week -2 to Day 1) and 
Visit 2 (Day 1). In cases where some endpoints may not capture multiple observations prior to Day 1 the 
single collected observation will be used. 
Change from Baseline 
Change from baseline is defined as (value at post-baseline visit – baseline value [as defined above]). 
Concomitant and Prior Medication 
Prior medications are defined as medications with a stop date prior to first dose of MBX-8025. Concomitant 
medications are defined as any medications ongoing at the start of MBX-8025 or with a start date on or 
after the first dose date. 
Duration of PBC 
Duration of PBC in years is defined as (date of informed consent - onset date of PBC in medical history 
CRF page +1)/365.25. See imputation of partial missing dates in Section 9.5.2 Methods for Handling 
Dropouts and Missing Data. If imputation is used and the result is the same as the date of first dose, then 
add 6 months to the duration of PBC calculation. 
End of Treatment 
Study End of Treatment (EOT) is defined as the last on treatment visit, for most patients this is Visit 14 
(Week 52). Subject EOT is defined as Date of Last Dose on CRF EOT form and is denoted EOT on the 
CRF. 
Last observation carried forward (LOCF) 
The imputation of data will only be used for the analysis of AP and the Composite Endpoint. Imputation 
where missing post-baseline data less than two days after EOT will be imputed by carrying forward the last 
non-missing on treatment post-baseline value (LOCF). 
Week 8 Endpoint 
The Week 8 Endpoint is defined as the Visit 7 (Week 8) response. If a subject discontinues from the study 
prior to Week 8 but after Week 6, the missing value for AP and Composite Endpoint will be imputed using 
LOCF.   
Week 12 Endpoint 
The Week 12 Endpoint is defined as the Visit 8 (Week 12) response. If a subject discontinues from the 
study prior to Week 12 but after Week 8, the missing value for AP and Composite Endpoint will be imputed 
using LOCF.  Otherwise, the Week 12 Endpoint is missing. 
Week 52 Endpoint 
Study Week 52 Endpoint is defined as Visit 14 (Week 52).  If a subject discontinues from the study prior to 
Week 52 but after Week 26, the values for AP and the Composite Endpoint will be imputed using LOCF.  
For all other endpoints no imputation will be performed.  
Percent change from Baseline 


 
 
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The percent change from baseline is calculated as (value at post-baseline visit – baseline value [as defined 
above]) X 100 / (baseline value [as defined above]). 
If the baseline value is 0 and the post-baseline value is also 0, then the percent improvement from baseline 
is set to 0. If the baseline value is 0 and the post-baseline value is non-zero, then the percent improvement 
from baseline is set to “missing” (or ‘.’). 
Study Day 1 
The first day of MBX-8025 administered. For subjects who are enrolled (randomized or registered) but not 
dosed, study day 1 is defined as the date of enrollment. 
Study Day 
Study Day is defined as the number of days from Study Day 1. 
• 
Before Study Day 1:  Study Day = (Date of Interest – Date of Study Day 1) 
• 
On or After Study Day 1:  Study Day = (Date of Interest – Date of Study Day 1) + 1 
Therefore, the day prior to Study Day 1 is -1.  
Study Completer 
Subjects will be considered to have completed the study if they complete Visit 14 (Week 52).  
Study Enrollment (Randomization or Registration)  
Study enrollment (randomization for 5 and 10 mg cohorts, registration for 2 cohort) is defined as when 
subject receives a treatment allocation via the IXRS system. 
UDCA daily dose 
UDCA daily dose (mg/day) = Visit UDCA dose (mg) x number of times per day.  
UDCA dose by weight (mg/kg/day) at each visit = (Visit UDCA dose (mg) x number of times per day) / visit 
weight (kg). 
UDCA compliance will be estimated based on the number of missed doses reported by the subject. UDCA 
compliance = (Total duration of study drug exposure in days – number of days UDCA doses missed)/ Total 
duration of study drug exposure in days. 
Visit Dose 
For presentation of study assessments, Visit Dose is defined as the MBX-8025 dose received at the 
previous visit, the dose related to the assessments.  
Visit Windows 
In general, CRF visits will be used for this study. Unscheduled visits will also be denoted as last_visit.1/2/3. 
Visit 14 is EOT and Visit 15 is Follow-up even if these (EOT and Follow-up) occur prior to the planned visit 
windows. 
 
Unscheduled visits include only lab assessments and AEs. Unscheduled visit lab assessments will be 
included in subject listings but not tables. Unscheduled visit AEs will be included in both tables and listings. 
 
AP Isozymes 
Three AP isozymes (Liver, Bone and Intestinal) which make up total AP measurements are provided in 
terms of percentage of total by Quest laboratory. Absolute conversions will be calculated in order to perform 
summaries on absolute measurements of these isozymes of AP response. The calculations will be 
performed for the following clinical laboratory parameters: 
• 
Bone-specific AP 


 
 
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• 
Liver AP 
• 
Intestinal AP 
The conversion is calculated as (proportion reported) X (Total AP). The Total AP used will be the result 
reported by Quest laboratories and the resulting units will be U/L. 
5.2 Efficacy 
5-D Itch 
The 5-D itch scale was developed as a five-dimension questionnaire designed to assess itching in clinical 
trials. The five dimensions are degree, duration, direction, disability and distribution. Detailed information 
on this scale can be found at Appendix D in the protocol. 
Single-item domain scores (duration, degree and direction) are equal to the value the response choice 
(range 1–5). 
The disability domain comprises four items that assess the impact of itching on daily activities: sleep, 
leisure/social activities, housework/errands and work/school. The score for the disability domain is the 
highest score on any of the four items. 
For the distribution domain, the number of affected body parts is tallied (potential sum 0–16) and the sum 
is sorted into five scoring bins: sum of 0–2 = score of 1, sum of 3–5 = score of 2, sum of 6–10 = score of 3, 
sum of 11–13 = score of 4, and sum of 14–16 = score of 5. 
The scores of each of the five domains are summed together to obtain a total 5-D score. 5-D scores can 
potentially range between 5 (no pruritus) and 25 (most severe pruritus). 
5-D Itch modified 
A modified score using the sum of 4 domains, will exclude the single item domain Direction. The scores of 
the remaining 4 domains will be summed to obtain a 5-D modified total score ranging from 4 (no pruritus) 
to 20 (most severe pruritus). 
This modification is due to the wording of the Direction item. Subjects with no pruritus often record 
“unchanged,” which has a score of 4 instead of “completely resolved,” a score of 1. 
Pruritus VAS  
The Pruritus VAS will be used as a secondary efficacy measure to evaluate pruritus in subjects with PBC. 
VAS has values (unit: mm) ranging from 0 to 100, where 0 means no itching and 100 represents worst 
possible itching. The scoring procedure can be found in Appendix E of the protocol. 
PBC Response Criteria  
The following biochemistry criteria will be used to measure the PBC subject response, where ULN refers 
to the upper limit of the normal range. Missing AP or total bilirubin at Initial and Extension Endpoint visits 
will be imputed by LOCF. 
1. Paris I: AP ≤ 3x ULN and AST ≤ 2x ULN and Total Bilirubin ≤ 1 mg/dL; 
2. Paris II:  AP ≤ 1.5x ULN and AST ≤ 1.5x ULN and Total Bilirubin ≤ 1 mg/dL 
3. Toronto I: AP ≤ 1.67x ULN 
4. Toronto II: 
• 
AP ≤ 1.76x ULN  
5. Mayo II 


 
 
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• 
AP ≤1.67x ULN and Total Bilirubin ≤ ULN 
 
6. Barcelona: 
• 
Normalization of AP or a Decrease of AP ≥ 40% 
 
7. Rotterdam: 
 
• 
Early: normal Total Bilirubin and normal Albumin 
• 
Moderately advanced: Either abnormal Albumin or abnormal Total Bilirubin 
• 
Advanced:  Both abnormal Albumin and abnormal Total Bilirubin 
• 
 
 
UK-PBC Risk Score  
The UK-PBC Risk Score calculator originally used information from the UK-PBC Research Cohort to 
estimate the risk (expressed in percentage) that a PBC subject established on treatment with UDCA will 
develop liver failure requiring liver transplantation within 5, 10 or 15 years from diagnosis. Similar UK-PBC 
risk score calculation is adapted for this trial with the formula as below: 
UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(AP12 x ULN-1.722136304) - 0.0422873*(((TA12 x 
ULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-
1.17673001)-0.4161954*(Platelet x LLN-1.873564875)) 
AP12, TA12 and BIL12 refers to the AP, transaminases (refers to the ALT, where available, otherwise the 
AST), and total bilirubin assessments, respectively, at specific visits. (Note:  where AP12, TA12 and 
BIL12 are specified, the value at that visit will be used.)  Albumin and platelet represent their baseline 
assessment. Missing AP12, TA12 or BIL12 at Initial and Extension Endpoint visits will not be imputed. 
Baseline survivor function will take values of 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years 
respectively.  
PBC-40 QoL 
PBC-40 is a disease-specific health related quality of life tool developed to specifically measure the 
psychometric profile of PBC subjects.  It covers six domains relevant to PBC including cognitive, social, 
emotional function, fatigue, itch, and other symptoms. See Appendix F of the study protocol for details.  
Within each domain, items are scored from 1 to 5 and the individual item scores are summed to give a total 
domain score. The direction of scoring of some items is reversed for calculation of domain scores so that 
in all cases, high scores represent high impact and low scores low impact of PBC on quality of life. 
 
MELD  and MELD-Na Score 
MELD(i) score = 10*[0.957 x LN(creatinine mg/dL) + 0. 378 x LN(bilirubin mg/dL) + 1.120 x LN (INR) + 
0.643].  
All laboratory values are rounded to 10th decimal place when calculating the score, and MELD(i) is 
rounded to the nearest whole number. 
All laboratory values less than 1.0 will be set to 1.0 when calculating a candidate’s MELD(i) score. 
Laboratory values for creatinine greater than 4.0mg/dL will be set to 4.0 mg/dL; sodium values less than 
125 mmol/L will be set to 125 and sodium values greater than 137 mmol/L will be set to 137. 
 
If MELD(i) is less than or equal to 11 then MELD = MELD(i). 
If MELD(i) is greater than 11 then MELD = MELD(i) + (1.32 *(137 - (Na)) – (0.033*MELD(i)*(137 – Na)) 


 
 
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MELD-Na = MELD(i) – Na – [0.025 * MELD(i) * (140 – Na)] + 140 
 
GLOBE Score 
GLOBE score = (0.044378 * age + 0.93982 * LN(total bilirubin/ULN) + (0.335648 * LN(alkaline 
phosphatase/ULN)) – 2.266708 * albumin /LLN – 0.002581 * platelet count per 109/L) + 1.216865. 
5.3 Safety 
Creatinine Clearance 
CrCl(mL/min/1.73 m2) = [ UCr (mg/dL) x Uvol (mL)] / [SCr (mg/dL) x time (min) ]  x  [ (1.73) / BSA ] 
Where U=urine, S=serum, and  
            DuBois & DuBois Body Surface Area (BSA) = 0.20247 x height (m)0.725 x weight (kg)0.425 
6.0 Analysis Sets 
Each subject can be titrated to a higher or lower dose, after Week 8 and may have more than one dose 
change.  All analyses will be performed using the treatment groups as defined in Section 5. 
6.1 Safety Population 
The safety population is defined as any enrolled (randomized or registered) subject who receives at least 
one dose of medication. All safety analyses will be completed using the safety population by the initial 
treatment group and 5 mg cohort groups as defined in Section 5. 
6.2 Intention-to-Treat Population (ITT) 
The ITT population is defined as any enrolled subject who receives at least one dose of medication and 
has at least one post-baseline AP evaluation. The ITT population will be used for analyzing the primary 
endpoint and selected secondary endpoints according to subjects’ initial treatment group as defined in 
Section 5. 
6.3 Modified intention-to-Treat Population (mITT) 
The mITT population is defined as all subjects in the ITT population who have confirmed PBC. The mITT 
population is the primary analysis population for all efficacy analyses. The efficacy analyses will be 
performed using the initial dose group and 5 mg cohort groups. 
6.4 Per Protocol Population (PP) 
The PP population is defined as all subjects in the mITT Population whose study drug compliance and 
UDCA compliance are between >=80% and <=120%.. Supportive efficacy analyses will be completed using 
the PP population using the same treatment groups as the mITT analyses. 
6.5 Pharmacokinetic Population (PK) 
All subjects who receive at least one dose of MBX-8025 and have at least one measurable drug 
concentration will be included in PK analyses. Analyses will be completed using the study dose received. 
PK visits occur at Day 1 and Week 2 or Week 12 Treatment study period. 
7.0 Interim and Final Analyses 
Four interim data reviews were conducted while the study is ongoing as follows. No aggregate or individual 
subject level data was unblinded in presentation of analysis results at any time. 


 
 
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7.1 Interim Analyses 
7.1.1 24 Subjects at 8 Weeks 
After the 24th subject in the 5 mg and 10 mg treatment groups completed the 8-week initial treatment period, 
a safety and efficacy data review was performed to determine whether the 20 mg treatment group should 
be initiated and the dose(s) to be used in the extension (2 mg, 5 mg, 10 mg, or 20 mg, see Section 3.0 
Study Design for titration details). 
7.1.2 24 Subjects at 12 Weeks  
After the 24th subject in the 5 mg and 10 mg treatment groups completed the 12-week endpoint period, a 
safety and efficacy data review was performed. For both interim analyses, only the first 24 subjects who 
qualify for the analysis were included in the efficacy results. This subject set was determined by the 24th 
subject to qualify for the first interim analysis. 
7.1.3 45 Subjects at 26 Weeks 
After the 45th enrolled subject had their Week 26 visit or early terminates from the study, a third interim 
analysis was conducted. Only the first 45 enrolled subjects were included in the analyses. 
7.1.4 Subjects at 52 Weeks 
After the 40th enrolled subjects had their Week 52 visit, a fourth interim analysis was conducted.  Analyses 
were conducted for the following subject groups:  12 week completers (all subjects who had completed at 
least 12 weeks of treatment); 26 week completers (all subjects who have completed at least 26 weeks of 
treatment); and 52 week completers (all subjects who had completed at least 52 weeks of treatment); 
8.0 Data Review 
8.1 Data Handling and Transfer 
Data will be entered and exported as SAS® version 9.4 datasets. Converted datasets will be created using 
SAS® and following standard Clinical Data Interchange Standards Consortium Standard Data Tabulation 
Model (CDISC SDTM, version 1.3, Implementation Guide version v3.1.3) conventions. Analysis datasets 
will be created using SAS® and following CDISC Analysis Data Model (ADaM, version 2.1, Implementation 
Guide 1.0) standards. 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1 at the time of the analysis to assign a system organ class (SOC) and preferred term (PT) to 
each event. Prior and concomitant medications will be coded using the WHO Drug 2019MAR03DDE B3 of 
the World Health Organization Collaborating Centre (WHOCC) at the time of the analysis. 
Additional details can be found in the PRA Data Management Plan for this study. 
8.2 Data Screening 
Review of a pre-freeze TFL dry run allows for further data screening prior to data base freeze for the primary 
analysis. The activities planned for pre-freeze phase can be found in the Data Management Plan. The pre-
freeze TFL will be discussed with the sponsor in a data review meeting to identify any final data issues and 
seek corrections prior to database freeze. Database lock will occur at the end of the study, after all follow-
up visits are complete. The PRA statistician and the sponsor must approve database lock. 
9.0 Statistical Methods 
All statistical analyses will be performed using SAS® (Version 9.4 or higher). 


 
 
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The final analysis will be performed at the end of the study (end of trial) after all subjects have completed 
the Week 56/Early Termination assessments and the follow-up assessment or have entered the long-term 
safety study.  
Unless otherwise specified, descriptive data summaries will be tabulated by treatment for all endpoints. 
Categorical data will be summarized using number of subjects (n), frequency and percentages of subjects 
falling into each category, with the denominator for percentages being the number of subjects in the study 
population for each treatment group, unless otherwise noted. Percentages will be rounded to one decimal 
place except for 100%, which will have no decimal place. 
All continuous variables will be summarized using mean, standard deviation (SD), standard error (SE), 95% 
confidence interval of mean, median, minimum, maximum, and number of subjects with observations. The 
mean and its confidence interval, median, SD, and SE will be presented to one decimal place greater than 
the original data, and the minimum and maximum will have the same number of decimal places as the 
original data. 
9.1 Subject Disposition 
The following information will be summarized for subject disposition and accountability: 
• 
Subject disposition (including number of subjects who were screened, randomized, treated with 
MBX-8025, completed treatment, discontinued treatment with reason of discontinuation, completed 
study, and discontinued study with reason of discontinuation). Number of subjects who have 
dosage adjustments due to adverse event (AE), defined as subjects who have checked 
‘Temporarily interrupted, restarted – lower dose’ for ‘Action taken with the study treatment’ in AE 
CRF page, will be provided as well. Summary will be presented overall, the Week 12 Treatment 
Period, the Week 52 treatment period and overall. 
• 
Summaries of analysis sets with reason for exclusion from the per-protocol analysis set for all 
enrolled (randomized and registered) subjects. 
Disposition summaries will be presented by initial treatment and the Cohort treatment group. 
9.2 Protocol Deviations 
Protocol deviations (PD) data will be entered into the Clinical Trials Management System (CTMS). The 
study team will conduct ongoing reviews of the PD data from CTMS and the resulting set of subjects to be 
included in the PP population throughout the study, adjusting the PD criteria as appropriate. The subjects 
to be included in the PP population will be finalized prior to database lock. 
Based on the PD data entered into CTMS, the important protocol deviations (IPD), which are defined in the 
PD guidance, thought to potentially impact the statistical analyses, will be listed and tabulated for the ITT 
population using incidence and percentages by deviation type and treatment group as defined in Section 
5. This also applies to the specific IPDs that will exclude subjects from the per protocol analysis set. 
9.3 Treatments 
9.3.1 Extent of Study Drug Exposure 
MBX-8025 will be supplied as 1 mg, 5 mg, and 10 mg capsules. MBX-8025 will be administered orally, once 
daily in doses of 2 mg, 5 mg, and 10 mg as described in the protocol. During the extension periods, dose 
may be up- or down-titrated based on individual subject review and the overall study safety and efficacy 
review as described in Section 3.0 Study Design. 
Summary statistics, defined below, will be provided for total number of doses taken, total duration (days) 
of MBX-8025 exposure, treatment compliance and the number of subjects having dose 
interruption/discontinuations due to AEs by treatment group as defined in Section 5. The analysis will be 
performed using the safety population, for the first 12 weeks, and for the entire study period (up to 52 
weeks). 


 
 
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Total duration of study drug exposure in days = date of last dose – date of first dose + 1. 
Total number of capsules planned = (date of last dose – date of first dose +1) * the number of capsules per 
day.  In the case that a subject takes multiple capsules per day, this will be included in the above calculation, 
e.g., two 5 mg tablets to achieve a daily dose of 10 mg. 
Total number of capsules received = sum of (number of capsules dispensed – number of capsules returned) 
for each kit record in DA2 CRF page across all kits. Kits not returned will have their capsules excluded from 
this calculation. 
Treatment compliance (%) = 100* (total number of capsules taken/ total number of capsules planned). 
A subject listing of MBX-8025 accountability and a listing of exposure in the study will be provided. 
A listing of subjects who titrated up or down (or both) at any time on study will be provided. 
9.3.2 Prior and Concomitant Medications/Procedures 
Prior and concomitant medications will be coded by World Health Organization Collaborating Centers 
(WHOCC) criteria and will be summarized by Anatomical Therapeutic Chemical (ATC) system class, 
generic name and treatment group as defined in Section 5. The analysis will be performed using the Safety 
population. 
The number and percentage of subjects using each medication will be displayed by treatment. Subjects 
taking more than one medication in the same generic name or ATC class will be counted once. 
A list of prior and concomitant medications and procedures will be presented. A list of UDCA medication at 
each visit will also be presented. 
9.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics including age, race, gender, ethnicity, height, weight and body 
mass index (BMI) will be summarized using descriptive statistics for continuous variables and frequency 
distributions for discrete variables for safety, and mITT populations by initial treatment group and 5 mg 
cohort groups as defined in Section 5.Age (in year) = (screening date – birth date +1)/365.25 
BMI (kg/m2) = weight (kg)/height (m)^2 
Medical history at screening will be summarized by SOC and PT and tabulated by treatment group and 
total for safety analysis population. 
PBC history will be summarized using the safety/ITT and mITT populations. 
9.5 Efficacy Analyses 
The primary efficacy analyses will be based on the mITT population using the initial treatment group defined 
in Section 5. The primary endpoint and secondary endpoints will also be analyzed on the ITT population 
according to subjects’ initial treatment group. All statistical testing will be performed using two-sided tests 
at the alpha=0.05 level of significance. 
Descriptive summary will be provided on the mITT population using the initial treatment group and 5 mg 
cohort groups 
Selected analyses will be repeated using PP population where indicated in the text below. 
9.5.1 Primary Variable 
Primary Analysis 
ANCOVA on percent change from baseline 
The primary endpoint is the percent change in AP serum level (U/L) from the baseline to the Week 8 
Endpoint (the 8 week visit (Visit 7), or end of treatment (EOT) if before 8 weeks). Primary analysis will be 
performed using mITT with missing assessments imputed by LOCF as defined in Section 5.1. The analyses 


 
 
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will assess the change from baseline in each treatment group and will assess the hypothesis that there are 
no differences in the percent change in AP serum level from baseline to 8 weeks between MBX-8025 
treatment groups. Paired comparisons between the doses will be performed.  
An ANCOVA model with treatment group as the main effect and the baseline AP assessment as a covariate 
will be used for the comparison of primary endpoint analysis. Sample SAS code for PROC MIXED is 
displayed below: 
PROC mixed data=datain; 
  CLASS treatment; 
  MODEL percent change= treatment baseline / clparm; 
   Lsmeans treatment/pdiff CL; 
   Estimate ‘MBX-8025 10 vs. 2’ treatment -1 0 1; 
   Estimate ‘MBX-8025 10 vs. 5’ treatment 0 -1 1; 
   Estimate ‘MBX-8025 5 vs.2’ treatment  -1 1 0; 
 
Note: Depending on treatment assignment coding, the contrast in the estimate statement may need to be 
revised. 
From the model, the least square means (LS Means), SE, 95% confidence interval of LS Means in the 
percent change in AP serum level from baseline to the visits of interest for each treatment group, the 
differences of LS Means (SE) between each MBX-8025 dose, and the corresponding p-values will be 
presented.  The visits of interest are:  Weeks 8, 12 and 52.  At Week 8 and 12 the comparisons will be 
made for the 3 initial dose groups, at Week 52 the comparison will be limited to the comparison of the initial 
dose groups of 5 and 10 mg.  Note:  that actual treatment through Week 12 will be the initial treatment at 
baseline since titration will not have occurred prior to that point. 
A descriptive summary of observed AP values at each visit including baseline and change from baseline 
as well as the percent change from baseline at each visit will be provided by treatment group. 
The above ANCOVA model and descriptive analysis will be repeated using the ITT population as supportive 
analyses. 
 
The within subject difference will be presented and a paired t-test will be used to show the subject 
differences between the baseline value and the Week 12 and Week 52 visit. 
Sensitivity Analyses 
ANCOVA Model assumptions including normality of the standardized residuals and homogeneity of 
variance between initial treatment groups will be assessed for the Week 8 endpoint. If any model 
assumptions are violated to the degree that model performance is in question, the Wilcoxon Mann-Whitney 
test (presenting Wilcoxon p-values) will be used to do pair-wise comparisons as the primary efficacy 
analysis with the sample SAS code listed below. Paired comparisons between MBX-8025 doses will not be 
adjusted for multiple comparisons.  
proc NPAR1WAY data=datain wilcoxon; 
 
title "Nonparametric test to compare percent change in AP between treatment groups"; 
             class treatment; 
 
var percent_change; 
 
exact wilcoxon; 
   run;  


 
 
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To assess the robustness of the primary analysis results, the same analysis models using the mITT 
population will be repeated using the PP population. 
To explore the impact of UDCA intolerant subjects the primary analysis will be repeated excluding UDCA 
intolerant subjects. 
Repeated measures of percent change from baseline 
AP percent change from baseline will also be analyzed based on a repeated measures analysis of 
covariance, where observed data from post-baseline visit assessments (no missing data imputation will be 
used) during the from baseline through Week 52 are included. Main effects will be treatment group and visit, 
an interaction of treatment and visit and baseline will be the covariate.   
The mixed model repeated measures analysis and will be implemented using PROC MIXED procedure in 
SAS, specifying the variance-covariance structure with the type which assumes the least underlying data 
structure that is able to converge (ie unstructured [UN], auto-regressive 1 [AR(1)], and compound symmetry 
[CS]). Example code for PROC MIXED is displayed below: 
Proc mixed data=datain; 
 
Class treatment visit subject; 
 
 
Model percent_change= treatment visit treatment*visit baseline; 
 
Repeated visit/subject=subject type=un/ar(1)/cs; 
 
Lsmeans treatment*visit/pdiff cl; 
Run; 
 
UDCA Intolerant Subjects 
The effect of treatment on UDCA intolerant subjects may be explored by creating individual response 
profiles. 
9.5.2 Methods for Handling Dropouts and Missing Data 
For the primary analysis based on mITT, missing values will be imputed using the LOCF method except for 
the repeated measure analysis. As sensitivity analyses, primary efficacy endpoints will also be analyzed for 
the PP analysis sets based on Observed Values in a repeated measures model as described in Section 
9.5.1. 
Imputation for Partial or Missing Dates 
If dates are missing or incomplete for an AE (including deaths) or concomitant medication, the following 
algorithm will be used for imputation: 
Table 2.  Imputation Rules for Partial or Missing Start Dates 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
<1st 
dose 
≥1st 
dose 
<1st 
dose 
yyyymm 
≥1st dose 
yyyymm 
<1st 
dose 
yyyy 
≥1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st 
dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st 
dose 
yyyymm 
2 
2 
2 
2 
2 
2 


 
 
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Partial: 
yyyy 
= 1st 
dose yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st 
dose yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute as the date of first dose 
2 = Impute as the first of the month 
3 = Impute as January 1 of the year 
4 = Impute as January 1 of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, then there is a data error 
and do not impute the start date. 
Imputation rules for partial or missing stop dates: 
1. Initial imputation 
a. For partial stop date “mmyyyy”, impute the last of the month. 
b. For partial stop date “yyyy”, impute December 31 of the year. 
c. For completely missing stop date, do not impute. 
2. If the stop date imputation leads to a stop date that is after the death date, then impute the stop 
date as the death date. 
3. If the stop date imputation leads to a stop date that is before the start date, then there is a data 
error and do not impute the stop date. 
Imputation rules for partial or missing death dates: 
1. If death year and month are available but day is missing: 
d. If “mmyyyy” for last contact date = “mmyyyy” for death date, set death date to the day after 
the last contact date. 
e. If “mmyyyy” for last contact date < “mmyyyy” for death date, set death date to the first day 
of the death month. 
f. 
If “mmyyyy” for last contact date > “mmyyyy” for death date, data error and do not impute. 
2. If both month and day are missing for death date or a death date is totally missing, set death date 
to the day after the last contact date. 
The imputed dates will be used to assess whether AEs should be considered as treatment emergent and 
if medications should be included in the safety summaries as prior or concomitant, however the original, 
partial dates will be included in data listings. 
9.5.3 Multiplicity 
Paired comparisons between MBX-8025 doses will be performed at the alpha=0.05 level of significance 
with no adjustment for multiple comparisons. 
9.5.4 Pooling of Sites 
All sites will be pooled for the analyses and site effect will not be evaluated. 
9.5.5 Secondary Variables 
All secondary analyses will be carried out using two-sided tests at the alpha=0.05 level of significance for 
the mITT population by the initial treatment groups. Select secondary endpoints (composite endpoint, total 
bilirubin, AST, ALT, GGT) will also be analyzed on the ITT population by the initial treatment groups. 
Analyses will be restricted to Week 12 and 52, in a similar manner to that above for the Primary Endpoint. 


 
 
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9.5.5.1 Composite Endpoint of AP and Total Bilirubin 
At each post-baseline visit, a subject is defined as a responder if their AP assessment and total bilirubin 
satisfy the composite endpoint definition, that is, AP<1.67 x upper limit of normal and a ≥15% decrease 
from baseline and total bilirubin within the normal limit. Two-sided p-values from the Fisher’s exact tests 
comparing MBX-8025 doses will be reported each study visit. The number (%) of responders and 
non-responders will be displayed by visit and treatment group, Statistical comparisons will be restricted to 
Weeks 12 and 52. 
This analysis will be repeated using the PP population. 
This analysis will be repeated excluding UDCA intolerant subjects. 
9.5.5.2 Biochemistry Measurements 
The percent changes from baseline in the following secondary biochemistry parameters as shown in 
Section 4.1.2. Secondary Variables will be analyzed separately by a similar ANCOVA model as that used 
for the primary efficacy variable. The difference in LS Means of percent change from baseline between 
MBX-8025 levels as well as their p-values and 95% confidence intervals will be presented, if available.  
9.5.5.3 Published PBC Response Criteria  
For each published PBC response criteria defined in Section 5.2, subjects who satisfy the criteria will be 
defined as responders. Otherwise, subjects will be considered non-responders if all the elements have a 
non-missing assessment at that visit. 
The number of non-responders of each published criteria will be descriptively summarized at baseline and 
Weeks 12 and 52. Fisher’s exact tests will test the difference between the responder rates between 
MBX-8025 treatment groups separately for each criterion. 
A listing of subject’s responses to each published criterion will be provided. 
9.5.5.4 5-D Itch 
At Week 12 and Week 52, the change and percent change from baseline in total 5-D score and modified 
total 5-D score between MBX-8025 treatment groups will be analyzed by ANCOVA models similar to the 
description for the primary variable, with percent change from baseline in total 5-D score and modified total 
as response variables, treatment group as factor and baseline total modified total 5-D itch scores as 
covariate. 
The total and modified total 5-D itch scores change from baseline and percent change from baseline will 
also be descriptively summarized at each visit. 
The individual domain score and total score will be displayed for each visit in a listing. 
9.5.5.5 Pruritus VAS 
The actual value and change from baseline at each visit in Pruritus VAS will be descriptively presented by 
Initial treatment group as defined in Section 5. Similar analyses to those described in Section 9.5.5.4 for 
5-D Itch will be conducted for Pruritus VAS change from baseline to Week 12 and Week 52 visits. A listing 
for Pruritus VAS measured at each visit will be provided. 
Additionally, three scatterplots to show the correlations between total 5-D itch score verse Pruritus VAS 
score will be provided at baseline, Week 12 and Week 52. 
9.5.5.6 PBC-40 QoL 
The change and percent change from baseline for individual domain score at Week 12 and Week 52 will 
be analyzed by the similar model as described in Section 9.5.5.5 for 5-D Itch. The actual individual domain 
scores as well as the change and percent change from baseline will also be summarized by visit and 
treatment groups.  


 
 
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The individual domain score and total score will be displayed for each visit in a listing. 
 
9.5.5.7 UK-PBC Risk Score  
The UK-PBC risk score for 5, 10 and 15 years will be calculated per Section 5.2 and a descriptive summary 
for each dose will be presented with LOCF imputed values for missing laboratory parameters assessment 
at Week 12 and Week 52. 
9.5.5.8 MELD Score  
The MELD scores will be calculated per Section 5.2 and a descriptive summary for each treatment group 
will be presented.  
9.5.5.9 GLOBE Score  
The GLOBE scores will be calculated per Section 5.2 and a descriptive summary for each treatment group 
will be presented. 
9.6 Safety Analyses 
All safety analyses will be performed on the Safety population based on subject’s initial treatment group 
and 5 mg cohort groups as defined in Section 5 and in total across treatment groups. Safety listings will 
also display the initial dose group as well as the last dose level taken prior to the measurement/event. 
9.6.1 Adverse Events 
An AE includes any condition that: 1) was not present prior to study treatment, but appeared or reappeared 
following initiation of study treatment, or 2) was present prior to study treatment, but worsened during study 
treatment. This would include any condition resulting from concomitant illnesses, reactions to concomitant 
medications, or progression of disease states. Pregnancy should be documented as an AE. AE severity 
will be graded from 1 to 5 according to the CTCAE version 4.0 criteria (V4.03, June 14. 2010). 
A treatment-emergent AE is defined as an AE with onset date at or after the first study medication 
administration and up to 30 days after the last study medication administration. Treatment-related AEs are 
AEs with relationship to the study treatment characterized as ‘Possible’ or ‘Related’ in the CRF. 
All reported AEs will be coded to the appropriate SOC and PT according to the version 22.1 of MedDRA. 
A listing of all AEs will be provided. 
Subject incidence of the following AEs will be tabulated by treatment groups and by SOC and PT: 
• 
treatment-emergent AEs 
• 
treatment-related AEs 
• 
treatment-emergent AEs leading to discontinuation of treatment 
• 
treatment-emergent AEs leading to discontinuation from study 
Subject incidence of the following AEs will be tabulated by preferred term in descending order of frequency: 
• 
treatment-emergent AEs occurring in ≥5% of subjects in any treatment group 
• 
grade 3 or higher treatment-emergent AEs 
In addition, subject incidence of treatment-emergent AEs and treatment-related AEs will be tabulated by 
treatment and by SOC, PT, and maximum severity 
Counting of AEs will be by subject, and subjects will be counted only once within each SOC or PT. For 
tables categorized by severity, subjects with multiple events within a particular SOC or preferred term will 
be counted under the category of their most severe event with that SOC or preferred term. 


 
 
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The following listings will be also provided: 1) subject listing of AEs; 2) subjects with AEs leading to 
discontinuation of treatment; 3) Subjects with AEs leading to discontinuation from study; 4) Subjects with 
AE leading to dose adjustment; 5) Subjects experiencing pruritus, and 6) Subjects who met monitoring 
criteria listed in Section 10.5.1 of the protocol:  
Liver Safety Monitoring 
• 
Elevation of ALT/AST 
       Normal ALT/AST at baseline and 
• 
ALT/AST >5× ULN or 
• 
Total bilirubin is ≥ 1.5 × ULN or ≥ 2 mg/dL 
• 
Elevated ALT/AST at baseline  
• 
ALT/AST 3 × baseline and 
• 
PT/INR > 1.5 × ULN 
• 
Elevation of total bilirubin (>2 × ULN or > 1.5 × baseline), regardless of ALT or AST levels, and 
• 
eosinophilia > 5% 
Muscle Safety Monitoring 
I. 
CK > 5 × ULN  
II. 
CK > 2.5 × ULN and ≤ 5 × ULN 
Serum Creatinine Monitoring 
I. 
Serum creatinine > 2.0 × ULN 
II. 
Serum Creatinine > 1.5 × ULN and <2.0 × ULN 
Pancreatic Safety Monitoring 
I. 
Amylase > 3 × ULN and/or lipase > 3 × ULN 
9.6.2 Deaths and Serious Adverse Events 
Subject incidence of the following will be tabulated by SOC and PT: 
• 
serious treatment-emergent AEs 
• 
serious treatment-emergent treatment-related AEs 
A subject listing of SAEs and AEs with outcome of fatal will be also provided. 
9.6.3 Laboratory Data 
Blood samples will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject 
forgets to fast, the site will continue to draw labs.  
Routine hematology and biochemistry and urinalysis (spot) will be assessed at all visits including ET (early 
termination) and UNS (unscheduled) if applicable. Urinalysis (24-hr) will be collected at Visit 2 (Day 1) and 
Visit 4 (Week 2) or Visit 8 (Week 12)., over two intervals 0-6 hours and 6-24 hours. 
Laboratory results which are BQL will be given a value of the lower level of quantification. PK results which 
are BQL will be assigned values as described in Section 4.2.4. 
Routine Hematology: 
Erythrocyte Count (RBC), Hemoglobin, Hematocrit, Leukocyte Count (WBC), WBC Differential (absolute 
and percentage), Platelets, PT/INR. 


 
 
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Routine biochemistry: 
AP, AST, ALT, GGT, 5’ nucleotidase, Protein, Albumin, Total Bilirubin, Conjugated Bilirubin, Troponin I, 
Unconjugated Bilirubin, Bone-specific AP (absolute units), Liver AP(absolute units), Intestinal AP(absolute 
units), Aldolase, Sodium, Potassium, Chloride, Bicarbonate, BUN/Urea, Creatinine, eGFR, CK (if above 
upper limit of normal, CK-MM, CK-MB, and CK-BB will be measured), venous blood glucose, LDH, TG, 
TC, HDL-C, and LDL-C, Amylase, Creatine, Lipase. 
 
Shift tables of the most extreme post-baseline value (CTCAE grade 1-5, or low/normal/high) relative to 
baseline will be presented by treatment for parameters that have both non-missing baseline and 
post-baseline values. 
Additional biochemistry measurements will be analyzed as described in Section 9.7 Exploratory Analyses 
and are listed in Section 4.1.3 Exploratory Variables. 
 
Urinalysis (spot):  
Sample will be analyzed via dip stick. Blood, Glucose, Ketones, Leukocyte Esterase, Nitrites, pH, and 
Protein will be measured. If positive, microscopic examination of sediments (Urinary White Blood Cells, 
Urinary Red Blood Cells) will be performed. Urine myoglobin will be measured if muscle injury is 
suspected. 
 
Urinalysis (24-hr): 
Will be analyzed for urine creatinine, and creatinine clearance (24-hr) will be calculated.  
Conventional units and ranges will be used for reporting. Out of range of ‘High’ and ‘Low’ will be evaluated. 
Shift tables of worst post-baseline value relative to baseline will be presented by treatment for parameters 
that have both non-missing baseline and post-baseline values. 
Laboratory variables that are included in Section 4.1 Efficacy, will be analyzed as described in section 9.5 
Efficacy Analyses. Descriptive summary will be provided for these variables as well as for Creatine, INR, 
CK, Lipase, Amylase and Serum Creatinine. 
A by-subject listing of abnormal laboratory values will also be presented, where the laboratory parameter 
name along with its out-of-range grade will be specified, for example, “Hemoglobin (low),” Hemoglobin 
(high),” etc. will be displayed in the listing. 
 
9.6.4 Vital Signs 
Vital signs (temperature, heart rate, respiratory rate, blood pressure recorded in the sitting position after at 
least 5 minutes rest) and weight will be assessed on all visits, i.e., Visit 1 (Week -2) through Visit 15 
(Week 56), and ET Visit (if applicable). Height measurement will be performed only on Visit 1 (Week -2). 
Observed and change from baseline in vital signs will be summarized by parameter and treatment group 
as defined in Section 5. Descriptive statistics will be shown for baseline, each post-baseline time point, and 
the change from baseline to each post-baseline time point. 
9.6.5 Physical Examinations and Electrocardiogram (ECGs) 
Complete physical examinations will be performed at screening (Visit 1 Week -2), Visit 7 (Week 8), Visit 14 
(Week 52), Visit 15 (Week 56), and ET visit (if applicable). Symptom-directed (brief) examinations will be 
performed at Visit 2 (Day 1) through Visit 6 (Week 6), and at Visit 8 (Week 12) through Visit 13 (Week 39). 
Shift tables will summarize the worst post-baseline evaluation as compared to baseline visit by Treatment 
Group as defined in Section 5. 
Clinically significant abnormal findings from brief physical examinations will be listed by subject.  
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest at Visit 1 (Week - 2) 
through Visit 15 (Week 56), and ET Visit (if applicable). At Visit 2 through Visit 11 ECG will be performed 


 
 
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approximately 60-90 minutes after dosing. Shift tables will summarize the worst post-baseline evaluation 
as compared to baseline visit. A by-subject listing of abnormal ECG values will be provided. 
9.7 Exploratory Analyses 
The descriptive summaries of the exploratory variables listed in Section 4.1.3 Exploratory Variables will be 
provided for baseline, change and percent change from baseline at Week 12 and Week 52 by Initial dose 
dose groups and 5 mg cohort groups  for the mITT population. 
The correlation between clinical and biochemical/hematological biomarkers listed in Section 4.1.3 may be 
explored. For example, the correlation between total AP and bone-specific AP. 
9.8 Subgroup Analyses 
Subgroup analysis by cirrhotic status at baseline will be performed for the following endpoints: 
• 
Efficacy endpoints: ALP, ALT, Total bilirubin, pruritus, VAS. The analyses will be performed by the 
initial treatment groups using the mITT population  
• 
Safety:  AE will be summarized by the initial treatment groups using the safety population. 
 
10.0 Planned Differences from Protocol 
10.1 Timing of Interim Analyses 
The protocol states that an interim analysis for safety and efficacy will be performed after the 24th subject 
is enrolled. The first interim analysis was performed after the 24th subject performs their Week 8 visit. In 
addition, a second interim analysis was performed when the 24th subject completed their Week 12 visit. A 
third interim analysis was performed when the 45th subject completed their Week 26 visit. A fourth interim 
analysis was performed when the 40th subject completed their Week 52 visit. 
10.2 Clinical Laboratory Analysis Baseline 
The protocol states that two baselines will be used for the analysis of clinical laboratory assessments which 
are described as Baseline 1 and Baseline 2. This analysis plan uses the planned definition for Baseline 1 
for all clinical laboratory assessments, 
10.3 Study Completer 
The protocol states that a subject must complete the Week 56 visit in order to be considered a study 
completer, however most subjects are expected to go directly from this study into the open label long term 
safety study at Week 52. Subjects who roll over into the long term safety study will be considered a 
completer in this study. 
10.4 Analysis Treatment Group 
The protocol states that analyses will be performed by the treatment group the subject was assigned at 
baseline. Additional treatment groups, 5 mg cohort groups, are included in the SAP. 
10.5 Study Populations 
The mITT population defined in the protocol is renamed as ITT population in the SAP.   A revised mITT 
population is defined in the SAP as the primary population for efficacy analyses.   
11.0 Validation 
The programming (including quality control) of the analysis datasets and TFLs will be conducted by PRA 
Health Sciences (PRA). The programming will be conducted under PRA's standard operating procedure 


 
 
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Protocol no: CB8025-21629 
26 November, 2019 Final Version 2.2 
 
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Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved. 
PRS 050 and documented accordingly. The entire set of tables, figures and listings (TFLs) will be checked 
for completeness and consistency prior to its delivery to the Sponsor by the lead statistician and a senior 
level statistician, or above. 
The PRA validation process will be repeated any time TFLs are redelivered using different data. Execution 
of this validation process will be documented through the study Table of Programs that will be provided to 
the client at study conclusion. 
12.0 References 
Hafner KB and Ruberg SJ (1996).  Factorial dose response studies using frequency and magnitude of dose.  
Journal of Biopharmaceutical Statistics, 6(3), 253-262.  
Elman, L.S. Hynan, V. Gabriel, and M.J. Mayo The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 
2010 162:587-93. 


 
 
Sponsor: CymaBay Therapeutics, Inc. 
Statistical Analysis Plan 
Protocol no: CB8025-21629 
26 November, 2019 Final Version 2.2 
 
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Appendix 1 Glossary of Abbreviations 
7α-HC 
7α-hydroxycholesterol 
7-DHC 
7-dehydrocholesterol 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMA 
Anti-Mitochondrial Antibodies 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline Phosphatase 
Apo B-100 
Apolipoprotein B-100 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATV 
Atorvastatin 
AUC 
Area Under the Curve 
β-SITO 
β-sitosterol 
BUN 
Blood Urea Nitrogen 
BQL 
Below Quantifiable Limit 
C4 
7α-hydroxy-4-cholesten-3-one (bile acid precursor) 
CA 
Cholic Acid 
CAMP 
Campesterol 
CD-1 
Crl:CD1(ICR) Mice 
CDCA 
Chenodeoxycholic Acid 
CK 
Creatine Kinase 
CK-MM 
Creatine Kinase Muscle Type 
Cmax 
Maximum Plasma Concentration 
COPR 
Coprostanol 
CRO 
Contract Research Organization 
CSTN 
Cholestanol 
CTX 
C-terminal Telopeptide 
CYP 
Cytochrome P450 
DCA  
Deoxycholic Acid 
DESM 
Desmosterol  
DSMB 
Data Safety and Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay 


 
 
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26 November, 2019 Final Version 2.2 
 
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EOS 
End of Study 
EOT 
End of Treatment 
FDA 
U.S. Food and Drug Administration 
FGF19 
Fibroblast Growth Factor 19 
GCA 
Glycocholic Acid 
GCDCA 
Glycochenodeoxycholic Acid 
GCP 
Good Clinical Practice 
GDCA 
Glycodeoxycholic Acid 
GGT 
Gamma-glutamyl Transferase 
GLCA 
Glycolithocholic Acid 
GUDCA 
Glycoursodeoxycholic Acid 
HDL-C 
High Density Lipoprotein Cholesterol 
HoFH 
Homozygous Familial Hypercholesterolemia 
hs-CRP 
High sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IgM 
Immunoglobulin M 
IXRS 
Interactive Voice/Web Response System 
LANO 
Lanosterol  
LATH 
Lathosterol 
LCA 
Lithocholic Acid 
LDH 
Lactate Dehydrogenase 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOAEL 
Lowest Observed Adverse Effect Level 
LOCF 
Last Observation Carried Forward 
M 
MBX-8025 Metabolite 
MedRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OCA 
Obeticholic Acid, Ocaliva 
P1NP 
Procollagen Type 1 N-terminal Propeptide 
PBC 
Primary Biliary Cholangitis/Primary Biliary Cirrhosis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 


 
 
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PPARδ 
Peroxisome Proliferator-activated Receptor Delta 
PV 
Pharmacovigilance 
q.d. 
Once Daily 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SQLN 
Squalene  
STIG 
Stigmasterol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
TC 
Total Cholesterol 
TCA 
Taurocholic Acid 
TCDCA 
Taurochenodeoxycholic Acid 
TDCA 
Taurodeoxycholic Acid 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLCA  
Taurolithocholic Acid 
Tmax 
Time to Cmax 
TUDCA 
Tauroursodeoxycholic Acid 
UDCA 
Ursodeoxycholic acid 
UK-PBC 
United Kingdom Primary Biliary Cirrhosis Score 
ULN 
Upper Limit of Normal 
UNS  
Unscheduled 
VAS 
Visual Analog Score 
VLDL-C 
Very Low Density Lipoprotein Cholesterol 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WHOCC 
World Health Organization Collaborating Centers 
 
 


 
 
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Statistical Analysis Plan 
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Appendix 2 List of Inferential Analysis Supportive SAS Output 
Appendices 
TFL Appendix 
Appendix Title 
 
 
 
 
 




 
 
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Statistical Analysis Plan 
Protocol no: CB8025-21629 
26 November, 2019 Final Version 2.2 
 
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Added "for PK Analyses" to subsection title 
Deleted Current Max Dose definition 
Deleted Study Period 
Deleted Week 26 Endpoint 
UDCA compliance text was added under UCDA daily 
dose 
Added MELD and MELD-Na Score formula to the general 
deinitions section 
Added GLOBE Score formula to the general definitions 
Updated ITT population definition, and added mITT 
population 
Fourth Interim Analysis added 
Updated Total number of capsules planned formula 
Added "ITT and mITT populations" to PBC history 
summarization 
Added more text to specify populations used for efficacy 
analysis 
Estimate statements in PROC mixed syntax have been 
updated 
Deleted Secondary Analyses 
Baseline was added as a predictor in PROC mixed 
syntax 
"ANCOVA on change from Baseline" and Linear Trend 
Test for Dose Response" was removed 
"Subjects with Cirrhosis" was removed 
MELD score and GLOBE score were added under 
Secondary Analyses section 
Updates were made to Live Safety Monitoring 
Treatment-emergent fatal Aes was removed 
Texts about shift table summaries were added 
Texts about shift table summaries were added 
Subgroup analysis was added 
Additional reference added 
26 November, 2019 
 
Clarify per protocol definition 
Made correction in definition of PBC Response Criteria 
Clarify UDCA compliance definition