A Phase 2b Randomized, Double-Blind, Placebo-controlled, Multicenter Study Evaluating Safety and Efficacy of EDP-305 in Subjects With Liver Biopsy Proven Non-alcoholic Steatohepatitis (NASH) (ARGON-2)
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis
Sponsor: Enanta Pharmaceuticals, Inc



 
Clinical Study Protocol 
 
   
 
        
        Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
 
 
CONFIDENTIAL 
 
Page 3 of 87 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
Principal Investigator:   
 
Signed: 
 
Date: 
 
 
 
 
 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
Page 4 of 87 
 
TABLE OF CONTENTS 
CONTACT INFORMATION .................................................................................................................... 2 
SIGNATURE PAGE ................................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................................... 4 
LIST OF FIGURES .................................................................................................................................... 8 
LIST OF TABLES ...................................................................................................................................... 8 
LIST OF APPENDICES ............................................................................................................................ 8 
LIST OF ABBREVIATIONS .................................................................................................................... 9 
PROTOCOL SYNOPSIS ......................................................................................................................... 12 
1. 
INTRODUCTION........................................................................................................................ 23 
1.1. 
OVERVIEW ....................................................................................................................................... 23 
1.2. 
BACKGROUND ................................................................................................................................. 23 
1.2.1. 
NASH and Farnesoid X Receptor (FXR) .......................................................................... 23 
1.2.2. 
Rationale for Development of EDP-305 for NASH........................................................... 23 
1.3. 
NONCLINICAL STUDIES .................................................................................................................... 24 
1.3.1. 
Mechanism of Action and Pharmacology ......................................................................... 24 
1.3.2. 
Safety Pharmacology ........................................................................................................ 26 
1.3.3. 
Pharmacokinetics ............................................................................................................. 26 
1.3.4. 
Toxicology ........................................................................................................................ 28 
1.4. 
CLINICAL STUDIES ........................................................................................................................... 28 
1.4.1. 
Phase 1 Clinical Studies ................................................................................................... 28 
1.4.2. 
Phase 2 Clinical Study: EDP 305-101 .............................................................................. 31 
1.5. 
POTENTIAL RISKS AND BENEFITS .................................................................................................... 33 
1.5.1. 
Potential Risks to Subjects Enrolled in the Study ............................................................. 33 
1.5.2. 
Potential Benefits to Subjects Enrolled in the Study ......................................................... 34 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................................ 35 
2.1. 
OBJECTIVES ..................................................................................................................................... 35 
2.1.1. 
Primary Objective ............................................................................................................. 35 
2.1.2. 
Secondary Objectives ........................................................................................................ 35 
2.1.3. 
Exploratory Objectives: .................................................................................................... 35 
2.2. 
ENDPOINTS ...................................................................................................................................... 35 
2.2.1. 
Primary Endpoint ............................................................................................................. 35 
2.2.2. 
Secondary Endpoints: ....................................................................................................... 36 
2.2.3. 
Exploratory Endpoints:..................................................................................................... 36 
3. 
SELECTION OF SUBJECTS .................................................................................................... 37 
3.1. 
SUBJECT INCLUSION CRITERIA ........................................................................................................ 37 
3.2. 
SUBJECT EXCLUSION CRITERIA ....................................................................................................... 38 
3.3. 
ADDITIONAL CONTRACEPTION DETAILS/REQUIREMENTS................................................................ 41 
4. 
STUDY DESIGN .......................................................................................................................... 42 
4.1. 
DOSE AND TREATMENT SCHEDULE.................................................................................................. 42 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
Page 5 of 87 
 
4.2. 
RATIONALE FOR STUDY DESIGN ...................................................................................................... 42 
4.2.1. 
Justification of Design, Endpoints and Patient Population .............................................. 42 
4.2.2. 
Justification of EDP-305 Dose ......................................................................................... 44 
5. 
STUDY DRUG AND TREATMENT OF SUBJECTS ............................................................. 47 
5.1. 
DESCRIPTION OF STUDY DRUG ........................................................................................................ 47 
5.2. 
PACKAGING AND LABELING ............................................................................................................ 47 
5.3. 
STORAGE ......................................................................................................................................... 47 
5.4. 
ACCOUNTABILITY ............................................................................................................................ 47 
5.5. 
HANDLING AND DISPOSAL ............................................................................................................... 47 
5.6. 
TREATMENT ASSIGNMENT/ RANDOMIZATION ................................................................................. 48 
5.7. 
STUDY DRUG DOSE AND ADMINISTRATION ..................................................................................... 48 
5.7.1. 
Dispensing of Study Drug ................................................................................................. 48 
5.7.2. 
Treatment Compliance ...................................................................................................... 49 
5.8. 
CONCOMITANT MEDICATIONS ......................................................................................................... 49 
5.8.1. 
Coadministration of Vitamin E and Pioglitazone ............................................................. 49 
5.8.2. 
Coadministration of EDP-305 and Metformin ................................................................. 49 
5.8.3. 
Coadministration of Antihypertensives ............................................................................. 50 
5.9. 
PROHIBITED MEDICATIONS .............................................................................................................. 50 
5.9.1. 
Inhibitors and Inducers of CYP34 .................................................................................... 50 
5.9.2. 
Lipid Lowering Agents ...................................................................................................... 50 
5.9.3. 
Antidiabetic Treatments .................................................................................................... 50 
5.9.4. 
Immunosuppressants ......................................................................................................... 50 
5.9.5. 
Vaccines, Investigational Products and Treatments for NASH ........................................ 51 
5.10. 
OTHER RESTRICTIONS...................................................................................................................... 51 
6. 
BLINDING ................................................................................................................................... 52 
6.1. 
BLINDING OF STUDY SAMPLES ........................................................................................................ 52 
6.1.1. 
Blinding of MRI/MRE, NASH FibroSure, and Liver Biopsy ............................................. 52 
6.1.2. 
Blinding of Pharmacokinetic Samples .............................................................................. 52 
6.2. 
UNBLINDING .................................................................................................................................... 52 
6.3. 
24/7 ACCESS FOR URGENT PROTOCOL-RELATED MEDICAL ISSUES/QUESTIONS ............................. 53 
7. 
STUDY CONDUCT AND VISIT SCHEDULE ........................................................................ 54 
7.1. 
STUDY VISITS .................................................................................................................................. 54 
7.1.1. 
Screening .......................................................................................................................... 54 
7.1.2. 
Baseline (Day 1) ............................................................................................................... 55 
7.1.3. 
Treatment Period Visits (Day 7 through Week 72/EOT) .................................................. 55 
7.1.4. 
Safety Follow-up Period (End of Study Visit) ................................................................... 56 
7.2. 
SUBJECT WITHDRAWAL / EARLY TERMINATION .............................................................................. 56 
7.2.1. 
Withdrawal Criteria .......................................................................................................... 57 
7.2.2. 
Documentation of Withdrawal of Subjects........................................................................ 57 
7.3. 
SITE OR STUDY DISCONTINUATION .................................................................................................. 57 
7.3.1. 
Study Discontinuation ....................................................................................................... 57 
7.3.2. 
Site Termination................................................................................................................ 58 
7.3.3. 
Study Termination Procedures ......................................................................................... 58 
8. 
STUDY PROCEDURES/EVALUATIONS ............................................................................... 59 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
Page 6 of 87 
 
8.1. 
TIMING OF ASSESSMENTS ................................................................................................................ 59 
8.2. 
DEMOGRAPHICS AND MEDICAL HISTORY ........................................................................................ 59 
8.3. 
CLINICAL EVALUATIONS ................................................................................................................. 59 
8.3.1. 
Vital Sign Measurements, Body Temperature and Electrocardiograms ........................... 59 
8.3.2. 
Physical Examination ....................................................................................................... 60 
8.3.3. 
Weight and Body Mass Index (BMI) ................................................................................. 60 
8.3.4. 
Quality of Life Assessment ................................................................................................ 60 
8.3.5. 
Assessment of Pruritus ...................................................................................................... 60 
8.3.6. 
Adverse Events .................................................................................................................. 61 
8.4. 
CLINICAL LABORATORY AND DIAGNOSTIC PROCEDURES ................................................................ 61 
8.4.1. 
Safety Laboratory Assessments ......................................................................................... 61 
8.4.2. 
Noninvasive Evaluations of Fibrosis ................................................................................ 62 
8.4.3. 
Markers of Inflammation .................................................................................................. 62 
8.4.4. 
Pharmacodynamic Biomarkers for FXR activity .............................................................. 63 
8.4.5. 
Pharmacokinetic Samples ................................................................................................. 64 
8.4.6. 
Pregnancy and Menopausal Laboratory Testing .............................................................. 65 
8.4.7. 
Liver Magnetic Resonance Imaging ................................................................................. 66 
8.4.8. 
Liver Biopsy ...................................................................................................................... 66 
8.4.9. 
Exploratory Research Samples ......................................................................................... 67 
9. 
SAFETY MONITORING AND REPORTING ........................................................................ 68 
9.1. 
DEFINITIONS .................................................................................................................................... 68 
9.1.1. 
Pretreatment Events .......................................................................................................... 68 
9.1.2. 
Adverse Events .................................................................................................................. 68 
9.1.3. 
Serious Adverse Events (SAEs) ......................................................................................... 68 
9.2. 
DOCUMENTING AND REPORTING OF ADVERSE EVENTS (INCLUDING SERIOUS ADVERSE 
EVENTS) .......................................................................................................................................... 69 
9.2.1. 
Documenting and Reporting Adverse Events .................................................................... 69 
9.2.2. 
Assigning Attribution of Adverse Events ........................................................................... 70 
9.2.3. 
Classifying Action Taken with Study Drug ....................................................................... 70 
9.2.4. 
Classifying Adverse Event Outcome ................................................................................. 71 
9.2.5. 
Documenting and Reporting Serious Pretreatment Events and Serious Adverse 
Events................................................................................................................................ 71 
9.2.6. 
Documenting and Reporting of Pregnancy ....................................................................... 72 
9.3. 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................... 72 
9.4. 
SPONSOR’S REVIEW OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................... 72 
9.5. 
DATA SAFETY MONITORING BOARD ............................................................................................... 72 
10. 
SUBJECT SAFETY MANAGEMENT ...................................................................................... 73 
10.1. 
INDIVIDUAL SUBJECT STOPPING RULES ........................................................................................... 73 
10.2. 
MANAGEMENT OF LIVER ENZYME ELEVATIONS .............................................................................. 73 
11. 
STATISTICAL CONSIDERATIONS ....................................................................................... 75 
11.1. 
GENERAL CONSIDERATIONS ............................................................................................................ 75 
11.2. 
SAMPLE SIZE CONSIDERATIONS ....................................................................................................... 75 
11.3. 
ANALYSIS POPULATIONS ................................................................................................................. 75 
11.4. 
SUBJECT DISPOSITION AND DEMOGRAPHIC DATA ........................................................................... 75 
11.5. 
METHOD OF TREATMENT ASSIGNMENT ........................................................................................... 76 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
Page 7 of 87 
 
11.6. 
PRIMARY EFFICACY ANALYSIS ........................................................................................................ 76 
11.6.1. Secondary Efficacy Analysis ............................................................................................. 76 
11.7. 
SAFETY ENDPOINTS ......................................................................................................................... 77 
11.7.1. Treatment Compliance ...................................................................................................... 77 
11.7.2. Adverse Events .................................................................................................................. 77 
11.7.3. Clinical Laboratory Data ................................................................................................. 77 
11.7.4. Electrocardiogram Data ................................................................................................... 78 
11.7.5. Vital Signs ......................................................................................................................... 78 
11.7.6. Concomitant Medications ................................................................................................. 78 
11.7.7. Physical Examinations ...................................................................................................... 79 
11.8. 
PRURITUS ANALYSES ....................................................................................................................... 79 
11.9. 
NON-INVASIVE TESTS (NITS) .......................................................................................................... 79 
11.10. 
PHARMACOKINETIC ANALYSES ....................................................................................................... 79 
11.11. 
PHARMACODYNAMIC ANALYSES ..................................................................................................... 79 
11.12. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ..................................................................... 79 
11.13. 
QUALITY OF LIFE SCALES (SF-36 AND CLDQ-NASH) AND CARDIOVASCULAR RISK SCORE 
ANALYSES (ASCVD) ...................................................................................................................... 79 
11.14. 
INTERIM ANALYSES ......................................................................................................................... 79 
11.15. 
MULTIPLICITY ................................................................................................................................. 80 
11.16. 
SUBGROUP AND COVARIATE ANALYSIS ........................................................................................... 80 
12. 
STUDY ADMINISTRATION ..................................................................................................... 81 
12.1. 
ETHICAL CONSIDERATIONS ............................................................................................................. 81 
12.1.1. Ethical Conduct of the Study ............................................................................................ 81 
12.1.2. Ethical Review .................................................................................................................. 81 
12.1.3. Written Informed Consent ................................................................................................. 81 
12.1.4. Investigator Compliance ................................................................................................... 81 
12.2. 
DATA COLLECTION .......................................................................................................................... 82 
12.3. 
STUDY MONITORING ....................................................................................................................... 82 
12.4. 
QUALITY ASSURANCE ..................................................................................................................... 82 
12.5. 
RETENTION OF RECORDS ................................................................................................................. 83 
12.6. 
INFORMATION DISCLOSURE ............................................................................................................. 83 
12.6.1. Confidentiality .................................................................................................................. 83 
12.6.2. Publication Policy ............................................................................................................ 83 
13. 
REFERENCES ............................................................................................................................. 84 
14. 
APPENDICES .............................................................................................................................. 86 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 8 of 87 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..................................................................................................................... 42 
Figure 2: 
Probability of Pruritus and ALT response as a function of EDP-305 exposure ............... 46 
 
LIST OF TABLES 
Table 1: 
Safety Pharmacology Studies ........................................................................................... 26 
Table 2: 
EDP-305 Phase 1 Clinical Studies Conducted under the NASH IND .............................. 29 
Table 3: 
Laboratory Evaluations ..................................................................................................... 64 
Table 4: 
Options for Action Taken with Study Drug ...................................................................... 70 
Table 5:  
Classification and Definition of AE Outcomes................................................................. 71 
Table 6: 
Retest Frequency Recommendations ................................................................................ 74 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments .................................................................................................. 86 
 
 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 9 of 87 
 
 
LIST OF ABBREVIATIONS 
AE, AR 
adverse event(s), adverse reaction(s) 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
apo 
apolipoproteins  
APRI 
AST to Platelet Ratio Index 
ASCVD 
atherosclerotic cardiovascular disease 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BA 
bile acid 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BSEP 
bile salt export pump 
C4 
7-alpha-Hydroxy-4-cholesten-3-one 
CK18 
cytokeratin 18 
Cmax 
maximum concentration 
CRO 
contract research organization 
CRP 
C-reactive protein 
CV 
cardiovascular 
CYP 
cytochrome P450 
CYP7A1 
cholesterol 7α-hydroxylase 
DLQI 
dermatology life quality index 
EC 
ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELF 
enhanced liver fibrosis 
EOS 
end-of-study 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor  
FIH 
first-in-human 
FIB-4 
fibrosis-4 score 
FSH 
follicle stimulating hormone 
FXR 
farnesoid X receptor 
GCP 
good clinical practice 
GGT 
Gamma-Glutamyl Transferase 
GLP 
good laboratory practice 
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycated hemoglobin 
HDL-C 
high density lipoprotein cholesterol 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 10 of 87 
 
 
HEK293 
human embryonic kidney 293 cells 
HOMA 
homeostasis model assessment 
HV 
healthy volunteers 
IA 
interim analysis 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL-C 
low density lipoprotein cholesterol 
MAD 
multiple ascending dose 
MATE1, MATE2-K 
multidrug and toxin extrusion proteins 
MRGPR 
Mas-related G-protein coupled receptor 
MRE 
magnetic resonance elastography 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging - proton density fat fraction 
mRNA 
messenger ribonucleic acid 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NAS 
NAFLD activity score 
NFS 
NAFLD fibrosis score 
NOAEL/NOEL 
no observed adverse effect level / no observed effect level 
OCA 
obeticholic acid 
OCT2  
organic cation transporter 2 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PIIINP 
procollagen III amino terminal peptide 
PK 
pharmacokinetics 
PD 
pharmacodynamics 
PN 
presumptive NAFLD 
PR 
electrocardiographic interval occurring between the onset of the P wave and 
the QRS complex, representing time for atrial and ventricular depolarization, 
respectively 
PRO C3 
type 3 procollagen 
PSC 
primary sclerosing cholangitis 
QD 
once daily 
QoL 
quality of life 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 11 of 87 
 
 
QRS 
electrocardiographic deflection between the beginning of the Q wave and 
termination of the S wave, representing the time for ventricular 
depolarization 
QT 
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur 
QTcF 
QT interval corrected by Fridericia's formula 
RR 
interval between successive heart beats using the R-wave peaks 
SAD 
single ascending dose 
SAE 
serious adverse event(s) 
SAP 
statistical analysis plan 
SHP 
small heterodimer partner 
T2DM 
type 2 diabetes mellitus 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglyceride(s) 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
TNF 
tumor necrosis factor 
TGR5 
Takeda G-protein-coupled receptor 5/ also known as M-BAR 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog score 
WBC 
white blood cell 
 
 
 
 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 12 of 87 
 
 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Enanta Pharmaceuticals, Inc. 
Name of Investigational Product: EDP-305 
Study Title: A Phase 2b Randomized, Double Blind, Placebo-Controlled, Multicenter Study 
Evaluating Safety and Efficacy of EDP-305 in Subjects with Liver Biopsy Proven Non-
Alcoholic Steatohepatitis (NASH) (ARGON-2) 
Protocol Number:  EDP 305-102  
Phase of Development: 2b 
Study Center: This will be a multicenter global study (including for example, North America, 
Europe, Asia-Pacific (APAC) and Latin America (LATAM)) 
Number of Subjects Planned: 
 
Investigational Product, Dosage, Duration and Mode of Administration:  EDP-305 will be 
supplied as 0.5 mg and 1 mg tablets for oral administration; doses administered will be EDP-
305 1.5 mg, EDP-305 2 mg, or matching placebo taken once daily (QD) for 72 weeks. 
Duration of Treatment: 72 weeks 
Study Objectives: 
Primary Objective:  
To evaluate the effect of EDP-305 compared to placebo on liver histology in non-cirrhotic 
NASH subjects with stage 2 or 3 fibrosis   
Secondary Objectives: 
• To evaluate the effect of EDP-305 on liver histology by assessing: 
 Improvement of fibrosis by at least 1 stage and/or resolution of NASH, without 
worsening of either  
 No worsening of fibrosis and no worsening of NASH 
 Resolution of fibrosis 
 Improvement in each histological feature of NASH by at least 1 point  
 Improvement of fibrosis by ≥ 2 stages 
 Improvement in NAS by at least 2 points with no worsening of fibrosis 
 Improvement of fibrosis and resolution of NASH as a composite endpoint and as 
defined by both endpoints being met in the same subject 
 Resolution of NASH and no worsening of liver fibrosis 
 Histological progression to cirrhosis based on the overall assessment made 
• To evaluate the safety of EDP-305  
• To evaluate the effect of EDP-305 on pruritus 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
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Eligibility Criteria:  
 
Subject Inclusion Criteria  
A subject must meet all the following criteria in order to participate in the study: 
1. Informed consent documentation signed and dated by the subject. 
2. Male and female subjects, of all ethnic origins, between the ages of 18 and 75 years, 
inclusive. 
3. Subjects of all ethnic origins should have a Body Mass Index (BMI) > 25 kg/m2 and ≤45 
except for Asian subjects who qualify for the study with BMI > 23kg/m2.                                        
4. Histological evidence of definite NASH based on NASH Clinical Research Network 
(CRN) criteria obtained from assessment of a liver biopsy by the central 
histopathologist. The biopsy may be obtained either 1) during the Screening window or 
2) within 26 weeks prior to the Screening visit. [Note:  if the liver biopsy needs to be 
performed as part of the Screening assessments, it may be scheduled following informed 
consent, but must not be performed until the subject has qualified for study entry based 
on completion of all other Screening assessments and procedures.] 
5. NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each 
component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, 
ballooning scored 0-2). 
6. Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System. 
7. For subjects taking Vitamin E or pioglitazone, the following three criteria apply: 
• subjects must have been on a stable dose for at least 12 weeks prior to the qualifying 
biopsy, and 
• treatment with Vitamin E or pioglitazone cannot have started after the qualifying 
biopsy, and 
• it is expected that subjects will continue on the same dosing regimen throughout 
study participation unless required to adjust doses due to safety reasons. 
8. Subjects who had previously been taking Vitamin E or pioglitazone (but are no longer 
taking either one), must have discontinued Vitamin E or pioglitazone a minimum of 12 
weeks prior to the qualifying biopsy. 
9. Weight change <5% after the qualifying biopsy.  
10. Subjects must have Screening laboratory values for Hepatitis B surface antigen 
(HBsAg), anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus 
(HIV) 1 and 2 antibodies (Ab) as seronegative. [Note: subjects previously infected by 
chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained 
virologic response (SVR) for at least 3 years will be allowed.] 
11. For hypertensive patients, blood pressure should be controlled by stable dose of anti-
hypertensive medication for at least 8 weeks prior to Screening with the intention to 
keep the regimen stable during the study.  
12. A woman of childbearing potential who is sexually active (see Section 3.3 for 
clarification) with a male must agree to use two effective methods of contraception from 
the date of Screening until 30 days after the last dose of study drug. Effective methods of 
contraception are defined as: 
A condom with or without spermicide for the male partner and at least one of the 
following for the female subject: 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 17 of 87 
 
 
a. Intrauterine device 
b. Occlusive cap (diaphragm or cervical/vault caps) 
c. Established oral, injectable, implantable, transdermal, or intravaginal hormonal 
contraceptive (started a minimum of 2 weeks prior to Screening) 
d. Bilateral tubal ligation or fallopian tube inserts 
The above does not apply to a female subject who has a vasectomized male as the sole 
partner or who is of nonchildbearing potential (i.e., physiologically incapable of 
becoming pregnant) as defined below: 
a. Has had a hysterectomy ≥12 weeks prior to dosing or 
b. Has had a bilateral oophorectomy (ovariectomy), or bilateral salpingectomy, or 
c. Is postmenopausal, defined as  
• Having a total cessation of menses for at least 2 years, or  
• Having a cessation of menses between 1 to 2 years together with a follicle 
stimulating hormone [FSH] level of >35 mIU/mL  
13. A male subject who has not had a vasectomy and is sexually active with a woman of 
childbearing potential must agree to use effective contraception from the date of 
Screening to 90 days after the last dose of study drug (Note: For a male subject who has 
had a vasectomy, use of a condom with or without spermicide will still be required). 
Effective contraception is defined as a condom and spermicide and at least one of the 
following for a female partner: 
a. Intrauterine device 
b. Occlusive cap (diaphragm or cervical/vault caps) 
c. Established oral, injectable, implantable, transdermal, or intravaginal 
contraceptive (started a minimum of 2 weeks prior to Screening) 
d.  Bilateral tubal ligation or fallopian tube inserts 
14. Male subjects must agree to refrain from sperm donation from the date of Screening 
until 90 days after the last dose of study drug. 
15. Subject must be willing and able to adhere to the assessments, visit schedules, 
prohibitions and restrictions, as described in this protocol. 
16. AST > 30 IU/L. 
17. Magnetic resonance imaging - proton density fat fraction (MRI-PDFF) ≥8%. 
 
Subject Exclusion Criteria  
Subjects will not be eligible to participate in the study if they meet any of the following criteria: 
1. Laboratory Screening results as indicated below: 
• Total white blood cells (WBC) <3000 cells/mm3 
• Absolute neutrophil count (ANC) <1500 cells/mm3 
• Platelet count <140,000/mm3 
• International Normalized Ratio, INR >1.2 (unless due to use of anticoagulants) 
• Estimated glomerular filtration rate (eGFR) < 60 mL/min according to the 
Modification of Diet in Renal Disease (MDRD) equation 
• AST ≥5× ULN 
• ALT ≥5× ULN 
• ALP ≥ 2x ULN 

Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 18 of 87 
 
 
• Total bilirubin > 1.5 times ULN during Screening. 
[Note: Patients with Gilbert’s syndrome will be allowed following review by the 
Medical Monitor if they have a known history of Gilbert’s syndrome with a normal 
direct bilirubin value and normal reticulocyte count.] 
2. Pregnant or nursing females. 
3. MELD: Model for End-stage Liver Disease score >12.  
4. Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver 
disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), 
autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, 
drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC).  
5. History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute 
biliary obstruction), unless the subject has had a cholecystectomy (more than 12 weeks 
prior to Screening). 
6. History of liver transplant, or current placement on a liver transplant list. 
7. Hepatorenal syndrome (type I or II).  
8. Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh 
Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks 
of Screening and/or histological presence of liver cirrhosis.  
9. Prior or planned ileal resection, or prior or planned bariatric surgery. [Note: Subjects 
who have undergone gastric surgeries that do not affect drug absorption (e.g., gastric 
band or gastric sleeve procedures) will be allowed if they are stable for at least 1 year 
prior to Screening. Gastrectomy or Roux-en-Y bypass will be allowed if stable for at 
least 3 years prior to Screening.]  
10. Subjects with clinically or otherwise documented cardiovascular or cerebrovascular 
disease including clinically significant anomalies of rhythm or pattern of ECG, that in 
the judgement of the Principal Investigator (PI) could affect the safety of the subject or 
their ability to comply with the study requirements. 
11. HbA1c ≥ 9.5% within 60 days prior to Day 1. 
12. Use of a new antidiabetic regimen in the months prior to Screening including metformin, 
GLP-1 agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or 
dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated 
receptor (PPAR)γ agonists (e.g. pioglitazone or rosiglitazone). For pre-existing 
antidiabetic treatment, subjects should be on a stable dose of antidiabetic drugs: (1) for at 
least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 
inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to 
Screening with the intention to keep the regimen stable during the study. [Note: 
Sulfonylureas and insulin are only permitted if glycemia is self-monitored by the subject; 
subjects treated with insulin are eligible if clinically stable on insulin treatment (i.e., no 
recurrent acute hypo- or hyperglycemic episodes diagnosed clinically with serum 
glucose levels of <50 mg/dL or >200 mg/dL) for at least 8 weeks prior to Screening.] 
13. Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to 
Screening. [Note: Subjects on a stable dose of statins or other lipid lowering agents for 
at least 12 weeks prior to Screening are allowed with the intention to keep the regimen 
stable during the study.]  

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14. Use of a new fibrate regimen from 12 weeks prior to Screening. [Note: Subjects on a 
stable dose of fibrates for at least 12 weeks prior to Screening are allowed with the 
intention to keep the regimen stable during the study.] 
15. Subjects with contraindications to MRI imaging, or not being able to have the MRI 
performed. [Note: Contraindications to MRI include insurmountable claustrophobia, 
implantable, metal devices, girth, etc. Stents or other devices allowed at PI’s discretion, 
if they do not interfere with functioning MRI.] 
16. Subject has received any investigational agent (including investigational vaccine) or 
biological product within 30 days or 5 times the half-life (whichever is longer) prior to 
the planned first dose of study drug. [Note: This includes agents administered during 
clinical trial participation; See Section 5.9.5.]  
17. Use of an experimental or approved treatment for NASH within 26 weeks of Screening. 
[Note: Subjects enrolled in a previous clinical trial for EDP-305 who discontinued due 
to safety reasons within any time window are not eligible for enrollment.] 
18. Prior use of obeticholic acid (OCA) within 26 weeks of Screening and/or concurrent 
treatment with OCA (or any other FXR agonists). [Note: Subjects who have previously 
received OCA and who discontinued due to safety reasons within any time window are 
not eligible for enrollment.] 
19. Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in 
duration within 1 year prior to Screening with the intention to continue during the study 
(chronic use of inhaled, topical, ophthalmological, nasal corticosteroids is allowed).  
20. Use of any prohibited concomitant medications, including systemic CYP3A4 inhibitors 
and inducers, within 14 days prior to the first dose of study drug and for the duration of 
the study. 
21. Clinically significant history of drug sensitivity or drug allergy, as determined by the PI. 
22. Current or history of significant alcohol consumption defined as: >14 standard drinks per 
week and/or ≥4 standard drinks per occasion for males and >7 standard drinks per week 
and/or ≥3 standard drinks per occasion for females. [Note: A standard drink is 12 oz of 
beer (5% alcohol), 5 oz table wine (12% alcohol), or 1.5 oz of spirits (40% alcohol).] 
23. History of substance (including alcohol) abuse and in the judgment of the PI, the subject 
would not be suitable for participation in the study. 
24. Any other condition(s) that would compromise the safety of the subject or compromise 
the quality of the clinical study, as judged by the PI. 
25. Use of medication for weight loss or appetite reduction (e.g.  orlistat, 
bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-
prescription supplements) at Screening. [Note: Subjects on a stable dose for at least 12 
weeks prior to Screening or time of pre-treatment liver biopsy are allowed if intended to 
be continued at the same dose during the study.  However start of new medications 
during the study is not allowed.]    
26. History of malignancy of any organ system (other than localized and considered cured 
cutaneous basal or squamous cell carcinoma, or in situ cervical cancer), treated or 
untreated, within 5 years of Screening. 

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Subject Withdrawal: 
Subjects may be discontinued from the study at any time if the subject, PI, or Sponsor 
determines that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include: 
• Adverse Event 
• Lack of efficacy 
• Lost to Follow-up 
• Withdrawal by subject 
• Protocol Deviation (including non-compliance with study drug dosing or study 
procedures) 
• Pregnancy 
• Study terminated by Sponsor 
• Other   
Subjects who prematurely withdraw from the study for any reason after having been randomized 
will not be replaced. Subjects who prematurely discontinue treatment early and received at least 
one dose of study drug should return to the clinic within one week to complete the EOT Visit 
and for the Safety Follow up Visit, 4 weeks after their last dose.  
Statistical Methods: 
Detailed statistical analysis will be outlined in the Statistical Analysis Plan (SAP).   
Analyses Populations 
• Safety Population (SAF): All subjects who receive at least one dose of study drug. 
Subjects will be included in the treatment group that corresponds to the study drug 
received during the study. 
• Intent-to-treat (ITT) Population: ITT subjects will be considered those randomized to 
treatment. ITT subjects will be analyzed according to the treatment to which they were 
randomized. In the event the SAF is the same as ITT only the ITT will be reported. This 
will be the primary efficacy population. 
• Per Protocol (PP) Population: All randomized and treated subjects that do not have 
major protocol deviations which could unduly influence the efficacy analysis. 
• Pharmacokinetic Population: All subjects receiving active study drug and having any 
measurable plasma concentration of study drug at any time point. 
Safety Analyses: Statistical methods for the safety analyses will be primarily descriptive in 
nature. No formal statistical comparisons of EDP-305 dose levels will be made. Safety data, 
including AEs, vital signs, ECGs, concomitant medications, and laboratory values will be 
summarized separately for each treatment group. Change from baseline will be included in 
summary tables for vital signs, ECG parameters, and laboratory parameters. Shift tables will 
also be generated for each safety laboratory parameter. All laboratory data will be included in 
the data listings and all test values outside the normal range will be flagged. Adverse events will 
be summarized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class and preferred term by treatment group.  

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1. 
INTRODUCTION 
1.1. 
Overview 
EDP-305 (also known as EPS-2305, EPC-2305 or EP-022305) is a farnesoid X receptor (FXR) 
agonist being investigated by Enanta Pharmaceuticals, Inc. (Enanta) as a potential treatment for 
Nonalcoholic Steatohepatitis (NASH) with liver fibrosis. This study, EDP 305-102, is a 
randomized, double-blind, placebo-controlled, phase 2b study designed to assess the safety and 
efficacy of EDP-305 compared to placebo in subjects with liver biopsy proven NASH.  
1.2. 
Background  
1.2.1. 
NASH and Farnesoid X Receptor (FXR) 
Non-alcoholic fatty liver disease (NAFLD) is defined by excess accumulation of lipids in the 
liver which develops in the absence of other causes for secondary hepatic fat accumulation. 
Historically, NAFLD encompasses a wide spectrum of conditions from nonalcoholic fatty liver 
(NAFL) characterized by simple steatosis with minimal or no inflammation to NASH which is 
characterized by hepatic steatosis and inflammation with hepatocyte damage (ballooning) and 
with or without fibrosis (Bertot & Adams, 2016; Chalasani et al., 2012). 
Bile acids (BA) play a key role in regulating liver and metabolic homeostasis including 
regulation of lipid and glucose metabolism mediated through two receptor pathways, FXR and 
Takeda G-protein-coupled receptor 5 (TGR5). FXR is a member of the nuclear hormone receptor 
superfamily and is considered a master regulator of many BA activities including feedback 
regulation of BA synthesis, gluconeogenesis and glycogenolysis in the liver, and peripheral 
insulin sensitivity in adipose tissue (McMahan et al., 2013). Given the critical role BAs play in 
liver homeostasis and the role of FXR in regulating BA biosynthesis, FXR has become a target 
for therapeutic intervention in NASH. 
1.2.2. 
Rationale for Development of EDP-305 for NASH 
NASH is considered a serious disease with unmet medical need (FDA, 2018) and if not treated, it 
can progress to life-threatening conditions such as cirrhosis and hepatocellular carcinoma. 
Recently, NASH has been associated with an approximate 10-fold increase in liver-related 
mortality when compared to an identical age and sex-matched population (Ratziu, 2013). Over 
the past decade the frequency of NASH as the primary indication for liver transplant has 
increased dramatically, and is continuing to rise (Agopian et al., 2012). Based on the United 
Network for Organ Sharing and Organ Procurement and Transplantation Network 
(UNOS/OPTN) registry, from 2004 to 2013, the number of registrants diagnosed with NASH 
demonstrated the greatest change, increasing 170% (from 804 to >2000 registrants) to become 
the second leading etiology of chronic liver disease among new waitlist registrants in 2013 
(Wong et al., 2015). Data showed that patients with NASH were less likely to undergo liver 
transplantation and less likely to survive for 90 days on the waitlist than patients with hepatitis C 
virus (HCV) infection, alcoholic liver disease (ALD), or combination of HCV and ALD. In 
addition, by 2012 NASH had become the second leading etiology of hepatocellular carcinoma 
(HCC) leading to liver transplantation in the United States (US) (Wong et al., 2015). 

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FXRs are nuclear hormone receptors expressed in high amounts in body tissues that participate 
in BA metabolism including the liver, intestines, and kidneys. BAs are the natural ligands of the 
FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, 
which is the rate-limiting enzyme in BA synthesis. Additionally, FXRs play a critical role in 
carbohydrate and lipid metabolism and in the regulation of insulin sensitivity. These receptors 
also modulate liver growth and regeneration during liver injury.  
Data have shown that hepatic expression of FXR is decreased in NAFLD patients, which is 
associated with hepatic triglyceride (TG) accumulation and hepatic steatosis. Effects observed in 
FXR deficiency animal models include hepatic steatosis, hyperlipidemia, hyperglycemia, BA 
overload, inflammation and fibrosis (Xu et al., 2014). Moreover, studies have shown that these 
metabolic dysfunctions can be improved by FXR activation, indicating that FXR agonism may 
represent a new modality for NASH treatment.  
In line with these findings, and to address the unmet medical need of NASH, Enanta is 
developing EDP-305 as a selective FXR agonist. Nonclinical studies have shown that EDP-305 
can decrease the expression of genes that encode lipogenic enzymes, as well as inflammation and 
fibrosis-related genes. In models of NASH and dyslipidemia, EDP-305 has demonstrated the 
potential for reduction in NASH and improvement in insulin sensitivity. In a First-in-Human 
(FIH) clinical study, EDP-305 was generally safe and well tolerated and appeared to positively 
affect levels of biomarkers associated with FXR activity (Ahmad et al., 2018). In the phase 2 
clinical study, EDP 305-101, 12-week therapy with EDP-305 led to statistically significant 
improvements in liver biochemistry and hepatic steatosis. Pharmacokinetic (PK) exposures were 
associated with strong target engagement as measured by 7-alpha-Hydroxy-4-cholesten-3-one 
(C4) and gamma-glutamyl transferase (GGT) reductions and fibroblast growth factor -19 (FGF-
19) and alkaline phosphatase (ALP) increases. EDP-305 was generally safe, with the majority of 
treatment-emergent adverse events (TEAEs) being mild to moderate. Thus, due to its promising 
nonclinical safety and pharmacological profile, and clinical efficacy and safety results to date, 
the Sponsor plans to continue investigation of EDP-305 as a potential treatment for NASH with 
fibrosis.  
1.3. 
Nonclinical Studies 
1.3.1. 
Mechanism of Action and Pharmacology 
A summary of pharmacology studies is presented below. Additional details for each study as 
well as details on additional studies can be found in the Investigator’s Brochure (IB). As noted 
for each study, the natural agonist of FXR, chenodeoxycholic acid (CDCA) and/or its close 
synthetic analog obeticholic acid (OCA), were used as controls. Obeticholic acid is approved for 
the treatment of primary biliary cholangitis (PBC) and is being evaluated for the treatment of 
NASH. 
1.3.1.1. 
Mechanism of Action 
EDP-305 is an FXR agonist which, as discussed above, plays an essential role in the feedback 
regulation of BA biosynthesis. The efficacy and potency of EDP-305 was demonstrated in 
several in vitro assays.   

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1.4.2. 
Phase 2 Clinical Study: EDP 305-101 
A Phase 2 Dose Ranging, Randomized, Double Blind, and Placebo-Controlled Study Evaluating 
the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects with Non-
Alcoholic Steatohepatitis (NASH) 
EDP 305-101 (ARGON-1) was a phase 2 dose-ranging, randomized, double blind, and placebo-
controlled study evaluating the safety, tolerability, PK, and efficacy of EDP-305 in subjects with 
NASH. A total of 134 subjects with a diagnosis of NASH were enrolled into the study. Presence 
of NASH was based on either histologic evidence (a historical liver biopsy within 24 months of 
Screening and consistent with NASH with fibrosis and no cirrhosis) or phenotypic diagnosis of 
NASH based on elevated ALT and diagnosis of Type 2 diabetes mellitus (T2DM) or pre-
diabetes. In both cases, subjects had a Screening magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) with >8% steatosis and elevated ALT. This study evaluated two active 
doses of EDP-305 versus placebo; 1 mg and 2.5mg for 12 weeks. The primary objectives of the 
study were to evaluate the change in ALT levels at week 12 and to evaluate the safety and 
tolerability of EDP-305. Key secondary endpoints included change from baseline in percentage 
of fat in the liver measured by MRI-PDFF, PK, change from baseline in lipids, and target 
engagement as measured by C4 and FGF-19. 
The ALT change from baseline at week 12 was statistically significant (P = .0495) at the 2.5 mg 
dose compared to placebo. There was a numerically higher value in the 1 mg dose compared to 
placebo that did not reach statistical significance (P = .3039). The least square (LS) mean change 
(week 12) were -27.9, -21.7, and -15.5, following doses of 2.5 mg, 1 mg, and placebo, 
respectively. At week 12, >20 U/L reduction in ALT was observed in 61% of subjects treated 
with EDP-305 2.5 mg, 52% treated with EDP-305 1 mg, and 35% with placebo, and >30 U/L 
reduction in ALT was observed in 37% of subjects treated with EDP-305 2.5 mg, 40% treated 
with EDP-305 1 mg, and 20% with placebo. 
Overall, EDP-305 was generally safe, with the majority of TEAEs being mild to moderate. The 
most common (≥5%) TEAEs with EDP-305 included pruritus, rash, gastro-intestinal (GI) related 
symptoms (nausea, vomiting, diarrhea), urinary tract infection, dizziness, decreased appetite and 
cough. As for tolerability of EDP-305 in this 12-week phase 2a study, pruritus was present in 
approximately 51% of the subjects in the 2.5 mg arm compared to less than 10% in the 1 mg arm 
and less than 5% in the placebo arm, with the majority being mild or moderate in severity. 
Among subjects with severe pruritus, there were 2 subjects in the 2.5 mg arm and 2 subjects in 
the 1 mg arm compared to none in the placebo arm. There were no study discontinuations due to 
severe pruritus except for one subject in the 1 mg arm. Overall, the incidence of treatment 
discontinuation due to pruritus was 1.8% for 1 mg and 20.8% for 2.5 mg and none in the placebo 
arm, with all the discontinuations in the 2.5 mg arm being due to moderate pruritus. 
Based on Common Terminology Criteria for Adverse Events (CTCAE) grading, there were very 
few treatment-emergent laboratory abnormalities in the EDP-305 arms: Grade 3 increase in 
serum/plasma glucose were observed more frequently in subjects taking EDP-305 with 7% in the 
1 mg arm, 21% in the 2.5 mg arm, and 4% in the placebo arm. Likewise, grade 3 uric acid 
increase were observed more frequently in subjects taking EDP-305 with 18% in 1 mg, 19% in 
2.5 mg and 4% in placebo. In addition, one subject with a Grade 3 amylase, and one subject with 
a Grade 3 ALT were reported in the 2.5 mg arm. 

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There were no clinically significant changes in ECG or vital signs, and no other clinically 
significant laboratory abnormalities.   
The absolute change from baseline in liver fat content (measured by MRI-PDFF) at week 12 was 
statistically significant (P = .0009) at the 2.5mg dose compared to placebo but not at the 1mg 
dose (P = .4946). The LS mean changes (week 12) were -7.1, -3.3, and -2.4 following doses of 
2.5 mg, 1 mg, and placebo, respectively. The percentage change from baseline in liver fat 
(measured by MRI-PDFF) at week 12 was statistically significant (P = .0065) at the 2.5 mg dose 
compared to placebo but not at the 1 mg dose (P = .6097). The LS mean percentage changes 
(week 12) were -30.5, -15.3, and -11.9 following doses of 2.5 mg, 1 mg, and placebo, 
respectively. Approximately 45%, 26% and 25% of subjects were MRI-PDFF responders (i.e. 
≥30% fat reduction), following doses of 2.5 mg, 1 mg, and placebo, respectively. Within the 
MRI-PDFF responders, mean change in ALT reduction was more profound in the EDP-305 arms 
compared to placebo, with >30 U/L ALT reduction in 2.5 and 1 mg compared to 16 U/L in 
placebo. 
Changes in lipids at 12 weeks were minimal. Across the lipid profile, only reductions in high-
density lipoproteins (HDL) following the 2.5mg dose was statistically significant compared to 
placebo (P < .0001). The reduction was numerically small (LS mean change of -8.3 mg/dL in 2.5 
mg compared to -1.9 mg/dL in 1 mg, and -0.15 mg/dL in placebo). Small, numeric increases not 
statistically significant in low-density lipoproteins (LDL) were observed with EDP-305 
compared to placebo (LS mean changes of 6.5 (P = .0897), 4.7 (P = .1411), and -5 mg/dL 
following doses of 2.5 mg, 1 mg, and placebo, respectively). The small numeric changes in HDL 
and LDL are not likely to be clinically relevant.  
In Study EDP 305-101, mean (range) predose concentrations (week 12) of 6 (1, 15) ng/mL and 
18 (1.7, 38) ng/mL at 1 and 2.5 mg, were observed respectively. At comparable suspension doses 
(2x tablet) in Study EDP 305-001, mean predose concentrations of 1.8-2.6 ng/mL and 6-11 
ng/mL following suspension doses of 2.5 and 5 mg, were observed, across healthy volunteers 
(HV) and subjects with presumptive NAFLD (PN). Mean (range) systemic exposures measured 
by AUC from time 0 to 8 hours (AUC0-8) [week 12] were 119 (17, 436) ng•hr/mL and 208 (24, 
469) ng•hr/mL at 1 and 2.5 mg, respectively. At comparable suspension doses (2x tablet) in 
Study EDP 305-001, mean AUC0-8 (Day 14) of 62-64 ng•hr/mL and 108-169 ng•hr/mL 
following suspension doses of 2.5 and 5 mg, were observed, across HVs and subjects with PN. 
Overall, higher EDP-305 PK exposures were observed in terms of steady state (predose) and 
systemic exposures (AUC) compared to previous studies (Study EDP 305-001, (Ahmad et al., 
2018). 
EDP-305 exposures in study EDP 305-101 were associated with strong target engagement as 
assessed by several biomarkers and generally consistent with previous data from study EDP 305-
001 (Ahmad et al., 2018). Statistically significant reductions (P < .001) in C4 at week 12 were 
observed following EDP-305 compared to placebo with mean changes of -72%, -42%, and 17% 
following doses of 2.5 mg, 1 mg, and placebo, respectively. The C4 reductions were 
accompanied with increases in FGF-19 with mean changes of 574%, 64%, and 73% following 
doses of 2.5 mg, 1 mg, and placebo, respectively.  
C4 reductions and FGF-19 increase in 2.5 mg were also associated with changes in ALP and 
GGT that reflect FXR target engagement at week 12. For ALP, statistically significant increases 
(P < .0001 for 2.5 mg and P < .0128 for 1 mg) were observed following EDP-305 compared to 

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placebo (LS mean changes of 46.8%, 20.1%, and -0.7% following doses of 2.5 mg, 1 mg, and 
placebo, respectively). For GGT, statistically significant reductions (P < 0.0001 for 2.5 mg and 1 
mg) were observed following EDP-305 compared to placebo (LS mean changes of -54.6%, -
34.8%, and -5.2% following doses of 2.5 mg, 1 mg, and placebo, respectively). 
In summary, the primary and key secondary endpoints, ALT and liver fat content reduction as 
measured by MRI-PDFF, respectively at week 12, were met in the 2.5 mg dosing group. EDP-
305 was generally safe, with the majority of TEAEs being mild to moderate. Higher incidence of 
moderate pruritus was noted in the 2.5 mg, that led to approximately 20% discontinuations. PK 
exposures were associated with strong target engagement as measured by C4 and GGT 
reductions and FGF-19 and ALP increases. These results support further evaluation of EDP-305 
in patients with NASH. 
1.5. 
Potential Risks and Benefits 
1.5.1. 
Potential Risks to Subjects Enrolled in the Study 
To date, potential risks to subjects receiving EDP-305 have been estimated based on safety data 
from 10 clinical studies including one phase 2 study in subjects with PBC. 
EDP-305 has been administered in approximately 480 subjects, including approximately 110 
subjects with NASH who received 1 mg or 2.5 mg of EDP-305 up to 12 weeks. 
EDP-305 has been shown to be generally safe and overall well-tolerated in the 8 completed or 
ongoing phase 1 studies where healthy subjects or hepatic impaired patients (Child Pugh A and 
B) received either a single or multiple doses up to 20 mg (suspension) for up to 14 days, and in 
subjects with NASH in the 12-week phase 2 study who received multiple doses at 1 mg or 2.5 
mg (tablet) for up to 12 weeks. 
In the 12-week phase 2 study with EDP-305 in subjects with NASH (EDP 305-101; ARGON-1), 
the following were the most commonly (i.e. in more than ≥5% subjects who received EDP-305) 
reported TEAEs in subjects who received at least one dose of EDP-305 (1 or 2.5 mg/day) for up 
to 12 weeks:  
• Pruritus generalized or localized  
• Rash 
• GI related disorder (nausea, vomiting, diarrhea) 
• Urinary tract infection 
• Dizziness 
• Decreased appetite 
• Cough 
Pruritus was identified as the most frequent TEAE associated with the use of EDP-305 (2.5 mg). 
Grade 3 increase in serum/plasma glucose and uric acid were observed more frequently in 
subjects taking EDP-305. In addition, Grade 3 treatment-emergent laboratory abnormalities were 
observed: one subject with G3 amylase and one subject with G3 ALT. 
Other clinically significant laboratory abnormalities that led to drug discontinuation across all 
studies were: 

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• One transient, moderate liver enzyme elevation (ALT/AST) in one subject (MAD-HV-
20mg) that led to drug discontinuation; the ALT/AST returned to normal (Study EDP 
305-001) 
1.5.2. 
Potential Benefits to Subjects Enrolled in the Study 
Currently, there are no approved drugs for the treatment of NASH. Given the high prevalence of 
NASH, the associated morbidity, the growing burden of end-stage liver disease, and limited 
availability of livers for organ transplantation, identifying therapies that will slow the progress 
of, halt, or reverse NASH and NAFLD will address an unmet medical need (FDA, 2018). 
As mentioned in Section 1.2.2, FXRs are nuclear hormone receptors expressed in high amounts 
in body tissues that participate in BA metabolism including the liver, intestines, and kidneys. 
BAs are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for 
cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. 
Additionally, FXRs play a critical role in carbohydrate and lipid metabolism and in the 
regulation of insulin sensitivity. These receptors also modulate liver growth and regeneration 
during liver injury.  
Data have shown that hepatic expression of FXR is decreased in NAFLD patients, which is 
associated with TG accumulation and hepatic steatosis. Effects observed in FXR deficiency 
animal models include hepatic steatosis, hyperlipidemia, hyperglycemia, BA overload, 
inflammation and fibrosis (Xu et al., 2014). Moreover, studies have shown that these metabolic 
dysfunctions can be improved by FXR activation, indicating that FXR agonism may represent a 
new modality for NASH treatment.  
EDP-305 is a selective FXR agonist. Nonclinical studies have shown that EDP-305 can decrease 
the expression of genes that encode lipogenic enzymes, as well as inflammation and fibrosis-
related genes. In models of NASH and dyslipidemia, EDP-305 has demonstrated the potential for 
reduction in NASH and improvement in insulin sensitivity (Section 1.2.2). In a FIH clinical 
study, EDP-305 was generally safe and well-tolerated and appeared to positively affect levels of 
biomarkers associated with FXR activity (Ahmad et al., 2018). In the phase 2 clinical study in 
subjects with NASH, (EDP 305-101), 12-week therapy with EDP-305 led to statistically 
significant improvements in liver biochemistry and hepatic steatosis. PK exposures were 
associated with strong target engagement as measured by C4 and GGT reductions and FGF-19 
and ALP increases. EDP-305 was generally safe, with the majority of TEAEs being mild to 
moderate. Thus, due to its promising nonclinical safety, pharmacological, clinical efficacy and 
safety profile to date, the Sponsor is investigating EDP-305 as a potential treatment for NASH 
with fibrosis. Recently, OCA, an FXR agonist with a similar mechanism of action to EDP-305, 
was shown to have positive effects on liver fibrosis in NASH patients (Younossi et al., 2019). 
It is not known whether EDP-305 will have similar effects to OCA in this study.  
 

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3. 
SELECTION OF SUBJECTS 
A total of approximately 336 subjects with a diagnosis of NASH as proven by liver biopsy are 
planned for enrollment into this study.   
3.1. 
Subject Inclusion Criteria  
A subject must meet all the following criteria in order to participate in the study: 
1. Informed consent documentation signed and dated by the subject. 
2. Male and female subjects, of all ethnic origins, between the ages of 18 and 75 years, 
inclusive. 
3. Subjects of all ethnic origins should have a Body Mass Index (BMI) > 25 kg/m2 and ≤45 
except for Asian subjects who qualify for the study with BMI > 23kg/m2. 
4. Histological evidence of definite NASH based on NASH Clinical Research Network 
(CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. 
The biopsy may be obtained either 1) during the Screening window or 2) within 26 weeks 
prior to the Screening visit. [Note:  if the liver biopsy needs to be performed as part of the 
Screening assessments, it may be scheduled following informed consent, but must not be 
performed until the subject has qualified for study entry based on completion of all other 
Screening assessments and procedures.] 
5. NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each 
component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning 
scored 0-2). 
6. Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System. 
7. For subjects taking Vitamin E or pioglitazone, the following three criteria apply: 
• subjects must have been on a stable dose for at least 12 weeks prior to the qualifying 
biopsy, and 
• treatment with Vitamin E or pioglitazone cannot have started after the qualifying 
biopsy, and 
• it is expected that subjects will continue on the same dosing regimen throughout 
study participation unless required to adjust doses due to safety reasons. 
8. Subjects who had previously been taking Vitamin E or pioglitazone (but are no longer 
taking either one), must have discontinued Vitamin E or pioglitazone a minimum of 12 
weeks prior to the qualifying biopsy. 
9. Weight change <5% after the qualifying biopsy.  
10. Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), 
anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 
2 antibodies (Ab) as seronegative. [Note: subjects previously infected by chronic hepatitis 
C and treated with direct acting antivirals (DAAs) with sustained virologic response 
(SVR) for at least 3 years will be allowed.] 
11. For hypertensive patients, blood pressure should be controlled by stable dose of anti-
hypertensive medication for at least 8 weeks prior to Screening with the intention to keep 
the regimen stable during the study.  
12. A woman of childbearing potential who is sexually active (see Section 3.3 for 
clarification) with a male must agree to use two effective methods of contraception from 

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the date of Screening until 30 days after the last dose of study drug. Effective methods of 
contraception are defined as: 
A condom with or without spermicide for the male partner and at least one of the 
following for the female subject: 
a. Intrauterine device 
b. Occlusive cap (diaphragm or cervical/vault caps) 
c. Established oral, injectable, implantable, transdermal, or intravaginal hormonal 
contraceptive (started a minimum of 2 weeks prior to Screening) 
d. Bilateral tubal ligation or fallopian tube inserts 
The above does not apply to a female subject who has a vasectomized male as the sole 
partner or who is of nonchildbearing potential (i.e., physiologically incapable of becoming 
pregnant) as defined below: 
a. Has had a hysterectomy ≥12 weeks prior to dosing or 
b. Has had a bilateral oophorectomy (ovariectomy), or bilateral salpingectomy or 
c. Is postmenopausal, defined as  
a. Having a total cessation of menses for at least 2 years, or  
b. Having a cessation of menses between 1 to 2 years together with a follicle 
stimulating hormone [FSH] level of >35 mIU/mL.   
13. A male subject who has not had a vasectomy and is sexually active with a woman of 
childbearing potential must agree to use effective contraception from the date of 
Screening to 90 days after the last dose of study drug (Note: For a male subject who has 
had a vasectomy, use of a condom with or without spermicide will still be required). 
Effective contraception is defined as a condom and spermicide and at least one of the 
following for a female partner: 
a. Intrauterine device 
b. Occlusive cap (diaphragm or cervical/vault caps) 
c. Established oral, injectable, implantable, transdermal, or intravaginal 
contraceptive (started a minimum of 2 weeks prior to Screening) 
d. Bilateral tubal ligation or fallopian tube inserts 
14. Male subjects must agree to refrain from sperm donation from the date of Screening until 
90 days after the last dose of study drug. 
15. Subject must be willing and able to adhere to the assessments, visit schedules, 
prohibitions and restrictions, as described in this protocol. 
16. AST >30 IU/L 
17. Magnetic resonance imaging – proton density fat fraction (MRI-PDFF) ≥8%. 
3.2. 
Subject Exclusion Criteria 
Subjects will not be eligible to participate in the study if they meet any of the following criteria: 
1. Laboratory Screening results as indicated below: 
• Total white blood cells (WBC) <3000 cells/mm3 
• Absolute neutrophil count (ANC) <1500 cells/mm3 
• Platelet count <140,000/mm3 
• International Normalized Ratio, INR >1.2 (unless due to use of anticoagulants) 
• Estimated glomerular filtration rate (eGFR) < 60 mL/min according to the 
Modification of Diet in Renal Disease (MDRD) equation 

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• AST ≥5× ULN 
• ALT ≥5× ULN 
• ALP ≥ 2x ULN 
• Total bilirubin > 1.5 times ULN during Screening. 
[Note: Patients with Gilbert’s syndrome will be allowed following review by the 
Medical Monitor if they have a known history of Gilbert’s syndrome with a normal 
direct bilirubin value and normal reticulocyte count.] 
2. Pregnant or nursing females. 
3. MELD: Model for End-stage Liver Disease score >12.  
4. Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver 
disease, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-
antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular 
carcinoma (HCC).  
5. History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute 
biliary obstruction), unless the subject has had a cholecystectomy (more than 12 weeks 
prior to Screening). 
6. History of liver transplant, or current placement on a liver transplant list. 
7. Hepatorenal syndrome (type I or II).  
8. Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class 
A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of 
Screening and/or histological presence of liver cirrhosis.  
9. Prior or planned ileal resection, or prior or planned bariatric surgery. [Note: Subjects who 
have undergone gastric surgeries that do not affect drug absorption (e.g., gastric band or 
gastric sleeve procedures) will be allowed if they are stable for at least 1 year prior to 
Screening. Gastrectomy or Roux-en-Y bypass will be allowed if stable for at least 3 years 
prior to Screening.]  
10. Subjects with clinically or otherwise documented cardiovascular or cerebrovascular 
disease including clinically significant anomalies of rhythm or pattern of ECG, that in the 
judgement of the Principal Investigator (PI) could affect the safety of the subject or their 
ability to comply with the study requirements. 
11. HbA1c ≥ 9.5% within 60 days prior to Day 1. 
12. Use of a new antidiabetic regimen in the months prior to Screening including metformin, 
GLP-1 agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or 
dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated 
receptor (PPAR)γ agonists (e.g., pioglitazone or rosiglitazone). For pre-existing 
antidiabetic treatment, subjects should be on a stable dose of antidiabetic drugs: (1) for at 
least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 
inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to 
Screening with the intention to keep the regimen stable during the study. [Note: 
Sulfonylureas and insulin are only permitted if glycemia is self-monitored by the subject; 
subjects treated with insulin are eligible if clinically stable on insulin treatment (i.e., no 

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recurrent acute hypo- or hyperglycemic episodes diagnosed clinically with serum glucose 
levels of <50 mg/dL or >200 mg/dL) for at least 8 weeks prior to Screening.] 
13. Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to 
Screening. [Note: Subjects on a stable dose of statins or other lipid lowering agents for at 
least 12 weeks prior to Screening are allowed with the intention to keep the regimen 
stable during the study.]  
14. Use of a new fibrate regimen from 12 weeks prior to Screening. [Note: Subjects on a 
stable dose of fibrates for at least 12 weeks prior to Screening are allowed with the 
intention to keep the regimen stable during the study.] 
15. Subjects with contraindications to MRI imaging, or not being able to have the MRI 
performed. [Note: Contraindications to MRI include insurmountable claustrophobia, 
implantable, metal devices, girth, etc. Stents or other devices allowed at PI’s discretion, 
if they do not interfere with functioning MRI.] 
16. Subject has received any investigational agent (including investigational vaccine) or 
biological product within 30 days or 5 times the half-life (whichever is longer) prior to 
the planned first dose of study drug. [Note: This includes agents administered during 
clinical trial participation; See Section 5.9.5.]  
17. Use of an experimental or approved treatment for NASH within 26 weeks of Screening. 
[Note: Subjects enrolled in a previous clinical trial for EDP-305 who discontinued due to 
safety reasons within any time window are not eligible for enrollment.] 
18. Prior use of OCA within 26 weeks of Screening and/or concurrent treatment with OCA 
(or any other FXR agonists). [Note: Subjects who have previously received OCA and who 
discontinued due to safety reasons within any time window are not eligible for 
enrollment.] 
19. Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in 
duration within 1 year prior to Screening with the intention to continue during the study 
(chronic use of inhaled, topical, ophthalmological, nasal corticosteroids is allowed).  
20. Use of any prohibited concomitant medications, including systemic CYP3A4 inhibitors 
and inducers, within 14 days prior to the first dose of study drug and for the duration of 
the study. 
21. Clinically significant history of drug sensitivity or drug allergy, as determined by the PI. 
22. Current or history of significant alcohol consumption defined as: >14 standard drinks per 
week and/or ≥4 standard drinks per occasion for males and >7 standard drinks per week 
and/or ≥3 standard drinks per occasion for females. [Note: A standard drink is 12 oz of 
beer (5% alcohol), 5 oz table wine (12% alcohol), or 1.5 oz of spirits (40% alcohol).] 
23. History of substance (including alcohol) abuse and in the judgment of the PI, the subject 
would not be suitable for participation in the study. 
24. Any other condition(s) that would compromise the safety of the subject or compromise 
the quality of the clinical study, as judged by the PI. 
25. Use of medication for weight loss or appetite reduction (e.g.  orlistat, 
bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-prescription 

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supplements) at Screening. [Note: Subjects on a stable dose for at least 12 weeks prior to 
Screening or time of pre-treatment liver biopsy are allowed if intended to be continued at 
the same dose during the study.  However start of new medications during the study is not 
allowed.]    
26. History of malignancy of any organ system (other than localized and considered cured 
cutaneous basal or squamous cell carcinoma, or in situ cervical cancer), treated or 
untreated, within 5 years of Screening 
3.3. 
Additional Contraception Details/Requirements 
In the context of this study, sexual abstinence is considered a highly effective method of birth 
control only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. Subjects who practice true abstinence, because of the 
subject’s lifestyle choice (i.e., the subject should not become abstinent just for the purpose of 
study participation) are exempt from contraceptive requirements. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active, they must agree to use 
contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
Vasectomy 
Vasectomized male partner is a highly effective birth control method provided that the partner is 
the sole sexual partner of the woman of child bearing potential, trial female participant and that 
the vasectomized partner has received medical assessment of the surgical success. 
Birth control methods that are considered unacceptable in clinical trials 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception.  
• Female condom and male condom should not be used together. 
• Norethindrone is an oral progestin-only pill that is available at a dose that is substantially 
lower than the dose in any combination estrogen-progestin contraceptive pill. In contrast 
to estrogen-progestin oral contraceptive pills and other progestin-only pills, ovulation is 
not consistently suppressed with norethindrone pills. As such, norethindrone progestin-
only pills may have a higher typical use failure rate than combination pills or other 
progestin-only pills. 

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As summarized in Section 1.4, EDP-305 underwent extensive evaluation in eight phase 1 studies 
and a proof of concept study in NASH.  
A total of 328 subjects received at least one dose of EDP-305 in the phase 1 program. The phase 
1 program assessed the PK and PD of EDP-305 over broad range of doses. The PK of EDP-305 
was well characterized providing support for once daily dosing. EDP-305 demonstrated target 
engagement as measured by reduction in C4 and increase in FGF-19 (Study EDP 305-001), 
which combined with the safety data provided the basis for dose selection in the early phase 2 
program. Drug-drug interaction studies provided the needed information to guide dosing 
recommendation of EDP-305 when administered concomitantly with medications most 
commonly used by NASH patients, including statins, antidiabetic and antihypertensive drugs. 
EDP-305 was safe and well tolerated across the phase 1 program.   
In Study EDP 305-101 (Section 1.4.2), 12-week therapy with EDP-305 led to statistically 
significant improvements in liver biochemistry and hepatic steatosis. EDP-305 was generally 
safe, with the majority of TEAEs being mild to moderate. PK exposures were associated with 
strong target engagement as measured by C4 and GGT reductions and FGF-19 and ALP 
increases.  
This phase 2b study aims to evaluate the safety and efficacy of two doses of EDP-305 compared 
to placebo for the treatment of NASH in subjects with liver biopsy proven NASH. As suggested 
in the Food and Drug Administration (FDA) guidance (FDA, 2018), this late stage phase 2 trial 
will explore the effect of EDP-305/placebo treatment on histological endpoints. The endpoints 
will include improvement in fibrosis measured using liver biopsy as well as reduction of 
inflammatory changes.  
The patient population selected for inclusion in the trial is designed to represent the target 
population for treatment. Specifically, in patients with liver disease, there is a significant overlap 
of NASH and various metabolic conditions including obesity and T2DM. In order to be 
reflective of the NASH population, these patients will not be excluded from participation in this 
trial. However, they must be on stable medication regimens prior to study entry so as not to 
confound study results due to medication changes (dose modifications are allowed for safety 
reasons). Likewise, many NASH patients take pioglitazone or Vitamin E and these patients will 
not be excluded from study entry, but the study will be stratified based on whether or not a 
subject is taking these medications. A liver biopsy proven diagnosis of NASH will be required 
for study entry. As recommended (FDA, 2018), the liver biopsy must be obtained within 6 
months of the Screening Visit (or within the Screening period) so as to represent the most 
accurate status of disease possible. To ensure patients have evidence of steatohepatitis and 
significant liver fibrosis without cirrhosis, the population with the greatest benefit risk ratio, they 
must have a NAS ≥ 4 and a CRN fibrosis score of 2 or 3.  
As suggested in the FDA guidance (FDA, 2018), non-invasive markers including imaging and 
biochemical markers will be assessed in this study. These markers will contribute to the 
understanding of the correlation between histological changes and non-invasive assessments.  
According to the FDA guidance on non-cirrhotic NASH (FDA, 2018), the duration of phase 2 
trials should be at least 12–18 months, given that histological changes take time. Subjects in this 
study will take blinded study drug for 72 weeks to allow assessment of improvement in fibrosis 
and other histological endpoints. Of note, in a recent phase 3 Study, OCA (an FXR agonist) 

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showed improvement in fibrosis in non-cirrhotic NASH over a study duration of 18 months 
(Younossi et al., 2019).   
Finally, to control bias in interpretation of results, the trial will be a double-bind, placebo-
controlled design. 
4.2.2. 
Justification of EDP-305 Dose 
The dose selection was based on comprehensive evaluation of efficacy, safety, tolerability, PK, 
and target engagement data from a proof-of-concept study EDP 305-101 (ARGON-1), as well as 
relevant literature data for other FXR agonists. Based on this evaluation, doses of 1.5 mg and 2 
mg were selected for the current study. These doses are expected to provide: 
• Exposures in the anticipated therapeutic range 
• A strong target engagement 
• A maximal efficacy in terms of histologic improvement  
• A balanced profile in terms of efficacy and tolerability 
An exposure-response (clinical utility analysis) of EDP-305 evaluating relationships between PK 
and efficacy (reduction in ALT and liver fat) and safety (frequency of pruritus) was also 
conducted, as described below, to further support the dose selection. 
To date, the molecular mechanisms underlying the pruritus induced by FXR agonists such as 
EDP-305 and OCA have not been fully resolved. BAs, including OCA, are reported to activate 
the bile acid-sensing TGR5 (D'Amore et al., 2014; Maruyama et al., 2002; Rizzo et al., 2010). 
Subsequently, TGR5 was shown to mediate bile acid-induced itch in mice (Alemi et al., 2013; 
Lieu et al., 2014), however, a direct link between activation of TGR5 by OCA or its metabolites 
and pruritus has not been established and, moreover, EDP-305 does not significantly activate the 
TGR5 receptor (See IB). Emerging data suggest that Mas-related G-protein coupled receptor 
(MRGPR) family play a central role in bile acid-induced pruritus but, to date, the relevance of 
these observations to pruritus observed with EDP-305 and OCA has not been explored 
(Meixiong et al., 2019; Sanjel et al., 2019; Yu et al., 2019). In the absence of a detailed 
understanding of the mechanism of EDP-305-induced pruritus and a lack of validated animal 
models to assess itching, it has not been possible to determine an exposure-effect relationship for 
pruritus in a preclinical setting. As a result, dose selection for EDP-305 is based exclusively on 
data derived from clinical observations across the current clinical program and particularly from 
Study EDP 305-101 (Section 1.4.2). 
As mentioned in Section 1.4.2, efficacy as measured by ALT change from baseline at week 12 
was statistically significant (P = .0495) at the 2.5 mg dose compared to placebo. There was a 
numerically higher value in the 1 mg dose compared to placebo that did not reach statistical 
significance (P = .3039). The least square (LS) mean changes (week 12) were -27.9, -21.7, and -
15.5, following doses of 2.5 mg, 1 mg, and placebo, respectively. At week 12, >20 U/L reduction 
in ALT was observed in 61% of subjects treated with EDP-305 2.5 mg, 52% treated with EDP-
305 1 mg, and 35% with placebo, and >30 U/L reduction in ALT was observed in 37% of 
subjects treated with EDP-305 2.5 mg, 40% treated with EDP-305 1 mg, and 20% with placebo. 
The absolute change from baseline in liver fat content (measured by MRI-PDFF) at week 12 was 
statistically significant (P = .0009) at the 2.5 mg dose compared to placebo but not at the 1 mg 
dose (P = .4946). The LS mean changes (week 12) were -7.1, -3.3, and -2.4, following doses of 
2.5 mg, 1 mg, and placebo, respectively. Approximately 45%, 26%, and 25% of subjects were 

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Based on a comprehensive evaluation of data from Study EDP 305-101, an exposure-response 
(clinical utility analysis) and, relevant literature, doses of 1.5 mg and 2 mg were selected in the 
current study. Both doses are expected to: 
• Result in PK exposures in the anticipated therapeutic range  
• Be associated with optimal target engagement (measured by C4, FGF-19, ALP) and 
reduction in GGT 
• Result in ALT responses (ALT reduction of >20 U/L) in the range of 50-60%, which is 
expected to translate into favorable histologic improvement (Loomba & Adams, 2019) 
• Be potentially associated with a lower rate of pruritus compared to 2.5 mg (≤25%) 
• Have similar MRI-PDFF (liver fat) responses that may correlate with steatosis 
improvement (Patel et al., 2016) 
 
Figure 2: 
Probability of Pruritus and ALT response as a function of EDP-305 exposure 
 
                                Dashed lines show median AUCs corresponding to 1, 1.5, 1.75, 2 and 2.5 mg (left to right) 
 

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Enanta will provide instructions for the destruction of any unused study drug. If Enanta 
authorizes destruction at the study site, the PI must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy and any special 
instructions provided by Enanta, and, that the destruction was adequately documented.  
5.6. 
Treatment Assignment/ Randomization 
Subjects will be randomized to study treatment using an IWRS. Subjects will be randomized to 
the treatment groups shown below: 
• Treatment Group 1 (N=112); EDP-305 1.5 mg orally for 72 weeks 
• Treatment Group 2 (N=112); EDP-305 2 mg orally for 72 weeks 
• Treatment Group 3 (N=112); Placebo orally for 72 weeks 
In addition, subjects will be stratified based on 1) use of Vitamin E and/or pioglitazone and 2) 
type 2 diabetes mellitus (T2DM) status.  
The randomization code will be produced by Enanta (or designee). The Enanta unblinded 
biostatistician or designee will review and approve the final randomization list. 
During the Screening period, subjects will be identified by a unique Screening number assigned 
by the clinical site. Subjects who have completed Screening assessments and are eligible for 
participation in the study will be randomized before the first dose of study drug (Day −1 or Day 
1) and assigned a unique subject number which will be used to identify the subject throughout 
the study.   
5.7. 
Study Drug Dose and Administration 
Complete instructions for dispensing and administering study drug are presented in the Pharmacy 
Manual.  
On scheduled clinic visit days, the visit should be scheduled close to the time that the subject 
normally takes the study drug so that dosing can occur at the site. Subjects should bring their 
study drug with them. If the clinic visit occurs within 4 hours of the time the subject normally 
takes their daily dose of study drug, subjects will be administered their daily dose of study drug 
at the clinic. If the clinic visit is scheduled to occur more than 4 hours after the time the subject 
normally takes their daily dose of study drug at home, then subjects should not wait until the 
clinic visit but should proceed to take the daily dose of study drug at home per their normal 
dosing routine. 
If a subject forgets to take study drug at their scheduled time, the dose may be taken later that 
day; however, the following rules apply: 
• no more than 1 dose should be taken on any calendar day and 
• there must be a minimum of 16 hours between doses. 
Stopping rules for study drug administration are provided in Section 10.1. 
5.7.1. 
 Dispensing of Study Drug 
Study drug (EDP-305 and matching placebo) must be dispensed by a qualified pharmacist or an 
authorized designee with appropriate training and only for administration to the study subjects.  

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chronic use of systemic immunosuppressants should not be enrolled into the study. Intraarticular 
or intramuscular injection of immunosuppressants is not allowed more than once during the 
duration of the study. 
Note that use (including chronic use) of inhaled, topical, ophthalmological, or nasal 
corticosteroids is allowed. Short courses of short acting corticosteroids (e.g.. for acute 
exacerbation of asthma) will be allowed for a maximum period of 2 weeks per treatment course 
to control the underlying disease. Systemic corticosteroids for the management of pruritus will 
not be allowed. 
A list of immunosuppressants and restrictions will be provided in the study binder. 
5.9.5. 
Vaccines, Investigational Products and Treatments for NASH 
In accordance with the exclusion criteria, subjects may not receive any investigational vaccine, 
investigational agent, or biological product within 30 days or 5 times the half-life (whichever is 
longer) prior to the first dose of study drug. Once enrolled into the study, subjects may not 
receive any investigational agent (including investigational vaccines) or biological product. 
However, vaccines administered per local standard of care including those for COVID-19,  
influenza, tetanus, polio, and pneumonia will be allowed during the study. Administration of 
these vaccines must be documented in the eCRF. 
Use of any medications for the treatment of NASH (other than study drug taken as part of this 
study) are prohibited during the study. Use of OCA within 26 weeks of Screening is exclusionary 
for study entry and use of OCA or any FXR agonist during the study is prohibited.  
5.10. 
Other Restrictions 
Gastrointestinal surgeries (e.g. ileal resection, bariatric surgery including gastric band or gastric 
sleeve procedures gastrectomy, cholecystectomy) will not be allowed during the study. However, 
if required for medical /safety reasons, the subject will be terminated from the study and must 
undergo early termination procedures. 
Potential start of new medications for weight loss or appetite reduction during the study is also 
not allowed. 
Refer to the Inclusion / Exclusion criteria listed in Section 3 for other protocol restrictions.  
 

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6. 
BLINDING  
The study will be double-blinded meaning the subjects, Sponsor, PIs, and site staff will be 
blinded to treatment assignment until the completion of the study. 
All study personnel will be blinded to treatment assignment except for the following individuals:  
• Unblinded Enanta/Clinical Research Organization (CRO) statistician for purpose of 
generating and monitoring the randomization list 
• Unblinded Drug Supply Chain personnel for the purpose of monitoring drug supplies 
• Enanta/CRO Pharmacovigilance Group and Regulatory Affairs representatives when 
required to satisfy regulatory reporting requirements 
• Bioanalytical Laboratory for the purpose of measuring drug concentrations 
• Data Safety Monitoring Board (DSMB) members or DSMB meeting attendees (including 
Enanta representatives not associated with the day-to-day conduct of the study) for the 
purposes of unblinded data review as outlined in the DSMB charter 
6.1. 
Blinding of Study Samples 
6.1.1. 
Blinding of MRI/MRE, NASH FibroSure, and Liver Biopsy  
The following results will be blinded to the PIs, site personnel, and Sponsor:  
• Postbaseline MRI and MRE results  
• Week 72/ET liver biopsy results  
• Postbaseline NASH FibroSure® results.  
Additionally, the MRI/MRE facilities and radiologist will be blinded to the subject’s study 
treatment and the MRI and MRE readings will be read centrally. 
6.1.2. 
Blinding of Pharmacokinetic Samples 
All PK sample concentration measurements will be blinded to all study personnel involved in 
study conduct, including the Sponsor, CRO, PIs, site staff, and study subjects. The laboratory 
performing bioanalytical analysis, however, will be provided the randomization scheme.  
6.2. 
Unblinding  
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will use the IWRS process. 
Unblinding of individual subject treatment by the PI should be limited to medical emergencies or 
urgent clinical situations in which knowledge of the subject's study treatment is necessary for 
clinical management. In such cases, where possible, the PI should attempt to contact the study 
Medical Monitor to discuss the need for unblinding. In situations in which the PI has attempted 
and failed to contact the Medical Monitor, and/or the urgency of the case required immediate 
action, PIs should use their best judgment, based on the nature and urgency of the clinical 
situation, and proceed with unblinding. 
• For unblinding, in the event the local CRO Medical Monitor cannot be reached, sites at 
all locations should call the following 24/7 global medical coverage hotline: (+1) 919-
674-5468. 

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Once a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the Medical Monitor should be notified within 24 hours of unblinding of the 
treatment. Information relating to unblinding (e.g., the reason, date) should be clearly recorded in 
the subject’s study file. In addition, the PI should consider whether the clinical event that 
prompted unblinding should be considered a serious adverse event (SAE), according to the 
regulatory definitions or criteria for SAEs, and if so, submit an SAE report as described in 
Section 9.2. 
The Safety and Risk Management group will also unblind any SAE reports in compliance with 
regulatory reporting requirements. In addition, Enanta may unblind individual subjects at any 
time for matters relating to safety concerns.  
6.3. 
24/7 Access for Urgent Protocol-Related Medical Issues/Questions 
In a study-related health emergency, when the study Medical Monitor(s) cannot be reached by a 
caller, an on-call physician can be reached 24 hours per day/7 days per week for discussion of 
urgent protocol medical-related questions. The on-call physician can be reached as follows:  
• Telephone: 
 (global reachable number)  (telephone number allowing a 
global reach from both landlines and mobile phones – NOT a toll-free number).  
• 
- This internet page contains a list of 
country-specific contact numbers. Countries not listed here need to dial the global 
reachable number as indicated above. There may be restrictions when dialing a country-
specific number from a mobile phone.  
 

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7. 
STUDY CONDUCT AND VISIT SCHEDULE 
7.1. 
Study Visits  
Details of assessments at each visit are presented in the Schedule of Assessments.  
7.1.1. 
Screening  
7.1.1.1. 
Initial Screening 
Screening procedures will occur after the subject signs and dates an Institutional Review Board 
(IRB) or Ethics Committee (EC) approved informed consent form (ICF) and provides 
authorization to use protected health information (See Section 12.1.3). The ICF will be 
completed prior to conduct of any study-specific procedures.  
Screening procedures will be conducted as listed in the Schedule of Assessments. Screening will 
occur over a ten-week period. All Screening assessments must occur no earlier than 70 days 
before the first dose of study drug at the Day 1 visit unless otherwise approved by the study 
Medical Monitor. Screening assessments should be performed and confirmed sequentially as 
follows: a) medical history and other non-invasive assessments, b) laboratory assessments, c) 
MRI-PDFF and MRE and, lastly, d) liver biopsy.  
Histological evidence of definite NASH based on the judgement of the central histopathologist is 
required for study entry. Tissue samples from a previous biopsy taken within 26 weeks of the 
Screening visit may be used or a biopsy may be performed during the Screening window. Refer 
to Section 8.4.8 and the study binder for detailed instructions. If a new liver biopsy is required to 
satisfy entry criteria, subjects must satisfy all other study entry criteria before the liver biopsy is 
performed. 
Slight extensions to the Screening window for such cases as delayed biopsy or imaging results, 
or for logistical reasons, may be permitted only with the approval of the Medical Monitor. In 
such cases, the Medical Monitor will determine if any Screening assessments, e.g., safety labs, 
may need to be repeated. 
7.1.1.2. 
Retest/Rescreen and Screen Failures 
After all Screening assessments are completed, subjects who satisfy all entry criteria (i.e., meet 
all inclusion criteria but none of the exclusion criteria) should be enrolled into the study.  
Retest: Subjects with an out-of-range lab value or multiple out of range values, not consistent 
with the subject’s medical history or that may reflect erroneous results based on PI judgement, 
may retest the respective lab(s). A retest and all remaining assessments must occur within the 8-
week Screening window. 
Rescreening: Subjects who did not qualify for study entry and are, or will be, out of the 10-week 
Screening window may be rescreened once under the following circumstances with the approval 
of the Medical Monitor. In each case, the Medical Monitor will determine which, if any, of the 
Screening assessments may not need to be repeated. 

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• Subjects who have abnormal laboratory results, which may potentially reflect erroneous 
results, based on PI judgement, and have exceeded the allowable Screening window for 
retesting of these parameters 
• Subjects who have recently initiated concomitant medications requiring a stable regimen 
or requiring a medically necessary dose modification, or who have recently discontinued 
medications and have not yet met the wash out period, but otherwise met all study criteria 
performed, may rescreen once these respective requirements are met per protocol 
• Subjects who are eligible based on completion of all Screening assessments but 
transiently (for personal reasons) unable to commit to all upcoming study visits and 
procedures 
• Subjects who were impacted by COVID-19 restrictions may rescreen provided the 
assessments conducted to date meet eligibility and/or retesting criteria. 
Screen Failures: Subjects who do not satisfy all entry requirements (i.e., meet all inclusion 
criteria and do not have any of the exclusion criteria) either following Screening or, if 
appropriate, following retest or rescreen will be considered screen failures. 
7.1.2. 
Baseline (Day 1) 
Subjects who meet all inclusion criteria and none of the exclusion criteria will report to the clinic 
on the morning of Study Day 1 after fasting overnight for a minimum of 8 hours. Site personnel 
will conduct a thorough review of applicable inclusion and exclusion criteria to ensure the 
subject satisfies all eligibility criteria; subjects who continue to satisfy eligibility requirements 
will be randomized in a 1:1:1 ratio to their treatment group. Predose assessments and procedures 
will be conducted as noted in the Schedule of Assessments and considered Baseline values. 
After predose study procedures are completed including predose blood collection for PK and 
biomarker analysis, subjects will receive the first dose of study drug in the clinic. Postdose blood 
samples for PK and biomarker analysis will be collected as described in Section 8.4 and shown 
in the Schedule of Assessments. 
Before leaving the clinic, subjects will receive study drug and instructions on how to take the 
drug at home. Subjects will also be given the two pruritus measurement scales (Section 8.3.5) 
with instruction on how to complete the scales at home.   
7.1.3. 
Treatment Period Visits (Day 7 through Week 72/EOT) 
Phone Contact: On Day 7, sites will contact subjects by phone to assess AEs, inquire about 
concomitant medications taken during the past week, and confirm subjects are taking study drug 
appropriately. Site personnel will also remind subjects to complete the pruritus visual analog and 
5D-itch scales and to bring the scales back with them to the next clinic visit. 
At Weeks 52, 60 and 68, the site will contact the subject by phone to assess drug accountability, 
concomitant medications, and AE/SAEs.  In addition, for females of child-bearing potential, the 
site will confirm that the at-home pregnancy test was performed and that the results were 
negative. If the results were positive, the procedures listed in Section 8.4.6 should be followed. 
Clinic Visits: All subjects will be requested to return to the clinic for on-treatment study visits as 
follows: Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 56, 64, and 72 following the Day 1 
(initial dosing) visit. Note that all treatment visit weeks are determined based on day of initial 

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dosing. Subjects will be instructed to fast overnight for a minimum of 8 hours prior to each visit 
so that safety laboratory samples can be drawn fasted. Treatment period assessments per visit are 
shown in the Schedule of Assessments.  
Refer to Section 5.7 for instructions on study drug dosing. Refer to Section 8.4 for instructions 
on collection of safety laboratory samples. 
At the end of the treatment period, subjects will complete the EOT visit. Subjects who complete 
the full scheduled 72 weeks of treatment will complete the EOT assessments at the Week 72 
visit. Subjects who discontinue treatment early should complete EOT assessments at the time of 
treatment discontinuation (if in the clinic) or within one week following last dose of study drug if 
the subject discontinues treatment while not in the clinic. Procedures performed are specified in 
the Schedule of Assessments. 
Subjects should take their last dose of study drug in the clinic at the Week 72 visit.  
7.1.4. 
Safety Follow-up Period (End of Study Visit) 
All subjects, including those who discontinue treatment early, should return to the clinic for the 
EOS visit 4 weeks after the last dose of study drug for follow-up safety assessments (Schedule of 
Assessments). For subjects who complete the study, the EOS visit will be scheduled during 
Week 76.  
Any subject with ongoing AEs/SAEs at the EOS visit should be followed until resolution of their 
AE/SAE or until the PI has determined that the event has stabilized as discussed in Section 9.3. 
7.2. 
Subject Withdrawal / Early Termination 
Subjects may withdraw from the study at any time at their own request, or subjects may be 
withdrawn at any time at the discretion of the PI or Enanta for safety, behavioral, or 
administrative reasons. However, the PI should consult with the Sponsor’s Medical Monitor 
where possible before prematurely removing a subject. For any subject who decides to withdraw 
from the study, the PI should inquire about the reason for withdrawal, request that the subject to 
return all unused investigational product(s), request that the subject return for a final visit, if 
applicable, and follow-up with the subject regarding any unresolved adverse events. Although a 
subject may discontinue study treatment, every effort must be made to continue the subject on 
the study, returning for the EOT visit (if prematurely discontinuing treatment) and the safety 
follow-up visit.  
If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Enanta may retain and continue to use any data collected before such withdrawal of 
consent. 
For safety monitoring purposes, subjects who withdraw after receiving study drug should return 
to the clinic within one week and undergo the EOT evaluations (Schedule of Assessments). 
Subjects should then return for the Safety Follow Up assessments (EOS visit) 4 weeks after the 
last dose of study drug. Any subject who withdraws with ongoing AEs/SAEs should be followed 
until resolution of their AE(s) or until the PI has determined that the AE(s) has stabilized. 

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Site personnel will attempt to contact any subject who does not return to the clinic for scheduled 
visit at least three times using the subject’s preferred method of communication, followed by a 
certified letter if the three attempts were unsuccessful. Any subject who still cannot be reached 
following those attempts will be considered Lost to Follow-up. These subjects will be included 
in the analysis as indicated in Section 11. 
7.2.1. 
Withdrawal Criteria 
Subjects may be discontinued from the study at any time if the subject, PI or Sponsor determines 
that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include: 
• Adverse Event 
• Lack of efficacy 
• Lost to follow-up 
• Withdrawal by subject 
• Protocol deviation (including non-compliance with study drug dosing or study 
procedures)  
• Pregnancy 
• Sponsor’s decision to terminate the study 
• Other 
Subject-specific stopping rules due to AEs and/or laboratory abnormalities are outlined in 
Section 10.1. 
Subjects who prematurely withdraw from the study for any reason after having been randomized 
will not be replaced. 
7.2.2. 
Documentation of Withdrawal of Subjects 
The reason for early withdrawal/termination/lost-to-follow-up of any subject from the study must 
be documented on the appropriate eCRF. If the reason for early withdrawal is an AE or an 
abnormal laboratory value, the specific event or test result, if available, should be recorded on 
the AE eCRF and the subject should be monitored until the event is resolved or deemed stable by 
the PI. 
7.3. 
Site or Study Discontinuation 
7.3.1. 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• A decision from the IRB/EC or regulatory authority to terminate the study. 
If the study is suspended or terminated for safety reasons, Enanta will promptly notify the PI and 
will also inform the regulatory authorities of the suspension or termination of the study and the 

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reasons for the action. The PI is responsible for promptly informing the IRB/EC and providing 
the reasons for the suspension or termination of the study. 
7.3.2. 
Site Termination 
A single site may warrant termination under the following conditions: 
• Failure of the site to enroll subjects into the study at an acceptable rate 
• Failure of the site to comply with pertinent governmental regulations as appropriate 
• Submission of knowingly false information from the research facility to the Sponsor, 
clinical monitor, or governmental authority 
• Failure to adhere to the protocol requirements 
• Data recording is inaccurate or incomplete 
• PI does not adhere to the protocol or applicable regulatory guidelines in conducting the 
study 
7.3.3. 
Study Termination Procedures 
If the study is terminated by Enanta for one of the reasons listed above, or upon completion of 
the study, the following activities must be conducted by the study monitor and/or site personnel: 
• Return of all study data to Enanta or designee 
• Respond to and complete all requests for data clarifications 
• Accountability and final disposition of used and unused study drug 
• Review of site records for completeness 
• Shipment of all applicable biological samples (including PK samples) to the designated 
laboratory 

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8. 
STUDY PROCEDURES/EVALUATIONS  
8.1. 
Timing of Assessments 
The timing of assessments is shown in Schedule of Assessments. 
8.2. 
Demographics and Medical History 
Demographics and baseline characteristics including date of birth, gender, race, ethnicity and 
medical history will be obtained from each subject and entered in the eCRF as reported. As a 
general rule, all medical events occurring within the last 6 months should be recorded. For events 
which occurred more than 6 months ago (and which are not ongoing), only significant or relevant 
events should be entered on the eCRF. Any items in the history that are still ongoing should be 
noted as such in the eCRF. All surgeries occurring in adulthood should be recorded in the eCRF. 
Whenever possible, the date of diagnosis of NASH should be recorded. 
8.3. 
Clinical Evaluations 
8.3.1. 
Vital Sign Measurements, Body Temperature and Electrocardiograms 
Vital signs will include heart rate (HR), respiratory rate, and blood pressure (BP). Vital signs will 
be measured at times shown in the Schedule of Assessments after the subject has been supine for 
5 minutes and before dosing.  
Body temperature should be taken at the Screening, Day 1, and EOS visits according to site 
standard practices. 
Resting 12-lead ECGs will be performed locally and recorded at the times indicated in the 
Schedule of Assessments after the subject has been supine for 5 minutes and before dosing. A 
standard bedside 12-lead ECG machine that calculates HR and measures the PR, QRS, QT, RR, 
and QTc (QTcF) intervals should be utilized. If the site does not have an ECG machine that 
calculates these values, the site will need to calculate the values.If a blood draw and ECG are 
scheduled at the same time, then the ECG should be obtained first.  
The normal ranges for the ECG are as follows: 
- 
PR: 120 - 220 msec  
- 
QRS: 70 – 120 msec  
- 
QT: ≤ 500 msec  
- 
QTcF: ≤ 450 msec  
- 
Heart Rate: 50 – 100 bpm 
The PI or designee should review the ECGs in real-time for gross abnormalities and interval 
measurements of concern (absolute readings and for postdose ECGs, change from baseline). 
Ranges outside of the normal ranges listed above should be recorded as abnormal. The clinical 
interpretation by the PI or designee of the ECGs should be recorded on a hard copy of the ECGs 
(i.e., normal, abnormal clinically significant [CS] or abnormal nonclinically significant [NCS]).  
The PI or designee must repeat any ECG where the QTcF interval >450 msec, or absolute QT > 
500 msec, or with a change from Baseline in QTcF >60 msec. These abnormal ECGs must be 
repeated once regardless of whether or not the values are considered clinically significant by the 
PI or designee. Also, ECGs may be repeated at the discretion of the PI to account for erroneous 
readings. 

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Prior to dosing, the Baseline ECG must be reviewed to confirm that no clinically significant 
cardiac abnormalities are present.  
8.3.2. 
Physical Examination 
The PI or designee will perform the physical examination. A full physical examination will be 
conducted at Screening, Week 12 and EOS as indicated in the Schedule of Assessments and will 
include a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat (EENT); 
respiratory; cardiovascular; chest, lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. All subsequent physical examinations will be targeted to new signs and symptoms 
including specific assessments of any changes from previous status. Only clinically significant 
abnormalities should be recorded in the eCRF (e.g., use of contact lenses does not need to be 
recorded). 
8.3.3. 
Weight and Body Mass Index (BMI) 
Height and body weight should be obtained with the subject in light clothes and no shoes. Body 
mass index should be calculated at Screening (to assess eligibility) according to the following 
equation: 
BMI=weight (kg)/height (m)2 
These measurements will be obtained as specified in the Schedule of Assessments. 
8.3.4. 
Quality of Life Assessment  
Quality of life will be assessed using standardized, validated questionnaires including SF-36 and 
CLDQ-NASH. In addition, Dermatology Life Quality Index (DLQI) will be completed by 
subjects who report pruritus. Instructions on administration of the questionnaires by the site and 
completion of the questionnaires by the subject will be provided in the study binder.  
8.3.5. 
Assessment of Pruritus 
Pruritus will be monitored in this study at the times indicated in the Schedule of Assessments. As 
listed below, two separate scales may be used to assess pruritus in subjects:   
• First, an itch visual analog scale (VAS) will be used to record the intensity of the event 
(Furue et al., 2013). Site personnel should instruct the subject to draw a line on the scale 
corresponding to the maximum intensity of itch within the last two weeks.   
• If VAS score is greater than zero (i.e. itch), a multidimensional 5D-itch scale developed 
by Elman (Elman et al., 2010) will be used to assess five different dimensions of pruritus 
within the last two weeks. The five dimensions assessed are duration, degree, direction, 
disability, and distribution.  
• The scales should be administered as indicated in the study binder. 
The scales will be completed by the subject in the clinic during the visit for the in-clinic visits as 
indicated in the Schedule of Assessments. For the Day 7 phone contact, the subject will be given 
a copy of the scales on Day 1 to take home so that he/she can record pruritus on Day 7 (±1 day), 
preferably immediately preceding or during the phone contact with the site.  
In addition, if a subject experiences pruritus between clinic visits the subject should contact 
the site as soon as possible: 

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- to discuss the event,  
- to obtain guidance on how to manage the side effect(s),  
- and to get specific instructions on how to complete the VAS, 5D-itch and additional 
evaluations through resolution of the event. 
Additional details relative to management of subjects who experience pruritus are included in a 
separate study binder.  
8.3.6. 
Adverse Events 
The PI is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE as provided in Section 9.1 of this protocol. All AEs and SAEs must 
be recorded in the source documents and eCRF as described below (Section 9.2). At all visits, 
the PI or designee should inquire about the occurrence of AEs. The following are examples of 
open-ended questions that may be used to obtain this information: “How are you feeling?”; 
"Have you had any medical problems recently?"; "Have you taken any new medicines since your 
last visit/assessment?" 
It is the PI’s responsibility to ensure any necessary additional therapeutic measures and follow-
up procedures are performed and documented in the subject source notes and eCRF. Any 
medication taken during the course of the study will be recorded with indication, dosage, route of 
administration, and start and stop dates of administration. All subjects will be questioned about 
concomitant medication at each clinic visit as indicated in the Schedule of Assessments.  
8.4. 
Clinical Laboratory and Diagnostic Procedures 
All laboratory samples will be analyzed by a centralized laboratory (i.e., ICON Laboratory) or 
designee. A laboratory reference manual will be provided to the site detailing kit contents, 
reordering supplies, sample collection (see below), handling, storage and shipment instructions. 
All unblinded laboratory values will be reviewed by the PI, documented, and the results 
maintained in the source documents. All out-of-range lab findings require an interpretation as to 
whether or not they are of clinical significance. Clinically significant laboratory findings in the 
opinion of the PI must be recorded as an AE (or SAE as appropriate) (Section 9.1).  
Blood samples for safety assessments should be collected predose for visits where study drug is 
administered in the clinic or at least 4 hours postdose if the subject took study drug at home (see 
Section 5.7 regarding when study drug is taken at home by the subject versus in the clinic during 
the visit). Additional samples collected for PK and PD analysis should be collected postdose as 
noted in the Schedule of Assessments. Additional clinical laboratory evaluations will be 
performed at other times if judged clinically appropriate by the PI, or if the safety review of the 
data suggests a more detailed assessment of clinical laboratory safety evaluations.  
For selected biomarker analysis, serum or plasma samples should be collected for analysis of 
FGF-19, BAs, and C4 as indicated in the Schedule of Assessments and according to instructions 
provided in the laboratory reference manual. 
8.4.1. 
Safety Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected according to the 
Schedule of Assessments. Subjects should be instructed to fast overnight for at least 8 hours prior 
to the blood draw for the safety laboratory testing where study drug is taken in the clinic. Where 

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study drug is taken at home at least 4 hours prior to the clinic visit, subjects must fast for a 
minimum of 4 hours prior to the blood draw for safety laboratory assessments. If subjects did not 
fast as indicated per protocol, the sample may be drawn anyway but the lack of fasting noted in 
the eCRF. Samples will be collected and processed according to the procedures provided by the 
clinical laboratory in the laboratory manual. Laboratory parameters to be collected are outlined 
in Table 3.  
eGFR will be calculated by the central laboratory using the MDRD equation using serum 
creatinine (SCr) and other demographic factors: 
MDRD formula:  
eGFR =175 x (SCr)-1.154 x(age)-0.203 x0.742 [if female] x1.212 [if Black] 
On line calculator can be found at: https://www.kidney.org/content/mdrd-study-equation 
8.4.2. 
Noninvasive Evaluations of Fibrosis 
The ELF panel combines 3 biomarkers that have been shown to correlate with the level of liver 
fibrosis assessed by a liver biopsy. These biomarkers include hyaluronic acid (HA), amino-
terminal propeptide-of-type-III-collagen (PIIINP), and tissue-inhibitor of matrix-
metaloproteinase-1(TIMP-1). These parameters along with PRO-C3 will be assessed as outlined 
in the Schedule of Assessments.  
Fibrosis will also be estimated using the APRI, FIB-4 formulae, and the NFS.  
The APRI will be calculated by the central laboratory using the following formula: 
([AST IU/L / AST ULN] / [Platelet count 109/L]) × 100 = APRI 
On line calculator can be found at:  http://www.hepatitisc.uw.edu/page/clinical-calculators/apri 
The FIB-4 will be calculated using the following formula:  
(Age [years] × AST [IU/L]) / (Platelet count [109/L] × ( √ ALT [IU/L]) ) 
On line calculator can be found at: http://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4 
The NFS will be calculated by the central laboratory using the following formula:  
-1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 
0.99 × AST/ALT ratio – 0.013 × platelet (×109/L) – 0.66 × albumin (g/dl) 
On line calculator can be found at: 
https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score 
NASH FibroSure ® is a noninvasive assessment of liver status. Quantitative results of 10 
biochemicals in combination with age, gender, height, and weight will be analyzed by the 
Central Laboratory using a computational algorithm to provide a quantitative surrogate marker 
(0.0 – 1.0) of liver fibrosis (Metavir F0 – F4), hepatic steatosis (0.0 – 1.0, S1 – S3), and 
nonalcoholic steatohepatitis (0.0 – 0.75, N0 – N2). Blood samples for analysis should be 
collected at Screening, Week 12 and EOT as shown in the Schedule of Assessments. 
8.4.3. 
Markers of Inflammation 
Markers of inflammation include fibrinogen, C-reactive protein (CRP), alpha2 macroblobulin, 
haptoglobin, tumor necrosis factor alpha (TNFα), tumor necrosis factor beta (TNFβ), and the 

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cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β). Blood for analysis of these markers 
will be collected as shown in the Schedule of Assessments. 
8.4.4. 
Pharmacodynamic Biomarkers for FXR activity 
See Table 3 and the Schedule of Assessments for a full list of biomarkers to be collected in this 
study. 
Serum or plasma samples should be collected before the daily dose of study drug for analysis of 
the FGF-19 (serum), C4 and BAs as shown in the Schedule of Assessments. At the Day 1, Week 
12, Week 36, and Week 72 visits, one predose and two postdose samples will be collected 
concomitantly with PK samples: the first postdose sample should be collected one to three hours 
postdose and the second postdose sample collected at least 1 hour later. If the subject took drug 
prior to their clinic visit, only one postdose sample should be collected.  

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Table 3: 
Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total, Indirect and Direct 
Blood urea nitrogen (BUN) 
BUN/Creatinine Ratio (calculation) 
Calcium, (Serum) 
Creatine Kinase  
Creatinine, Serum (and eGFR [MDRD]) 
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Gamma Glutamyl Transferase (GGT) 
Globulin, Total 
Lactate Dehydrogenase (LDH) 
Lipase 
Protein, Total, Serum 
HbA1c 
HOMA indices 
Fasting Insulinemia 
Fasting Plasma Glucose 
Total Cholesterol (TC) 
Triglycerides (TG) 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
Differential WBC Count (percentage and absolute): Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelets 
Red Blood Count (RBC) 
White Blood Cell (Count) (WBC) 
VIRAL DETECTION FOR ENTRY CRITERIA 
Human immunodeficiency virus (HIV)-1, HIV-2, Hepatitis B virus 
(HBV) (Hepatitis B surface antigen [HBsAg]), hepatitis C virus 
(HCV) 
MARKERS OF CV RISKS AND LIPIDS 
Triglycerides (TG) 
apoB 
Total Cholesterol (TC) 
High Density Lipoprotein – Cholesterol (HDL-C) 
Low-Density-Lipoprotein – Cholesterol (LDL-C) 
Total/HDL Cholesterol (CT) Ratio 
Adiponectin 
 
URINALYSIS 
Routine urinalysis to include:  Color and appearance, pH, 
SG, Bilirubin, Glucose, Ketones, Leukocytes, Nitrite, 
Occult 
blood, 
Protein, 
Urobilinogen, 
Microscopic 
(including RBCs and WBCs) 
 
BIOMARKERS FOR NASH 
Cytokeratin (CK)18 
GLP-1 (glucagon-like peptide-1) 
 
PD MARKERS FOR FXR ACTIVITY: 
Fibroblast growth factor (FGF)19  
Total bile acids (BAs)  
C4 (7α-OH-4-cholesten-3-one)  
PREGNANCY AND OTHER TESTS  
Serum pregnancy test  
Follicle-StimulatingHormone (FSH)  
 
FIBROSIS AND INFLAMMATORY MARKERS 
ENHANCED LIVER FIBROSIS (ELF) PANEL 
       -Hyaluronic acid (HA),  
  -Procollagen III amino terminal peptide (PIIINP)   
  -Tissue inhibitor of metalloproteinase 1 (TIMP-1) 
PRO C3 
Fibrinogen, CRP, alpha2 macroglobulin and haptoglobin 
Tumor necrosis factor alpha and beta (TNF-α, and β) 
IL-6. IL1β 
AST to Platelet Ratio Index (APRI) 
Fibrosis 4 (FIB-4) 
NAFLD fibrosis score (NFS score), NASH FibroSure 
COAGULATION TEST 
International Normalized Ratio (INR) 
Prothrombin Time (PT) 
Partial thromboplastin time (PTT) 
 
 
8.4.5. 
Pharmacokinetic Samples 
Plasma samples will be collected and processed according to the procedures provided and/or 
approved by Enanta. Plasma PK samples will be collected as shown in the Schedule of 
Assessments. More detailed information will be given in the Laboratory Manual.   
On all scheduled visits except for Day 7, PK samples will be collected predose. At the Day 1, 
Week 12, Week 36, and Week 72 visits, three PK samples should be collected, one predose and 

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two postdose. The first postdose sample should be collected 1 to 3 hours postdose and the second 
postdose sample should be collected at least one hour later. Where possible, the samples at each 
visit should be obtained at different times postdose relative to each other. If the subject took drug 
prior to their clinic visit, only one postdose sample should be collected. For subjects who 
discontinue treatment early, collect one postdose sample at the EOT visit.  
PK samples may be stored and used for future metabolite identification and/or further evaluation 
of the bioanalytical method. These data will be used for internal exploratory purposes and will 
not be included in the clinical study report. 
Actual date and time of PK sample collection will be recorded in the eCRF. 
8.4.5.1. 
Pharmacokinetic Sampling for Subjects with Transaminase or ALP Elevations 
For subjects with persistent transaminase or ALP elevations and evidence of liver injury, one 
additional sample will be collected for additional PK analysis at each visit where safety labs are 
obtained (see Section 10.2). 
It is important that the date and time of collection for each PK blood sample be accurately 
recorded in the source document. In addition, the site should record the time of last dose taken at 
home prior to the visit. 
8.4.5.2. 
Handling and Bioanalysis of Pharmacokinetic Samples 
EDP-305 and its metabolites in human plasma will be quantified by high performance liquid 
chromatography with tandem mass spectroscopy (LC-MS/MS) detection. The method will be 
fully validated by assessment of precision, accuracy, sensitivity, and specificity of EDP-305 and 
its metabolites by a laboratory selected by Enanta.   
Detailed procedures for the collection of blood samples and further procedures for processing, 
handling and shipping of samples for PK analysis will be provided in the Laboratory Manual.   
The lab performing bioanalytical analysis will be provided the randomization scheme and will 
generally analyze all samples for subjects randomized to EDP-305. In addition, a few samples 
from selected subjects randomized to placebo will also be analyzed and serve as control samples. 
8.4.6. 
Pregnancy and Menopausal Laboratory Testing 
All female subjects will undergo a serum pregnancy test at Screening and Baseline. In addition, 
all female subjects will have urine pregnancy testing at Baseline visit. A urine pregnancy test 
must be conducted and confirmed negative on Day 1 prior to the first dose of study drug. 
Thereafter, all female subjects being of child-bearing potential at the time of Screening will 
continue having urine pregnancy tests at each visit throughout the study. A serum pregnancy test 
must be completed at the EOS visit in these subjects. If the urine pregnancy test is positive, a 
serum pregnancy test should be obtained as soon as possible.  
FSH testing will be conducted as per below guidance:  
• 
FSH testing is not required in the following female subjects:  
o Who are of childbearing potential, or  
o Who have had a hysterectomy, bilateral oophorectomy (ovariectomy), or bilateral 
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o With cessation of menses ≤ 1 year at Screening as the subject is considered of 
childbearing potential.  In such cases the subject must agree to use contraception methods 
as required by the protocol.  
o With cessation of menses ≥ 2 years: the subject is of non-childbearing potential.   
 
FSH testing is mandatory in female subjects with cessation of menses between 1 to 2 years. To be 
considered postmenopausal a subject must have an FSH level >35 mIU/mL. 
Females of child-bearing potential will be given a pregnancy test kit so that they can perform a 
urine pregnancy test at home at Weeks 52, 60 and 68 (i.e., between clinic visits at Weeks 48 and 
56, 56 and 64, and 64 and 72, respectively). If the results of either the in clinic or at home urine 
pregnancy test are positive, a serum pregnancy test should be conducted as soon as possible.  
 
8.4.7. 
Liver Magnetic Resonance Imaging 
All eligible subjects must undergo a liver MRI-PDFF and liver MRE during the Screening 
period, Week 12 and at the EOT visit. Once a subject is considered eligible based on Screening 
laboratory values, a liver MRI-PDFF and MRE will be conducted prior to Baseline. For subjects 
who complete treatment, a final liver MRI and MRE will also occur at the end of treatment (i.e., 
Week 72). For subjects who discontinue treatment between Weeks 10 and 12, the EOT MRI and 
MRE must be conducted within 1 week of the final dose of study drug. If the MRI/MRE cannot 
be conducted within the 7-day timeframe, then it should not be conducted and the reason noted 
in the source documents. For subjects who had the MRI and MRE conducted at the Week 12 
visit but discontinue treatment prior to Week 36, no additional MRI and MRE will be conducted. 
For subjects who discontinue treatment at Week 36 or later, the MRI and MRE should be 
conducted within 2 weeks after discontinuing treatment.  
Details for the scheduling and conduct of the MRI-PDFF and MRE will be provided in the study 
binder.  
8.4.8. 
Liver Biopsy  
Baseline liver biopsy: Histological evidence of NASH from a liver biopsy read by a central 
histopathologist is required for study entry. The liver biopsy may be obtained during the 
Screening period after the subject has qualified for study entry based on all other criteria OR a 
sample from a previous biopsy may be used if it meets the following criteria: 
• Was obtained within 26 weeks of the Screening Visit 
• Is of sufficient quality to allow for a definitive diagnosis of NASH 
• Has samples available for review/confirmation by the central histopathologist 
If samples from the biopsy were sent to the central histopathologist and his/her assessment does 
not match with results provided by a local assessor, a site will be allowed to provide additional 
liver biopsy tissue to the central reader to be evaluated if the following conditions apply:  
• The subject is considered eligible except for liver histology 
• The site must request to provide additional tissue to the central reader before the subject 
is considered a screen failure.  
Note that in all cases, the central histopathologist will provide the final liver histology 
assessment for study entry. 

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Details for collection and processing of the liver biopsy can be found in the liver biopsy guidance 
in the study binder.  
EOT (Week 72) liver biopsy: End-of-treatment liver biopsies collected for analysis of the 
primary endpoint for subjects who have completed treatment will be performed 72 weeks after 
enrollment (window: 70-74 weeks). If a liver biopsy cannot be performed within the 70 to 74 
week window due to extreme circumstances, the PI should consult with the Medical Monitor to 
determine if the window can be extended for that subject to 66 to 78 weeks. 
Early Termination: Subjects who discontinue the study early but complete a minimum of 36 
weeks of dosing should have a liver biopsy within 2 weeks following the last dose of study drug. 
Subjects who discontinue the study prior to completing 36 weeks of dosing should forgo the 
EOT biopsy.  
8.4.9. 
Exploratory Research Samples 
Additional blood samples for exploratory research will be collected as described in the Schedule 
of Assessments. These samples will be used for research to better understand markers of health 
and disease, and responses to medicine used to treat disease. These samples will not be used for 
genomic testing. Further, samples will be stored anonymously such that the subject’s identity 
will be protected and the subjects name will not be attached to the sample. The samples will be 
stored for up to 1 year after the finalization of the Clinical Study Report for this study which 
includes study results. 
Subjects may withdraw consent to participate in this exploratory research at any time. 
Withdrawing consent to use these samples should be done in writing to the PI. Withdrawing 
consent to the storage and future testing of the sample will result in destruction of the sample. 
However, if the subject withdraws consent after the sample has been tested, the test results and 
research study/sample-related information must remain in any database(s) that was created for 
the research study. The reason for this is to comply with regulations that require the Sponsor to 
make data available for review by the US FDA or other appropriate regulatory authorities if the 
data is used to support an application for marketing approval of EDP-305. 
 

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9. 
SAFETY MONITORING AND REPORTING 
9.1. 
Definitions 
9.1.1. 
Pretreatment Events 
A pretreatment event is any event that meets the criteria for an AE/SAE and occurs after the 
subject signs the ICF but before receiving the first administration of study drug. 
9.1.2. 
Adverse Events 
An AE is any event, side effect, or untoward medical occurrence in a subject enrolled in a 
clinical study whether or not it is considered to have a causal relationship to the study drug. An 
AE can therefore be any unfavorable and unintended sign, symptom, laboratory finding outside 
of normal range with associated clinical symptoms or suspected latent clinical symptoms in the 
opinion of the PI, physical examination finding, or disease temporally associated with the use of 
the study drug, whether or not the event is considered related to the study drug.  
The occurrence of adverse events should be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination, laboratory test, or other 
assessments. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (e.g., surgery was performed earlier than 
planned). 
9.1.3. 
Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence at any dose that:  
• Results in death: This includes deaths that appear to be completely unrelated to study 
drug (e.g., a car accident).  
• Is a life-threatening event: An event that places the subject at immediate risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.  
• Requires inpatient hospitalization or prolonged hospitalization of an existing 
hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o elective or preplanned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the ICF 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the subject's 
general condition 
• Results in permanent or prolonged (at least 28 days in duration) disability or incapacity  
• Is a congenital anomaly or birth defect in the offspring of a study subject 
• Medically important event: An event that may not be immediately life-threatening, or 
result in death or hospitalization, or require intervention to prevent one of the outcomes 

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listed above, but is considered medically significant for other reasons.  An opportunistic 
or otherwise unusual infection for the PI's practice, such as tuberculosis, will be 
considered medically significant.  
The term severe is used to describe the intensity of a specific event (as in mild, moderate, or 
severe); the event itself, however, may be of minor medical significance (such as severe 
headache). This is not the same as serious, which is based on outcome of the event, as described 
above. Seriousness, not intensity, serves as a guide for defining regulatory reporting obligations. 
9.2. 
Documenting and Reporting of Adverse Events (Including Serious 
Adverse Events) 
Adverse Events will be evaluated and documented using the grading scales contained in the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
(Version 5.0). 
9.2.1. 
Documenting and Reporting Adverse Events 
All AEs regardless of the intensity, seriousness, or relationship to study drug will be reported 
from the time of informed consent to the end-of-study. AEs for each subject will be recorded in 
the subject’s source documents and in the subject’s AE eCRF and Clinical Trials SAE Form (if 
applicable).   
Grade AEs (serious and non-serious) in accordance with the NCI/CTCAE scale (available at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0_2010-06-14_QuickReference_8.5x11.pdf) as 
presented below:  
• Mild (Grade 1) asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Moderate (Grade 2) minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• Severe (Grade 3) Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• Life-threatening (Grade 4) Life-threatening consequences; urgent intervention indicated  
• Death (Grade 5) Death related to the AE. 
Any recurrence of an AE with similar causality to study drug will be reported as recurrence or 
exacerbation of the initial event, and not as a new event. Whenever possible, report AEs as a 
specific diagnosis or syndrome (e.g., flu syndrome) rather than as individual signs or symptoms. 
If no specific diagnosis or syndrome is identified, AEs should be reported as separate and 
individual events.  
An AE includes the following:  
• Progression or exacerbation of the subject’s underlying disease. Clinical sequelae that 
result from disease progression, such as pleural effusion or small bowel obstruction, are 
reportable as AEs.  
• Pre-existing event that increases in frequency or intensity  
• Condition detected or diagnosed during the study period, even though it may have been 
present, in retrospect, prior to the first dose of study drug 

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The PI is responsible for notifying 
/the Sponsor within 24 
hours of identifying an SAE, regardless of the presumed relationship to the investigational study 
drug. The SAE Form should be completed for new/initial events as well as to report follow-up 
information on previously reported events. The PI is asked to report follow-up information as it 
becomes available.  
Enanta or its designees, as study Sponsor, is responsible for reporting suspected, unexpected, 
serious adverse reactions (SUSARs) involving the study drug(s) to all regulatory authorities, and 
participating PIs, in accordance with FDA, International Conference on Harmonization (ICH) 
Guidelines, and/or local regional or country regulatory requirements, as applicable. 
9.2.6. 
Documenting and Reporting of Pregnancy 
Females must not become pregnant while taking study drug. However, as a precaution, all 
subjects will be counseled to inform the PI of any pregnancy that occurs during study treatment 
and for 90 days after the last dose of study drug. 
If a female subject or the female partner of a male subject becomes pregnant while participating 
in the study, study treatment must be permanently discontinued immediately. The PI must notify 
the Sponsor’s Medical Monitor and 
 within one business day 
of the sites’ knowledge of the subject’s (or partner’s) pregnancy, by utilizing the study-specified 
pregnancy report form. If confirmed to be on active drug, the subject or partner will be followed 
until end of pregnancy and the infant will be followed for one year after the birth, provided 
informed consent is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself does not constitute an AE. 
9.3. 
Follow-up of Adverse Events and Serious Adverse Events 
Follow all AEs (serious and nonserious) until resolution or otherwise explained (see Table 5), the 
subject dies, the event stabilizes and is not expected to further resolve with the maximum time 
limit for stabilization defined as 30 days after the occurrence of the event, or when alternative 
therapy is instituted, whichever occurs first. If alternative therapy is instituted, it should be 
documented. Enanta may request that the PI perform or arrange for supplemental measurements 
or evaluations to further clarify the nature of the event. 
9.4. 
Sponsor’s Review of Adverse Events and Serious Adverse Events 
Enanta will maintain an ongoing review of all AEs and SAEs. 
9.5. 
Data Safety Monitoring Board 
Safety data from this study will be reviewed by a Data Safety Monitoring Board (DSMB) 
throughout the study. The DSMB will be headed by a DSMB Chair and will include physicians 
with expertise in diseases of the liver including NASH. Procedures for data review including 
timing and potential outcomes will be governed by the DSMB charter. 

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10. 
SUBJECT SAFETY MANAGEMENT 
10.1. 
Individual Subject Stopping Rules 
Study drug will be discontinued in subjects with elevated ALT or AST (see below) and thorough 
evaluation and follow-up will be performed. Study drug will be discontinued once any one of the 
thresholds presented below is met. No repeat test is required. Reference Baseline is defined as 
the mean of Screening and Day 1 values. The following study drug stopping rules are applied:  
• If ALT or AST increases to >5× Reference Baseline (and is at least > 5x ULN)  
• If ALT or AST increases to >2× Reference Baseline (and is at least > 3x ULN) AND the 
increase is accompanied by  
o a concomitant total bilirubin increase to >2× Reference Baseline (and at least > 2x 
ULN) OR  
o the INR is concomitantly > 1.5  
• If ALT or AST increases to >2× Reference Baseline (and is at least > 3x ULN) AND  
o elevations of ALT/AST are accompanied by signs or symptoms of right upper 
quadrant abdominal pain, anorexia, nausea, vomiting, fever, eosinophilia (> upper 
limit of normal of absolute eosinophilia count), and/or rash.  
Refer to Section 10.2 for close monitoring guidelines for subjects who meet criteria for drug 
discontinuation due to elevated ALT/AST.   
10.2. 
Management of Liver Enzyme Elevations 
The FDA Guidance for Industry for Drug-Induced Liver Injury (FDA, 2009) provides guidance 
for the management of changes in liver transaminases (ALT/AST).  
Close monitoring activities will be initiated:  
• If ALT or AST increases > 2x Reference Baseline (and is at least > 3x ULN) OR  
• If ALT or AST increases > 8x ULN (whichever comes first) 
Following the initial alert, sites will be asked to perform the following laboratory tests and 
assessments within 48 – 72 hours.    
• Blood samples must be taken prior to taking study drug on that day (i.e., predose).    
o Clinical Chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, indirect 
bilirubin, ALP  
o Hematology: full red blood count  
o Coagulation: INR  
o PK sample: predose  
• Physical examination for detection of accompanying clinical symptoms potentially 
associated with deviation in liver function e.g. right upper quadrant abdominal pain, 
anorexia, nausea, vomiting, fever, or rash.  
• Sites will also be requested to comment/confirm  
o if the subject has any history of regular alcohol consumption exceeding 14 
drinks/week for females and 21 drinks/week for males within 6 months of Screening 
as well as any recent relevant alcohol intake  

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summarized. The denominator for the calculation of percentages will be from the number of 
subjects randomized.   
The following categories will also be summarized for subject disposition: 
• Completed study drug per protocol 
• Discontinued study drug early and the reason for discontinuation 
• Completed the study  
• Discontinued from the study early and the reason for discontinuation 
Subject demographics will be summarized by randomized treatment group for all subjects in the 
safety population. Appropriate baseline characteristics will be included in addition to 
demographic characteristics. No statistical testing will be performed. Additional details will be 
provided in the SAP. 
11.5. 
Method of Treatment Assignment 
Subjects who meet all criteria for enrollment will be randomized to blinded treatment on Day 1 
in a 1:1:1 ratio to EDP-305 2 mg, EDP-305 1.5 mg, or placebo. Assignment to treatment groups 
will be determined by a computer-generated random sequence using an IWRS. The IWRS will 
be used to assign double-blind investigational product to each subject. To achieve between-group 
comparability the randomization will be stratified by diabetes status and use of Vitamin E and/or 
pioglitazone. 
11.6. 
Primary Efficacy Analysis 
Logistic regression models will analyze the co-primary endpoints of (1) proportion of subjects 
who achieve ≥1 stage improvement in fibrosis without worsening of steatohepatitis (2) resolution 
of steatohepatitis without worsening of liver fibrosis as determined by liver biopsy at 72 weeks. 
Treatment groups will be compared for each endpoint at a 0.025 significance level. A responder 
will be considered any subject achieving either endpoint. The proportion of responders for each 
endpoint will be compared using a logistic regression model with treatment group, diabetes 
status and use of Vitamin E and/or pioglitazone and baseline covariate NAS as effects. The odds 
ratio and 97.5% confidence interval will be reported as well.  
A step-down sequential testing procedure will be used to control multiplicity in testing between 
doses. The high dose EDP-305 group (2 mg) will be compared to placebo using a two-sided 
alpha of 0.025 first, and if statistically significant, the EDP-305 1.5 mg group will be compared 
to placebo using a two-sided alpha of 0.025. The primary efficacy analyses will be performed 
using the ITT population. 
11.6.1. 
Secondary Efficacy Analysis 
Secondary endpoints will be analyzed for treatment group differences. Multiple sensitivity 
analyses will be performed on the primary efficacy endpoints.     
For categorical endpoints (e.g., proportions) a logistic regression model testing between 
treatment differences with terms for diabetes status and use of Vitamin E and/or pioglitazone and 
baseline covariate NAS included in the model. Odds ratio and the 95% confidence intervals will 
be reported. If convergence is encountered the Fisher’s exact test will be used to test treatment 
group differences. 

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For continuous endpoints (e.g., change from baseline) an analysis of covariance (ANCOVA) 
model testing treatment differences with terms for baseline diabetes status and use of Vitamin E 
and/or pioglitazone, baseline covariate NAS, and baseline parameter of interest included in the 
model. A type III sum-of-squares for the least-squares means and 95% confidence intervals will 
be reported.   
When continuous endpoints that are repeated over visits a restricted maximum likelihood-based 
mixed model repeated measures (MMRM) technique may be performed. The model will include 
treatment, baseline covariate NAS, baseline parameter, visit, treatment-by-visit interaction as 
fixed effects. An unstructured variance-covariance structure will be considered to model the 
within-patient error. If the unstructured covariance matrix results in a lack of convergence, the 
heterogeneous Toeplitz covariance structure should be used. The Kenward-Roger method will be 
used to estimate the denominator degrees of freedom. A type III sum-of-squares for the least-
squares means and 95% confidence intervals will be reported. 
11.7. 
Safety Endpoints 
11.7.1. 
Treatment Compliance 
Listing of randomization schedule and study drug dispensed with LOT number will be provided.  
Subjects will record study drug administration on the Drug Administration form.  Treatment 
compliance for each subject will be calculated as the number of subjects receiving the amount of 
drug taken divided by the amount prescribed multiplied by 100.   
11.7.2. 
Adverse Events 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term by treatment group. All subjects in the safety 
analysis set will be included in the summaries. Treatment-Emergent are defined as reported AEs 
that first occurred or worsened during the postbaseline phase compared to baseline. The 
maximum severity at baseline will be used as baseline severity. If the maximum severity during 
postbaseline is greater than the maximum baseline severity, then event is considered Treatment-
Emergent. No statistical testing will be performed.   
Summaries of AEs will include the following at a minimum: 
• An overall summary of AEs with a line for each of the categories provided below: 
• TEAEEs 
• Related TEAEs 
• Maximum Severity TEAEs 
• Treatment-Emergent by Severity 
• Treatment-emergent AEs leading to study drug discontinuation 
• AEs leading to death 
• SAEs 
• Related Treatment-Emergent SAEs 
11.7.3. 
Clinical Laboratory Data 
Laboratory assessments will be reported as mean change from baseline across scheduled visits, 
and as the incidence rate of shift change from baseline. Shift from baseline tables will be 
generated for each treatment group for selected analytes. Laboratory shifts will be displayed as 

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treatment-emergent abnormal, high, or low results. The following details the summary types 
where LLN = Lower limit of the normal range, ULN = Upper limit of the normal range. 
For categorical tests: Treatment-emergent abnormal is defined as a change from normal at 
baseline to abnormal at any postbaseline visit 
For continuous tests:   
• Treatment-emergent high is defined as a change from a result less than or equal to the 
high limit at baseline to a value greater than the high limit at any time postbaseline.   
Results will be reported according to any value greater than the high limit, any value 
greater than 2x ULN and 3x ULN 
• Treatment-emergent low is defined as a change from a result greater than or equal to the 
low limit at baseline to a value less than the low limit at any time postbaseline  
Results will be reported according to any value less than the lower limit, any value less 
than 2x LLN and 3x LLN. 
11.7.4. 
Electrocardiogram Data 
The QT interval has an inverse relationship with heart rate. The measured QT intervals will be 
corrected for heart rate in order to determine prolongation relative to baseline. The QT/QTc 
interval will be corrected based on Fridericia’s correction:  QTc = QT/(RR interval)1/3, in 
seconds.  The QT parameters will be summarized by observed and change from baseline over 
visits.  
A categorical analysis of QT/QTc will be based on the number and percentage of subjects 
meeting or exceeding the following: 
• Absolute QT/QTc interval prolongation 
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
• Change from Baseline in QTc interval 
o QTc interval increases from baseline >30 
o QTc interval increase from baseline >60. 
11.7.5. 
Vital Signs 
The incidence rate of subjects with treatment-emergent vital sign changes at any postbaseline 
visit will be summarized. Specific criteria for the classification of treatment-emergent will be 
documented in the SAP. Vital sign observed, change, and percent change will be summarized by 
treatment over visits. 
11.7.6. 
Concomitant Medications 
The number and percentage of subjects taking concomitant medications will be coded according 
to latest WHO ATC level 4 and WHO preferred term. Summaries will be provided by ATC level 
4 and preferred term. Subjects in the safety population will be summarized by treatment group. 

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12. 
STUDY ADMINISTRATION 
12.1. 
Ethical Considerations 
12.1.1. 
Ethical Conduct of the Study 
The study will be conducted in compliance with this protocol, principles of E6 Good Clinical 
Practice: Consolidated Guidance (ICH-GCP), Declaration of Helsinki, and all applicable local 
laws and regulations governing clinical trials. 
12.1.2. 
Ethical Review 
It is the PI’s responsibility to ensure that this protocol is reviewed and approved by an 
appropriate IRB/EC which conforms to the regulations set forth in 21Code of Federal 
Regulations (CFR), Part 56 and other national, country, and regional regulations as applicable. 
The PI must also submit the ICF, any other written documentation provided to the subject, and 
all advertisements that may be used for study-specific recruitment to the IRB/EC for review and 
approval before commencing study-specific activities. If it is necessary to amend the protocol 
during the study, then it is the responsibility of the PI to ensure that IRB/EC approval is obtained 
before implementation of the amended procedures. It is also the responsibility of the PI to 
provide the IRB/EC with any SAE or Investigational New Drug safety reports. A copy of the 
ICF approved by the IRB/EC must be forwarded to Enanta for regulatory purposes. 
12.1.3. 
Written Informed Consent 
The PI or designee must explain to each subject the purpose and nature of the study, the study 
procedures, the possible adverse effects, and all other elements of consent as defined in §21CFR 
Part 5, and other applicable national and local regulations governing informed consent. Each 
subject must provide a signed and dated ICF prior to enrollment into this study. Signed consent 
forms must remain in each subject’s study file and be available for verification by study monitors 
at any time. In accordance with individual local and national or country-specific subject privacy 
regulations, the PI or designee must explain to each subject prior to Screening that for the 
evaluation of study results, the subject’s protected health information obtained during the study 
may be shared with Enanta and its designees, regulatory agencies, and IRBs/ECs. As the study 
sponsor, Enanta will not use the subject’s protected health information or disclose it to a third 
party without applicable subject authorization. It is the PI’s or designee’s responsibility to obtain 
written permission to use protected health information from each subject. If a subject withdraws 
permission to use protected health information, it is the PI’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be collected 
from the subject. Any data collected on the subject prior to withdrawal will be used in the 
analysis of study results.   
12.1.4. 
Investigator Compliance 
No modifications to the protocol should be made without the approval of both the PI and Enanta. 
Changes that significantly affect the safety of the subjects, the scope of the investigation, or the 
scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification prior 
to implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects.   
If circumstances require an immediate departure from protocol procedures, the PI will contact 
Enanta to discuss the planned course of action. Contact should be made prior to the 

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implementation of any changes when possible. Any departures from protocol must be fully 
documented in the source documentation and in a protocol deviation log.   
12.2. 
Data Collection 
Study data for each randomized subject will be entered into an eCRF by site personnel. ̶There  
will be limited data entered in the eCRF for Screen Failed subjects. It is the PI’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, other observations, and subject status. The PI, or designated representative, should 
complete the eCRF as soon as possible after information is collected. An explanation should be 
provided for all missing data. 
After the subject has completed the study, the PI must review and sign the signature page of the 
eCRF indicating that he has reviewed the completed eCRF and pertinent clinical data for that 
subject and that, to the best of his knowledge, all data recorded in the eCRF accurately reflects 
the subject’s clinical performance in the study.   
Sites are responsible for abiding by the rules and regulations of their IRB/EC for recording and 
reporting protocol deviations. All deviations reported to the IRB/EC must be reported to Enanta 
and/or their designee and recorded as deviations as appropriate in the eCRF. 
12.3. 
Study Monitoring 
Representatives of Enanta or its designee will monitor this study until completion. Monitoring 
will be conducted through on-site visits with the PI and site staff as well as any appropriate 
communications by mail, fax, e-mail, or telephone. The purpose of monitoring is to ensure 
compliance with the protocol and the quality and integrity of the data. The study monitor will 
ensure that the investigation is conducted according to protocol and regulatory requirements, and 
as described in the Study Monitoring Plan. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this treatment, the PI agrees 
to allow the IRB/EC, representatives of Enanta, its designated agent, and authorized employees 
of the appropriate regulatory agencies to inspect the facilities used in this study and, for purposes 
of verification, allow direct access to the hospital or clinic records of all subjects enrolled into 
this study. A statement to this effect will be included in the ICF authorizing the use of protected 
health information. 
12.4. 
Quality Assurance 
At its discretion, Enanta or its designee may conduct a quality assurance audit of this study. If 
such an audit occurs, the PI will give the auditor direct access to all relevant documents and will 
allocate his time and the time of his staff to the auditor as required. In addition, regulatory 
agencies may conduct an inspection of this study. If such an inspection occurs, the PI will allow 
the inspector direct access to all source documents, CRFs, and other study documentation for 
source data check and/or on-site audit inspection.  

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12.5. 
Retention of Records 
The site will retain a copy of all study records in a safe, secure and accessible location for a 
minimum of 2 years after notification by Enanta that the investigations of EDP-305 have been 
discontinued or for 2 years following marketing approval of the drug, after which time Enanta 
will be contacted for instructions on the disposition of study materials. Study records will contain 
all of the appropriate documents as detailed in Section 8.0 of the E6 Good Clinical Practice: 
Consolidated Guidance (ICH-GCP).  
12.6. 
Information Disclosure 
12.6.1. 
Confidentiality 
Subject names will remain confidential and will not be supplied to Enanta or its designee. Only 
subject number, subject initials, and birth date will be recorded on the eCRF. If the subject name 
appears on any other document collected (eg, unit discharge summary), it must be obliterated 
before the document is transmitted to Enanta or its designee. All study findings will be stored in 
electronic databases. As indicated in the ICF, subjects will give permission for representatives of 
the Sponsor, regulatory authorities, and the IRB/EC to inspect their medical records to verify the 
information collected. Subjects will be informed that all personal information made available for 
inspection will be handled in the strictest confidence and in accordance with local data 
protection/privacy laws. 
Individual subject medical information obtained during this study is confidential and its 
disclosure to third parties other than those mentioned in the preceding paragraph is prohibited. 
Medical information obtained during this study may be provided to the subject’s personal 
physician or other appropriate medical personnel when required in connection with the subject’s 
continued health and welfare and with the subject’s prior knowledge and permission. 
12.6.2. 
Publication Policy 
It is the intention of Enanta to publish the results of this study in their entirety within a 
reasonable period of time following conclusion of the study. The Sponsor will determine when 
and where data will be first disclosed.   
All information generated from this study is the proprietary property of Enanta. Enanta reserves 
the right, among other things, to: 
• Modify or amend study material to ensure that no confidential or proprietary information 
is disclosed 
• Ensure that the reported data are factually correct 
• Utilize the information generated from or as a result of this study in any manner it deems 
appropriate, including but not limited to regulatory submissions, annual reports, and other 
scientific or business affairs of the company 
• Modify the publication or disclosure or delay it a sufficient time to allow Enanta to seek 
patent protection of any invention contained therein 

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13. 
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Ahmad, A., Sanderson, K., & Dickerson, D. (2018). Pharmacokinetics (PK), Pharmacodynamics 
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Elman, S., Hynan, L. S., Gabriel, V., & Mayo, M. J. (2010). The 5-D itch scale: a new measure of 
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Venereol, 93(2), 214-215.  
Ikenaga, N., Liu, S. B., Sverdlov, D. Y., Yoshida, S., Nasser, I., Ke, Q., . . . Popov, Y. (2015). A new 
Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset 
portal hypertension, and liver cancer. Am J Pathol, 185(2), 325-334. 
doi:10.1016/j.ajpath.2014.10.013 
Lieu, T., Jayaweera, G., Zhao, P., Poole, D. P., Jensen, D., Grace, M., . . . Bunnett, N. W. (2014). The bile 
acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology, 
147(6), 1417-1428. doi:10.1053/j.gastro.2014.08.042 
Loomba, R., & Adams, L. A. (2019). The 20% Rule of NASH Progression: The Natural History of 
Advanced Fibrosis and Cirrhosis Caused by NASH. Hepatology, 70(6), 1885-1888. 
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Maruyama, T., Miyamoto, Y., Nakamura, T., Tamai, Y., Okada, H., Sugiyama, E., . . . Tanaka, K. (2002). 
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1 Screening assessments should be conducted within 70 days prior to the first dose of study drug (ie, Study Days -70 to -1). 
2 At Weeks 52, 60 and 68, the site will contact the subject by phone to verify results of the home pregnancy test (for female subjects of child-bearing potential) and assess drug accountability, 
concomitant medications and AE/SAEs.  
3 On Day 1, all samples are to be collected predose; two additional PK and PD samples will be collected postdose as noted in Sections 8.4.4 and 8.4.5.   
4 Day 7 is a phone contact, not an in-clinic visit. 
5 Subjects should take their last dose of study drug at the Week 72 visit. Subjects who return for their EOT Visit after Week 72, should stop dosing during Week 72 as instructed by the site. Subjects 
who discontinue the study early should complete the EOT procedures within one week following discontinuation of study drug. For subjects who discontinued between Weeks 10 and 12, an MRI 
and MRE must be conducted within one week following the last dose of study drug (if it cannot be conducted within one week, it should not be conducted and the reason recorded in the source 
documents). For subjects who had the MRI and MRE conducted at the Week 12 visit but discontinue treatment prior to Week 36, no additional MRI and MRE will be conducted. For subjects who 
discontinue treatment at Week 36 or later, the MRI and MRE should be conducted within 2 weeks after discontinuing treatment, and only one PK sample will be obtained.  
6 Informed consent must be obtained prior to conducting any study-specific procedures or assessments. 
7 The biopsy may be obtained either 1) during the Screening window or 2) within 26 weeks prior to the Screening visit. If done during the study screening window, the biopsy should be performed 
once all other I/E criteria have been met.  
8 FSH testing required only in female subjects with cessation of menses between 1 to 2 years   
9 Serum pregnancy testing: All female subjects will undergo a serum pregnancy test at Screening and Baseline. In addition, all female subjects will have urine pregnancy testing at Baseline visit. 
Thereafter, all female subjects being of child-bearing potential at the time of Screening will continue having urine pregnancy tests at each visit throughout the study. A serum pregnancy test must be 
completed at the EOS visit in these subjects. If the urine pregnancy test is positive, a serum pregnancy test should be obtained as soon as possible.  
10 Urine pregnancy tests will be provided to females of child-bearing potential so that they can perform the test at home on Weeks 52, 60 and 68. If the urine pregnancy test is positive, a serum 
pregnancy test should be obtained as soon as possible. 
11 Height to be assessed at Screening only. 
12 Full physical exam (PE) at Screening, Week 12, and EOS Visit; subsequent PE should be targeted to review new signs and symptoms. 
13 Vital Signs include heart rate, respiratory rate, blood pressure, and will be measured predose. 
14 Safety laboratory tests include chemistry (including liver function tests), hematology, and urinalysis and should be collected predose at all visits; See Table 3 for details. eGFR will be calculated at 
all visits based on the MDRD formula. HbA1c will be obtained at Screening, Baseline, week 12, and Week 72.. 
15 Pruritus scales (up to 2 scales) will be utilized to measure pruritus for every subject regardless of whether or not a subject experiences pruritus. Please refer to Section 8.3.5 and additional details 
included in the study binder. 
16 QoL includes SF-36 and CLDQ-NASH. In addition, Dermatology Life Quality Index (DLQI) will be completed at each in-clinic visit by subjects who reported pruritus until resolution. Additional 
details can be found in the study binder. 
17 Lipids and CV risk markers to be collected are detailed in Table 3.  
18 Markers of inflammation include fibrinogen, CRP, IL-6, IL-1β, TNF-α, TNF-β, alpha2 macroglobulin and haptoglobin (See Table 3). 
19 One sample will be collected from all subjects predose. 
20 Samples should be collected before the subject takes the daily dose of study drug.  On Day 1 and Weeks 12, 36, and 72, samples should be collected predose and two samples postdose; the first 
postdose sample will be collected 1 to 3 hours after dosing and the second collected at least 1 hour later. At all other visits, samples will be collected only predose. If the subject took drug prior to 
their clinic visit, only one postdose sample should be collected. 
21 PK predose samples should be collected before the daily dose of study drug. On Day 1 and Weeks 12, 36, and 72, one PK sample should be collected predose and two samples postdose; the first 
postdose sample should be collected 1 to 3 hours postdose and the second postdose sample at least 1 hour later. At all other visits, PK samples will be collected predose. If the subject took drug prior 
to their clinic visit, only one postdose sample should be collected. For subjects who discontinue treatment early, collect one postdose sample at the EOT visit. For subjects with persistent 
transaminase or ALP elevations and evidence of liver injury and who remain on study drug, the one additional PK sample will be collected at each visit where safety labs are obtained. 
22 See Section 5.7 for details.