Conditions: Non-Alcoholic Steatohepatitis
Keywords: Fatty Liver, non-alcoholic fatty liver disease, NASH
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
A randomized, double-blind study to assess the safety and efficacy of EDP-305 in subjects with liver-biopsy proven Non-Alcoholic Steatohepatitis (NASH)

Detailed description:
The aim of this Phase 2b study aimed to evaluate safety and efficacy of the investigational novel FXR agonist, EDP-305, in a population of patients with liver biopsy proven NASH.

This Phase 2b study aimed 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 FDA guidance, this late stage Phase 2 study explored the effect of EDP-305/placebo treatment on histological endpoints. The patient population selected for inclusion in the study was 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 were not excluded from participation in this study.

Arms:
arm 1: Once a day orally for 72 weeks arm 2: Once a day orally for 72 weeks arm 3: Once a day orally for 72 weeks

Interventions: intervention 1: EDP-305 1.5 mg intervention 2: EDP-305 2 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Tablet

Protocol document:
Prot_000.pdf: 




 
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 
 
Page 16 of 87 
 
 
 
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 
 
 
   
 
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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 
salpingectomy, or 


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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 
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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.  


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
          CONFIDENTIAL 
 
Page 83 of 87 
 
 
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 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-102 v3.0 (Amendment 2.0) 
 
          CONFIDENTIAL 
 
Page 84 of 87 
 
13. 
REFERENCES 
 
Agopian, V. G., Kaldas, F. M., Hong, J. C., Whittaker, M., Holt, C., Rana, A., . . . Busuttil, R. W. (2012). 
Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann Surg, 256(4), 624-
633. doi:10.1097/SLA.0b013e31826b4b7e 
Ahmad, A., Sanderson, K., & Dickerson, D. (2018). Pharmacokinetics (PK), Pharmacodynamics 
(PD),and Safety/Tolerability Effects of EDP-305, a Novel Once-Daily Oral Farnesoid X Receptor 
(FXR) Agonist in Healthy Subjects and in Subjects with Presumptive Nonalcoholic Fatty Liver 
Disease (NAFLD). Paper presented at the EASL 2018, Paris, France.  
Alemi, F., Kwon, E., Poole, D. P., Lieu, T., Lyo, V., Cattaruzza, F., . . . Corvera, C. U. (2013). The TGR5 
receptor mediates bile acid-induced itch and analgesia. J Clin Invest, 123(4), 1513-1530. 
doi:10.1172/jci64551 
Bertot, L. C., & Adams, L. A. (2016). The natural course of non-alcoholic fatty liver disease. Int J Mol 
Sci, 17, 774.  
Chalasani, N. Z., Younossi, J. E., Lavine, A. M., Diehl, E. M., Brunt, K., Cusin, M., . . . Sanyal, J. (2012). 
The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the 
American Associateion for the Study of Liver Disesases, American College of Gastroenterology, 
and the American Gastroenterological Association. Hepatology, 55(6), 2005-2023.  
D'Amore, C., Di Leva, F. S., Sepe, V., Renga, B., Del Gaudio, C., D'Auria, M. V., . . . Limongelli, V. 
(2014). Design, synthesis, and biological evaluation of potent dual agonists of nuclear and 
membrane bile acid receptors. J Med Chem, 57(3), 937-954. doi:10.1021/jm401873d 
Derendorf, H., & Schmidt, S. (2019). Rowland and Tozer's Clinical Pharmacokinetics and 
Pharmacodynamics: Concepts and Applications (3rd ed.). 
Elman, S., Hynan, L. S., Gabriel, V., & Mayo, M. J. (2010). The 5-D itch scale: a new measure of 
pruritus. Br J Dermatol, 162(3), 587-593. doi:10.1111/j.1365-2133.2009.09586.x 
FDA. (2009). Drug-Induced Liver Injury: Premarketing Clinical Evaluation. U.S. Department of Health 
and Human Services Retrieved from https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
drugs-gen/documents/document/ucm174090.pdf. 
FDA. (2018). Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for 
Treatment, Guidance for Industry.  Retrieved from https://www.fda.gov/media/119044/download. 
Furue, M., Ebata, T., Ikoma, A., Takeuchi, S., Kataoka, Y., Takamori, K., . . . Ständer, S. (2013). 
Verbalizing extremes of the visual analogue scale for pruritus: a consensus statement. Acta Derm 
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. 
doi:10.1002/hep.30946 
Maruyama, T., Miyamoto, Y., Nakamura, T., Tamai, Y., Okada, H., Sugiyama, E., . . . Tanaka, K. (2002). 
Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res 
Commun, 298(5), 714-719. doi:10.1016/s0006-291x(02)02550-0 
McMahan, R. H., Wang, X. X., Cheng, L. L., Krisko, T., Smith, M., El Kasmi, K., . . . Rosen, H. R. 
(2013). Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and Improves 
Nonalcoholic Fatty Liver Disease. J Biol Chem, 288(17), 11761-11770.  


Clinical Study Protocol 
 
 
   
 
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EDP 305-102 v3.0 (Amendment 2.0) 
 
          CONFIDENTIAL 
 
Page 85 of 87 
 
Meixiong, J., Vasavda, C., Snyder, S. H., & Dong, X. (2019). MRGPRX4 is a G protein-coupled receptor 
activated by bile acids that may contribute to cholestatic pruritus. Proc Natl Acad Sci U S A, 
116(21), 10525-10530. doi:10.1073/pnas.1903316116 
Patel, J., Bettencourt, R., Cui, J., Salotti, J., Hooker, J., Bhatt, A., . . . Loomba, R. (2016). Association of 
noninvasive quantitative decline in liver fat content on MRI with histologic response in 
nonalcoholic steatohepatitis. Therap Adv Gastroenterol, 9(5), 692-701. 
doi:10.1177/1756283x16656735 
Ratziu, V. (2013). Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol, 10(11), 676-685.  
Reboussin, D. M., DeMets, D. L., Kim, K. M., & Lan, K. K. (2000). Computations for group sequential 
boundaries using the Lan-DeMets spending function method. Control Clin Trials, 21(3), 190-207.  
Rizzo, G., Passeri, D., De Franco, F., Ciaccioli, G., Donadio, L., Rizzo, G., . . . Adorini, L. (2010). 
Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X 
receptor and TGR5 agonist. Mol Pharmacol, 78(4), 617-630. doi:10.1124/mol.110.064501 
Sanjel, B., Maeng, H. J., & Shim, W. S. (2019). BAM8-22 and its receptor MRGPRX1 may attribute to 
cholestatic pruritus. Sci Rep, 9(1), 10888. doi:10.1038/s41598-019-47267-5 
Wong, R. J., Aguilar, M., Cheung, R., Perumpail, R. B., Harrison, S. A., Younossi, Z. M., & Ahmed, A. 
(2015). Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults 
awaiting liver transplantation in the United States. Gastroenterology, 148(3), 547-555. 
doi:10.1053/j.gastro.2014.11.039 
Xu, J. Y., Li, Z. P., Zhang, L., & Ji, G. (2014). Recent insights into farnesoid X receptor in non-alcoholic 
fatty liver disease. World J Gastroenterol, 20(37), 13493-13500. doi:10.3748/wjg.v20.i37.13493 
Younossi, Z., Ratziu, V., Loomba, R., & Rinella, M. (2019). Positive Results from REGENERATE: A 
Phase 3 International, Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid 
Treatment for NASH. Paper presented at the EASL, Vienna, Austria.  
Yu, H., Zhao, T., Liu, S., Wu, Q., Johnson, O., Wu, Z., . . . Li, Y. (2019). MRGPRX4 is a bile acid 
receptor for human cholestatic itch. Elife, 8. doi:10.7554/eLife.48431 
 
 




Clinical Study Protocol 
 
 
   
 
 
 
 
 
 
 
 
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EDP 305-102 v3.0 (Amendment 2.0) 
 
   
 
 
 
          CONFIDENTIAL 
 
Page 87 of 87 
 
 
 
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. 
 

SAP_001.pdf: 
Final Analysis 
Statistical Analysis Plan (SAP) 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
 
 
Protocol 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 
 
Protocol Version, Date 
Version 3.0 (Amendment 2.0), 21 March 2021 
 
ICON ID: 
3954/0002 
 
Document Version, Date: 
FINAL, 14 January 2022 
 
 
Prepared by: 
 
 
 
On behalf of: 
ENANTA Pharmaceuticals Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 1 of 62 




Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 3 of 62 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
 
 
REVISION HISTORY 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Draft 0.1/ 
06-Jul-2020 
Initial Draft 
N/A 
N/A 
Draft 0.2/ 
07-May-2021 
Second Draft 
All 
Implementing feedback 
from Enanta review of 
initial draft. 
Final 1.0/ 
14-Jan-2022 
Final 
9 
Updated post-study 
cancellation to identify 
analyses that will not be 
produced. 


Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 4 of 62 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................................. 2 
REVISION HISTORY ............................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................................... 7 
1 INTRODUCTION ............................................................................................................. 10 
2 STUDY OBJECTIVES ..................................................................................................... 11 
2.1 Primary objective ..................................................................................................... 11 
2.2 Secondary objectives ................................................................................................ 11 
2.3 Exploratory objectives .............................................................................................. 11 
3 STUDY DESIGN ............................................................................................................... 12 
3.1 General study design ................................................................................................ 12 
3.2 Dose and Treatment Schedule .................................................................................. 12 
Figure 1: Study Design ............................................................................................ 13 
3.3 Randomization and blinding .................................................................................... 13 
3.3.1 Randomization .............................................................................................. 13 
3.3.2 Blinding ........................................................................................................ 13 
3.4 Study treatments and assessments ............................................................................ 14 
Table 1: Schedule of Study Assessments ................................................................. 15 
4 STUDY ENDPOINTS ....................................................................................................... 18 
4.1 Primary efficacy endpoints ...................................................................................... 18 
4.2 Secondary efficacy endpoints .................................................................................. 18 
4.3 Exploratory endpoints .............................................................................................. 19 
4.4 Safety endpoints ....................................................................................................... 19 
5 SAMPLE SIZE AND POWER ......................................................................................... 20 
6 ANALYSIS POPULATIONS ........................................................................................... 21 
6.1 Safety population (SAF)........................................................................................... 21 
6.2 Intention-To-Treat (ITT) population ........................................................................ 21 
6.3 Per-Protocol population (PP) ................................................................................... 21 
6.4 Pharmacokinetic (PK) Population ............................................................................ 21 
6.5 Protocol deviations/violations and exclusions from analysis sets ........................... 22 
7 Statistical Considerations and analysis ............................................................................. 23 
7.1 Derived variables ...................................................................................................... 23 
Table 2: Derived variables ....................................................................................... 23 
7.2 Handling of missing data and outliers ..................................................................... 25 
7.2.1 Missing data analysis methods .................................................................... 25 
7.2.2 Handling of missing or incomplete dates .................................................... 25 
8 STATISTICAL METHODS .............................................................................................. 27 
8.1 General statistical conventions .................................................................................27 
8.2 Subject disposition....................................................................................................28 
8.3 Protocol deviations ...................................................................................................28 


Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 5 of 62 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
 
8.4 Demographics and baseline characteristics ..............................................................28 
8.4.1 Demographics ...............................................................................................28 
8.4.2 Baseline and disease characteristics .............................................................28 
8.4.3 Medical history ............................................................................................28 
8.4.4 Prior and concomitant medications/ procedures..........................................29 
8.5 Extent of exposure ....................................................................................................29 
8.5.1 Treatment duration .......................................................................................29 
8.5.2 Treatment compliance ..................................................................................29 
8.6 Efficacy analyses ......................................................................................................30 
8.6.1 Analysis methods .........................................................................................30 
8.6.1.1 Multiplicity ...................................................................................................31 
8.6.1.2 Treatment by center interaction analysis (multi-center study) .................32 
8.6.2 Analysis of primary efficacy endpoint(s) ....................................................32 
8.6.2.1 Sensitivity Analysis....................................................................................33 
8.6.3 Analysis of secondary efficacy endpoint(s) .................................................33 
8.6.3.1 Categorical Endpoints (Responder at Week 72) .........................................33 
8.6.3.2 Continuous Endpoints ..................................................................................34 
8.6.4 Analysis of exploratory endpoints ...............................................................35 
8.6.4.1 Change from baseline of noninvasive liver fibrosis markers (ELF panel), 
and PRO C3 at week 12 and week 72 ..........................................................35 
8.6.4.2  Change from baseline in NAFLD Fibrosis Score (NFS), AST to Platelet 
Ratio Index (APRI), NASH FibroSure and Fibrosis 4 score (FIB-4) at 
week 12 and week 72 ...................................................................................36 
8.6.4.3 Change from baseline in fibrinogen, CRP, IL-6, IL-1β, TNF-α, TNF-β, 
alpha2 macroglobulin and haptoglobin levels at week 12 and week 72 ......36 
8.6.4.4 Change from baseline in QoL (SF-36 and Chronic Liver Disease 
Questionnaire, CLDQ-NASH) through week 72 .........................................36 
8.6.4.5 Change from baseline in Cardiovascular Score (ASCVD score) at week 
72 ..................................................................................................................36 
8.6.4.6 Change from baseline in C4, FGF-19 and BA through week 72 ................37 
8.7 Safety Analyses ........................................................................................................37 
8.7.1 Adverse events .............................................................................................37 
8.7.2 Lab Based Stopping Rules ...........................................................................39 
8.7.2.1 Close Monitoring for Drug Discontinuation due to Elevated ALT/AST . 39 
8.7.3 Clinical laboratory evaluations ....................................................................39 
8.7.4 Vital signs ....................................................................................................40 
8.7.5 Physical examinations ..................................................................................41 
8.7.6 Electrocardiograms (ECG) ...........................................................................41 
8.8 Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
Analysis ....................................................................................................................42 
8.8.1 Pharmacokinetic Analyses ...........................................................................42 
8.8.2 Pharmacodynamic Analyses ........................................................................42 
8.8.3 Pharmacokinetics/Pharmacodynamics (PK/PD) Analysis .......................... 42 
8.9 Subgroup Analysis ................................................................................................... 46 
8.10 Interim Analysis ....................................................................................................... 47 


Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 6 of 62 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
 
8.10.1 Interim Analysis 1 (IA1) .............................................................................. 47 
8.10.2 Interim Analysis 2 (IA2) .............................................................................. 47 
8.11 COVID-19 Impact on Study .................................................................................... 48 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL........................ 49 
10 REFERENCES .................................................................................................................. 50 
11 APPENDICES ................................................................................................................... 51 


Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
Version: FINAL 1.0, Date: 14 Jan 2022 
Page 7 of 62 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
LIST OF ABBREVIATIONS 
Abbreviation 
or Explanation 
 special term 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ASCVD 
Atherosclerotic cardiovascular disease 
ALT 
Alanine aminotransferase 
AST 
Alanine aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below limit of quantitation 
BMI 
Body Mass Index 
BP 
Blood Pressure 
C4 
7-alpha-Hydroxy-4-cholesten-3-one 
CEC 
Clinical Event adjudication Committee 
CI 
Confidence Interval 
CLDQ 
Chronic Liver Disease Questionnaire 
CM 
Concomitant Medication 
cm 
Centimetre 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELF 
Enhanced Liver Fibrosis 
EOS 
End of Study 
EOT 
End of Treatment 
FIB-4 
Fibrosis-4 score 


Final Analysis 
Statistical Analysis Plan (SAP) 
DocUUID : 75a1d9e8-60f5-459e-a7db-121dfcf87912 
 
FSH 
Follicle stimulating hormone 
HA 
Hyaluronic acid 
HDL 
High density lipoprotein cholesterol 
IA 
Interim Analysis 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IRT 
Interactive Response Technology 
ITT 
Intent To Treat 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LDL 
Low density lipoprotein cholesterol 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measurements 
MRE 
Magnetic resonance elastography 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging - proton density fat fraction 
NAS 
NAFLD activity score 
NASH 
Non Alcoholic Steatohepatitis 
OC 
Observed Cases 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PIIINP 
Procollagen III amino terminal peptide 
PK 
Pharmacokinetics 
PR 
electrocardiographic interval occurring between the onset of the P wave and the 
QRS complex, representing time for atrial and ventricular depolarization, 
respectively 
PP 
Per Protocol 
PRO-C3 
Type 3 procollagen 
PT 
Preferred Term 
 
Statistical Analysis Plan 
Protocol Number: EDP 305-102 
 
Version: FINAL 1.0, Date: 14 Jan 2022 
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Q1 
Lower Quartile 
Q3 
Upper Quartile 
QLS 
Quality of Life Scale 
QoL 
Quality of Life 
QRS 
electrocardiographic deflection between the beginning of the Q wave and 
termination of the S wave, representing the time for ventricular depolarization 
electrocardiographic interval between the beginning of the Q wave and 
QT 
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 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSP 
Study Specific Procedure 
T2DM 
Type 2 diabetes mellitus 
TC 
Total cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TG 
Triglyceride 
TIMP-1 
Tissue inhibitor of metalloproteinase 1 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Score 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
WOCF 
Worst Observation Carried Forward 
 
 
 
 
 
 
 
 
 
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3 
STUDY DESIGN 
 
3.1 
General study design 
This is a phase 2b randomized, double blind, placebo-controlled multicenter study evaluating 
the safety and efficacy of two doses of EDP-305 compared to placebo in subjects with liver 
biopsy proven NASH. 
The duration of the study will be approximately up to 84 weeks. The study will consist of a 
Screening, Treatment, and Safety Follow-up Periods as below. 
 
 
Study Period 
Duration 
Screening 
Up to 8 weeks (56 Days) 
Treatment 
72 weeks 
Safety Follow-up Period 
4 weeks 
Total approximate duration of 
participation 
up to 84 weeks 
 
 
• Screening period: includes the screening visit and may occur over a time period of 
56 days (8 weeks) prior to the first dose of study drug. 
• 
Treatment period: begins with the first dose of study drug on Day 1 and concludes 
with the end of treatment (EOT) visit. Subjects who complete dosing will have their 
EOT visit during Week 72. 
• Safety Follow-up period: commences following the last dose of study drug and 
concludes at the end of study (EOS) visit. Subjects who complete the safety follow- 
up period will have their EOS visit during Week 76. 
3.2 
Dose and Treatment Schedule 
Subjects will be randomized 1:1:1 to receive one of two oral doses of EDP 305 1.5 mg, EDP- 
305 2 mg or matching placebo. Every subject will receive a single daily dose of blinded 
study drug for a total of 72 weeks. An overview of the study design is shown in Figure 1. 
Study visits and assessments are detailed in the Table 1. 


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Figure 1: Study Design 
 
 
 
3.3 
Randomization and blinding 
3.3.1 
Randomization 
Subjects will be randomized to study treatment using an interactive web response system 
(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. 
3.3.2 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 


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• Enanta/
 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 
Refer Section 6.1 of the Study Protocol for Blinding of Study and Pharmacokinetic samples. 
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 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. 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. 
3.4 
Study treatments and assessments 
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. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the scheduled of study assessments in table below. 


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Table 1: Schedule of Study Assessments 
 
Study Event 
Screening1 
Study Assessments per Planned Study Day/Week 
Phone 
Contact2 
EOT 
EOS 
Visit Day/Week 
D-56 to D-1 D13 D74 W2 W4 W8 W12 Wks 16, 20, 
24, 28, 32 
W36 W40 & 
W44 
W48, W56, W64 
(Every 8 weeks) 
W52, W60, 
W68 
W725 
W76 
Visit Windows 
±1d ±2d ±2d ±2d ±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
ICF6; Demography; Medical History 
x 
Inclusion/Exclusion 
x 
Liver Biopsy (with centralized reading) 
x7 
x 
Elastrography: Liver Stiffness Assessment (MRE) 
x 
x 
x 
NASH FibroSure® 
x 
x 
x 
x 
APRI, FIB-4, and NFS 
x 
x 
x 
FSH8; HIV, HCV, and HBV 
x 
Pregnancy Test9 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
At Home Pregnancy Tests (Phone Contact) 10 
x 
Height, Weight and BMI11 
x 
x 
x 
x 
x 
x 
Physical Exam12 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Vital Signs13 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Body Temperature 
x 
x 
x 
ECG 
x 
x 
x 
W24 only 
x 
W48 & W64 only 
x 
Safety Lab. Tests14 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pruritus: Visual Analogue Score, 5D-itch scales15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QoL Scales16 
x 
x 
W24 only 
x 
W48 only 
x 
x 
Cardiovascular Score (ASCVD) 
x 
x 
PT/PTT and INR 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV Markers17 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MRI-PDFF 
x 
x 
x 
Inflammatory Markers18, 19 
x 
x 
x 
ELF Panel, PRO C3 17 
x 
x 
x 




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18 Markers of inflammation include fibrinogen, CRP, IL-6, IL-1β, TNF-α, TNF-β, alpha2 macroglobulin and haptoglobin (See Table 3 from protocol). 
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 protocol Section 5.7 for details. 


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4 
STUDY ENDPOINTS 
 
4.1 
Primary efficacy endpoints 
There are two primary efficacy endpoints for this study: (1) the proportion of subjects who 
achieve ≥1 stage improvement in fibrosis without worsening of steatohepatitis as determined 
by liver biopsy at 72 weeks, (2) the proportion of subjects with resolution of steatohepatitis 
and no worsening of liver fibrosis as determined by liver biopsy at 72 weeks [Note: No 
worsening of steatohepatitis is defined as no increase in NAS for ballooning, inflammation, 
or steatosis. Resolution of steatohepatitis is defined as absent fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for 
ballooning, and any value for steatosis] (Agopian, et.al.) 
4.2 
Secondary efficacy endpoints 
The secondary endpoints for this study are: 
• Proportion of subjects with improvement of fibrosis by at least 1 stage and/or 
resolution of NASH without worsening of either as determined by liver biopsy at 
week 72 
• Proportion of subjects with no worsening of fibrosis combined with no worsening of 
NASH as determined by liver biopsy at week 72 
• Proportion of subjects with resolution of fibrosis as determined by liver biopsy at 
week 72 
• Proportion of subjects with improvement in each histologic feature of NASH, by at 
least 1 point as determined by liver biopsy at week 72 
• Proportion of subjects with improvement of fibrosis by ≥ 2 stages by liver biopsy at 
week 72 
• Proportion of subjects with improvement in NAS by at least 2 points with no 
worsening of fibrosis as determined by liver biopsy at week 72 
• Proportion of subjects with improvement of fibrosis and resolution of NASH as a 
composite endpoint as defined by both endpoints being met in the same subject 
• Proportion of subjects with resolution of NASH and no worsening of liver fibrosis 
• Proportion of subjects with histological progression to cirrhosis as determined by 
liver biopsy at week 72 
• Frequency of adverse events (AEs), serious adverse events (SAEs), and AEs leading 
to discontinuation through week 72 and 4-week follow-up period 
• Change from baseline in 5D-itch scale and Visual Analog Score (VAS) through week 
72 
• Change from baseline in percentage of fat in the liver as assessed by magnetic 
resonance imaging proton density fat fraction (MRI PDFF) at week 12 and week 72 


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• Change from baseline in liver stiffness as assessed by MRE at week 12 and week 72 
• Change from baseline in triglyceride (TG), total cholesterol (TC), high density 
lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and 
adiponectin through week 72 
• Pharmacokinetic concentrations of EDP-305 (and metabolites) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4 
Safety endpoints 
• Treatment compliance 
• Adverse events 
• Clinical laboratory data 
• Electrocardiogram data 
• Concomitant medications 
• Vital Signs 
• Physical examinations 


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6 
ANALYSIS POPULATIONS 
 
6.1 
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 first study drug received during the study. 
6.2 
Intention-To-Treat (ITT) population 
ITT subjects will be considered those randomized to treatment. The ITT subjects will be 
analyzed according to the treatment to which they were randomized. In the event the safety 
population is the same as ITT, only the ITT will be reported. This will be the primary efficacy 
population. 
6.3 
Per-Protocol population (PP) 
PP population includes all subjects in the ITT population that do not have major protocol 
deviations which could unduly influence the efficacy analysis. This population will be 
reviewed and finalized prior to locking the database and unblinding the study. 
The per protocol population include patients who: 
• Satisfying all inclusion and exclusion criteria, 
• Receiving the full treatment regimen (i.e. all doses received and at least 80% of 
protocol-specified total dose taken for the entire treatment phase), 
• Did not take any prohibited medications within X weeks of the primary study time 
point (i.e., Week 72), and 
• Have a value for at least one of the primary endpoints. 
Subjects will be included in the analysis according to the treatment to which they were 
randomized. The list of subjects in the PP population will be finalized prior to unblinding. 
6.4 
Pharmacokinetic (PK) Population: 
All subjects receiving active study drug and having any measurable plasma concentration of 
study drug at any time point. 
Subjects will be included in the analysis according to the study drug received during the 
study. 


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6.5 
Protocol deviations/violations and exclusions from analysis sets 
Protocol deviations will be identified following the ICON SOPs, and after review and 
validation of the Enanta study team prior to locking the database and unblinding the 
treatment codes. If necessary, a meeting will be held to discuss and adjudicate any deviations 
that need classification (major vs. minor). Deviations will be identified using data listings 
provided by ICON Biometrics and from the deviation log maintained by ICON clinical. 
The listing of protocol deviations will be reviewed by Enanta team with focus from 
Biometrics/Medical in order to define the Per Protocol population. Subjects with a protocol 
violation or a major protocol deviation will be thus identified for exclusion from the per 
protocol population. 


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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
7.1 
Derived variables 
The below table provides the list of derived variables for demographic and baseline 
characteristics, various duration derivations, drug compliance, baseline derivations and 
other important derivations applicable for this study. 
Table 2: Derived variables. 
Variables 
Formula 
Demographic and Baseline characteristics 
Age at informed consent (in 
years) 
(Date of informed consent – Date of birth + 1)/ 365.25) 
Body mass index (BMI) (kg/m2) 
Weight (kg) / [Height (m)]^2 
Derivation of Duration 
Study day at any visit 
Date of interest – Date of first dose of study drug. One day is 
added if this difference is ≥ 0 
Extent of exposure (Days) 
Date of last randomized study drug intake – Date of first 
randomized study drug intake + 1 
Extent of exposure (Weeks) 
Extent of exposure (days)/7 
Drug Compliance 
Compliance 
100 × ((Amount of drug taken) / Exposure period) 
Baseline Derivations 
Baseline 
Last non-missing values collected prior to the first dose of 
study drug on day 1 
Screening 
The value obtained at screening. 
Change from baseline 
Post baseline value – Baseline 
Percentage change from baseline 
[(Change from baseline) / Baseline] * 100 
Reference baseline 
Mean of screening and day 1 value 
Other Derivation 
Improvement in liver fibrosis 
≥1 point decrement in fibrosis score compared to baseline 
No worsening in liver fibrosis 
No increment in fibrosis score compared to baseline 
Resolution of liver fibrosis 
If fibrosis score is 0 
Improvement in NAS score 
≥1 point decrement in NAS score (can occur in any of the 
ballooning, inflammation, or steatosis categories) 


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No worsening in NAS score 
No increase in NAS score for ballooning, inflammation, and 
steatosis all 
Resolution of steatohepatitis 
Defined as total absence of ballooning [score = 0], absent or 
mild inflammation [score 0-1], steatosis can be present [score 
0-3] 
Platelet Ratio Index (APRI) 
APRI = ([AST (IU/L) / AST ULN (IU/L)] / 
[Platelets(10^9/L)]) × 100 
ULN = upper limit of normal 
Online calculator can be found at: 
http://www hepatitisc.uw.edu/page/clinical-calculators/apri 
Fibrosis-4 score (FIB-4) 
FIB-4 = [Age (years) × AST (IU/L)] / [Platelets (109/L) × 
(√ ALT (IU/L) ) 
FIB-4 online calculator reference: 
http://www hepatitisc.uw.edu/page/clinical-calculators/fib-4 
NAFLD fibrosis score (NFS) 
NFS = -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 × Platelets (109/L) – 0.66 × Albumin (g/dL) 
NFS online calculator reference: 
https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver- 
disease-fibrosis-score 
Total NAS score 
Sum of scores for steatosis, lobular inflammation, and 
ballooning 
Histological progression to 
cirrhosis 
If Fibrosis score = 4 
5D-itch scale 
Refer Appendix B for derivation 
Visual Analog Score (VAS) 
Refer Appendix B for derivation 
SF-36 
Refer Appendix B for derivation 
CLDQ-NASH 
Refer Appendix B for derivation 
ASCVD Score 
Refer Appendix B for derivation 
QTc 
QT/(RR interval)1/3, in seconds (The QT/QTc interval 
will be corrected based on Fridericia’s correction) 


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7.2 
Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
For the primary analysis of the primary endpoints, no imputation will be performed (i.e., 
only subjects with endpoint values will be utilized). A sensitivity analysis will be conducted 
where subjects with missing primary endpoint data will be imputed as non-responders. 
7.2.2 Handling of missing or incomplete dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then: 
▪ If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start day as the day of first dose date; 
▪ Otherwise, impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
▪ If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start month and day as the month and day of first dose 
date; 
▪ Otherwise, impute the AE start month as January and the day as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query site and 
leave as missing. 
For missing and partial adverse event end dates, imputation will be performed as follows: 
If only the day of the month is missing, the last day of the month will be used to replace the 
missing day. If the day and month are missing or a date is completely missing, it will be 
considered as missing. 
Imputation rules for missing or partial medication start/stop dates are defined below: 
If only Day of CM start date is missing: 
If the CM start year and month are the same as that for the first dose date, then: 
▪ If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start day as the day of first dose date; 
▪ Otherwise, impute the CM start day as 1. 
If Day and Month of CM start date are missing: 


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If CM start year = first dose year, then: 
▪ If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start month and day as the month and day of first 
dose date 
▪ Otherwise, impute the CM start month as January and the day as 1. 
If Year of CM start date is missing: 
▪ 
If the year of CM start is missing or CM start date is completely missing, then query 
site and leave as missing. 


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8 
STATISTICAL METHODS 
 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using 
a significance (alpha) level of 0.05. Two-sided 95 % confidence intervals (CI) will be 
provided when relevant. Any p-value below 0.05 will be displayed to 4 decimal places. 
Any p-value less than 0.0001 will be displayed as <0.0001. Any p-value between 0.05 
(inclusive) and 0.10 will be displayed to 3 decimal places and any p-value greater than 
0.10 will be displayed to two decimal places. Any p-value greater than 0.9999 will be 
displayed as >0.99. 
All quantitative endpoints will be summarized using an 8-number summary (n, mean, 
standard deviation, median, 25th percentile, 75th percentile, minimum and maximum 
values). The mean and median and the percentiles will be rounded to one decimal place 
beyond the precision of the values being summarized, the standard deviation will be 
rounded to 2 additional decimal places beyond this precision and the minimum and 
maximum values will be displayed in the same precision. All qualitative endpoints will be 
summarized by the number of subjects meeting the endpoint and the percentage of subjects 
out of the appropriate population. The denominator will be displayed when needed and the 
percentage will be rounded to one decimal place 
All subject data, including those derived, will be presented in individual subject data 
listings. Unless otherwise stated, unscheduled visit results will be included in date/time 
chronological order, within subject listings only. All listings will be sorted by 
investigational site, patient number, date/time, and visit. The treatment group as well as 
patient’s sex and age will be stated on each listing. Unless otherwise stated, data listings 
will be based on all subjects randomized. 


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8.2 
Subject disposition 
All subjects who provided informed consent will be included in a summary of subject 
accountability. The number and percentage of subjects screened, randomized, randomized 
and treated, randomized and not treated, as well as the number and percentage of subjects in 
each analysis population (safety, ITT, PP, and PK) will be 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 by treatment 
group and overall: 
• Completed study drug per protocol 
• Discontinued study drug early and the primary reason for study drug 
discontinuation 
• Completed the study (i.e., completed safety follow-up at Week 76) 
• Discontinued from the study early and the main reason for discontinuation 
8.3 
Protocol deviations 
All protocol deviations identified will be summarized by treatment group and overall, all 
protocol deviations will be listed. 
Summaries of major protocol deviations (counts & percentages) will be provided by 
deviation categories & subcategories for all subjects that were randomized. 
8.4 
Demographics and baseline characteristics 
No statistical testing will be performed for the comparison between treatment groups on 
demographics and baseline characteristics. 
A by-subject listing will be provided. 
8.4.1 Demographics 
The following subject demographics will be summarized in the table by randomized 
treatment group for all subjects in the safety population: age, gender, ethnicity, race, height, 
weight and BMI at baseline. 
8.4.2 Baseline and disease characteristics 
 
T2DM status, use of Vitamin E and/or pioglitazone, fibrosis score, NAS score, individual 
NAS components (steatosis, lobular inflammation, ballooning) at baseline will be 
summarized for the safety population. The categorical baseline characteristics such as ECG 
and selected lab parameters (i.e., ALT, AST, Total Bilirubin, LDL, HDL, C4, and FGF) will 
be summarized using frequency counts for the safety population. 
8.4.3 Medical history 
A summary of medical and surgical history will be presented by system organ class (SOC) 
and preferred term (PT) using Medical Dictionary for Regulatory Affairs® (MedDRA) 
Version 23.0 or higher for the safety population. 


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A by-subject listing will be provided. 
8.4.4 Prior and concomitant medications/ procedures 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) version “WHO Drug Global B3 Mar2021”. 
Prior medications/ procedures: are defined as those medications/ procedures with a start 
date prior to the first dose of study drug. 
Concomitant medications/ procedures: are defined as those medications/ procedures with 
a start date on or after the first dose of study drug until the last dose. A medication/ procedure 
which started prior to dosing and continued after dosing will also be considered as 
concomitant medication/ procedure. 
Prior and Concomitant medications will be summarized descriptively using frequency tables 
by anatomical therapeutic chemical (ATC) class and preferred name by treatment group on 
the safety population. Concomitant diabetes medications will be summarized using the same 
format. 
Prior and Concomitant procedures will be summarized descriptively using frequency tables 
by treatment group on the safety population. 
A by-subject listing will be provided for prior and concomitant medications. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Section 7.2.2. 
8.5 
Extent of exposure 
8.5.1 Treatment duration 
Duration of study drug (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption. 
Study drug exposure will be summarised by treatment group on the safety population using 
descriptive statistics. 
8.5.2 Treatment compliance 
Study drug compliance will be based on the amount of drug taken. The derivation for the 
treatment compliance is provided in Table 2. The maximum percentage of drug taken will 
be 100%. 
Study drug compliance will be summarized by treatment group using 8-number summary. 
They will also be summarized in categories “<80%, 80% - <90%, 90% - <100% and “≥100% 
compliant” using frequency tables. 
Study drug compliance summaries will be based on the safety population. 
A by-subject listing of randomization schedule and study drug dispensed with LOT number 
will be provided. 


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8.6 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary, secondary, 
and exploratory efficacy variables. All the efficacy analyses will be performed using ITT 
population as primary analysis. 
8.6.1 Analysis methods 
Logistic Regression Model for proportion of responders 
Endpoints looking at a proportion of responders will be analyzed by logistic regression. The 
SAS procedure PROC GENMOD will be used. The preferred model will include the fixed 
categorical effects of treatment group, diabetes status and use of Vitamin E and/or 
pioglitazone. Baseline NAS score will be included as covariate. The model will be used to 
derive odds ratio, confidence interval and p value. A sample of SAS code for logistic 
regression is provided in Appendix A. 
Fisher exact test will be used to test the treatment difference in case the model does not 
converge. A sample of SAS code for Fisher exact test is provided in Appendix A. 
Analysis of Covariance (ANCOVA) Model for Change from baseline 
In summaries of efficacy endpoints examining change from baseline at week 12 and week 
72, ANCOVA of the differences between post-baseline and baseline measurements will be 
performed, with treatment group, baseline diabetes status and use of Vitamin E and/or 
pioglitazone as fixed effect and the baseline measurement of the parameter of interest along 
with baseline NAS score as covariate. A sample of SAS code for ANCOVA model is 
provided in Appendix A. 
The model will provide the least-squares means (using type III sum-of-squares), standard 
errors, p-value and 2-sided 95% confidence interval for treatment differences. 
Mixed Model Repeated Measures (MMRM) analysis 
A MMRM analysis will be performed for secondary efficacy endpoints that are continuous 
in nature and assessed over multiple study visits. The SAS procedure PROC MIXED will be 
used. The preferred model will include the fixed categorical effects of treatment group, visit, 
treatment-by-visit interaction as well as the continuous fixed covariates of baseline 
measurement for the parameter of interest and baseline NAS score. 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 sample of SAS code for MMRM is provided in 
Appendix A. 
The model will provide least-squares means (using type III sum-of-squares), standard errors, 
p-value and 2-sided 95% confidence interval for treatment differences for each visit. 
 




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8.6.1.2 Treatment by center interaction analysis (multi-center study) 
No analysis will be made to assess the treatment-by-center interaction. 
8.6.2 Analysis of primary efficacy endpoint(s) 
The primary efficacy analysis is a set of two primary endpoints. The primary endpoints 
comprise of proportion of subjects who achieve: 
• ≥1 stage improvement in liver fibrosis without worsening of steatohepatitis 
• Resolution of steatohepatitis without worsening of liver fibrosis 
as determined by liver biopsy at week 72. Derivation for steatohepatitis and fibrosis 
conditions (like improvement, worsening and resolution) are provided in Table 2. 
A responder will be defined for each primary endpoint separately. Any subject achieving the 
primary endpoint will be a responder for that primary endpoint. Subjects will not be 
categorized as responder or non-responder in case of missing response (score). 
The objective related to the primary endpoint is to evaluate the effect of EDP-305 compared 
to placebo with respect to proportion of responders defined as above. 
The hypothesis to test EDP-305 2 mg and placebo is formulated as: 
• H01: OR =1 v/s H11: OR ≠ 1 
Where OR is the odds ratio at week 72 for EDP-305 2mg and placebo treatment groups 
respectively. 
The hypothesis to test EDP-305 1.5 mg and placebo is formulated as: 
• H02: OR =1 v/s H12: OR ≠ 1 
Where OR is the odds ratio at week 72 for EDP-305 1.5mg and placebo treatment groups 
respectively. 
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 as 
fixed effects and baseline NAS score as covariate. Treatment groups will be compared for 
each endpoint at a 0.025 significance level. The odds ratio, 97.5% confidence interval and 
the p-value will be presented. In the event that the logistic regression model is unable to 
converge, a Cochran-Mantel-Haenszel test will be performed using the stratification factors 
of diabetes status and Vitamin E/pioglitazone use status. The frequency counts for 
responders and non-responders will also be presented in the table. The primary efficacy 
analyses will be performed using the ITT population. As an additional analysis, the primary 
endpoint will also be analyzed using PP population. Multiplicity control for this testing is 
noted in Section 8.6.1.1. 
A by-subject listing will be provided for the primary efficacy endpoints. 


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8.6.2.1 Sensitivity Analysis 
As a sensitivity analysis, the methodology utilized for the primary endpoints will be 
performed on all ITT subjects where those missing primary endpoint data will be imputed 
as a non-responder. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
All analysis of secondary efficacy endpoints will be performed on the ITT population. 
Secondary endpoint related to PK data will be analyzed using subjects in the PK population. 
Secondary endpoints will be analyzed for treatment group differences. 
8.6.3.1 Categorical Endpoints (Responder at Week 72) 
Secondary endpoints with categorical values are defined as below: 
Proportion of subjects with 
• improvement of fibrosis by at least 1 stage and/or resolution of NASH without 
worsening of either as determined by liver biopsy at week 72 
• no worsening of fibrosis combined with no worsening of NASH as determined by 
liver biopsy at week 72 
• resolution of fibrosis as determined by liver biopsy at week 72 
• improvement in each histologic feature of NASH, by at least 1 point as determined 
by liver biopsy at week 72 
• improvement of fibrosis by ≥ 2 stages by liver biopsy at week 72 
• improvement in NAS by at least 2 points with no worsening of fibrosis as determined 
by liver biopsy at week 72 
• improvement of fibrosis and resolution of NASH as a composite endpoint as defined 
by both endpoints being met in the same subject 
• resolution of NASH and no worsening of liver fibrosis 
• histological progression to cirrhosis as determined by liver biopsy at week 72 
Any subject who satisfies the criteria for the secondary endpoint will be a responder for that 
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 as 
fixed effects and baseline NAS score as covariate at week 72. Treatment groups will be 
compared for each endpoint at a 0.05 significance level. Odds ratio, 95% confidence interval 
and p value will be reported in the table. 
A Cochran-Mantel-Haenszel test stratifying by diabetes status and Vitamin E/pioglitazone 
usage will be utilized to test the treatment group differences in case of lack of convergence. 
The frequency counts for responders and non-responders along with the p-value will be 
presented in the table. 
A by-subject listing will be provided for observed and derived variables. 


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8.6.3.2 Continuous Endpoints 
Secondary endpoints with continuous values are defined as below: 
8.6.3.2.1 
Change from baseline in 5D-itch scale and Visual Analog Score (VAS) 
through week 72 
Pruritus will be monitored in this study at day 1, 7, weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, 56, 64, 72 and EOS. 
Observed values, change from baseline, and percentage change from baseline for VAS 
scores and each dimension of 5D-itch scale and overall score will be summarized using an 
8-number summary by visit and treatment group. 
Change from baseline for VAS and 5D-itch scale will be analyzed using a restricted 
maximum likelihood-based mixed model repeated measures (MMRM) technique. The 
model will include treatment, visit, treatment-by-visit interaction as fixed effects along with 
baseline NAS score and baseline score for VAS and 5D-itch scale as covariate respectively. 
Variance-covariance structure to be used to model the within-patient error and results to be 
presented are described in Section 8.6.1. The details for calculation of score is given in 
Appendix B. 
A by-subject listing will be provided for observed and derived variables for VAS and 5D- 
itch scale. 
8.6.3.2.2 
Change from baseline in percentage of fat in the liver as assessed by 
magnetic resonance imaging proton density fat fraction (MRI-PDFF) at 
week 12 and week 72 
Percentage of fat in the liver assessed by MRI-PDFF at screening, week 12 and week 72, 
change from baseline and percentage change from baseline will be summarized using an 8- 
number summary by visit and treatment group. 
Change from baseline in percentage of fat in the liver at week 12 and week 72 will be 
analysed using an analysis of covariance (ANCOVA) model with treatment, baseline 
diabetes status and use of Vitamin E and/or pioglitazone as fixed effect along with baseline 
NAS score and baseline MRI-PDFF value as covariate. Least-squares means (using type III 
sum-of-squares), standard errors, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for week 12 and week 72. Significance tests will be based on 
least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.2.3 
Change from baseline in liver stiffness as assessed by magnetic resonance 
elastograph (MRE) at week 12 and week 72 
The liver stiffness assessed by MRE at screening, week 12 and week 72, change from 
baseline and percentage change from baseline will be summarized using an 8-number 
summary by visit and treatment group. 
Change from baseline in liver stiffness at week 12 and week 72 will be analysed using an 
analysis of covariance (ANCOVA) model with treatment, baseline diabetes status and use 


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of Vitamin E and/or pioglitazone as fixed effect along with baseline NAS score and baseline 
MRE value as covariate. Least-squares means (using type III sum-of-squares), standard 
errors, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for week 12 and week 72. Significance tests will be based on least-squares means 
using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.2.4 
Change from baseline in TG, total cholesterol (TC), HDL cholesterol, LDL 
cholesterol and adiponectin through week 72 
The parameters, TG, TC, HDL cholesterol, LDL cholesterol and adiponectin are captured in 
lipid profile panel. All these parameters will be monitored in this study at day 1, weeks 2, 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 56, 64, 72 and EOS. 
Observed values, change from baseline, and percentage change from baseline for the 
parameters triglyceride (TG), total cholesterol (TC), HDL cholesterol, LDL cholesterol and 
adiponectin will be summarized using an 8-number summary by visit and treatment group. 
Change from baseline for each of the above parameters will be analyzed separately using a 
restricted maximum likelihood-based mixed model repeated measures (MMRM) technique. 
The model will include treatment, visit, treatment-by-visit interaction as fixed effects along 
with baseline NAS score and baseline value of the respective parameters as covariate. 
Variance-covariance structure to be used to model the within-patient error and results to be 
presented are described in Section 8.6.1. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.2.5 
Pharmacokinetic concentrations of EDP-305 (and metabolites) 
PK samples will be collected at day 1, weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
56, 64, and 72. On Day 1 and weeks 12, 36, and 72. 
The detailed information related to pharmacokinetics analysis is provided in Section 8.10. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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8.7 
Safety Analyses 
All safety analyzes will be based on the safety population and will be performed for all safety 
variables specified below. 
No statistical tests will be performed. 
8.7.1 Adverse events 
All Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and 
Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.0 or higher. All subjects in the safety analysis set will be included in 
the summaries. 
AEs will be classified as pre-treatment AEs and treatment emergent adverse events (TEAEs) 
and are defined as follows: 
Pre-treatment AE: A pre-treatment 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. 
TEAE: A TEAE is defined as an AE occurring or worsening on or after the first dose of 
study drug until the last dose of study drug. 
Relationship of each AE to study drug: 
Related: There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug and causes other than the 
study drug have been ruled out, and/or the event re-appeared on re-exposure to the study 
drug. 
Possibly Related: There is an association between the event and the administration of the 
study drug and there is a plausible mechanism for the event to be related to study drug, but 
there may also be alternative etiology, such as characteristics of the subject’s clinical status 
or underlying disease. 
Unlikely Related: The event is unlikely to be related to the study drug and likely to be related 
to factors other than study drug. 
Not Related: The event is related to an etiology other than the study drug (the alternative 
etiology must be documented in the study subject’s medical record). 


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Grade AEs: 
Grade AEs (serious and non-serious) in accordance with the NCI/CTCAE scale as presented 
below. 
Refer 
the 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf provided in reference for the same: 
• 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. 
Details for imputing missing or partial start dates of adverse events are described in Section 
7.2.2. Imputed Adverse Event dates will be used for determining treatment-emergence. 
Summaries of AEs will include the following: 
• TEAEs 
• Related TEAEs 
• Maximum Severity TEAEs 
• TEAEs by severity 
• TEAEs leading to study drug discontinuation 
• TEAEs leading to study discontinuation 
• AEs leading to death 
• SAEs 
• Related Treatment-Emergent SAEs 
All TEAEs will be summarized by SOC, PT and treatment group using frequency counts 
and percentages. In addition, an overall summary for the categories above will be prepared 
by treatment group and overall. 
On-treatment AEs will be summarized separately from those events that occurred during 
treatment-free follow-up. Those events that occurred during treatment-free follow-up will 
be summarized by randomized treatment group. The denominator for these events will be 
only those subjects who entered into the 4 week treatment free follow-up period. 


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Where a subject has the same adverse event, based on preferred terminology, reported 
multiple times in the treatment period, the subject will only be counted once at the preferred 
terminology level in adverse event frequency tables. 
Where a subject has multiple adverse events within the same system organ class in the 
treatment period, the subject will only be counted once at the system organ class level in 
adverse event frequency tables. 
When reporting adverse events by severity, in addition to providing a summary table based 
on the event selection criteria detailed above, summary table will also be provided based on 
the most severe event during the treatment period - independent of relationship to study 
treatment. 
8.7.2 Lab Based Stopping Rules 
Summaries will be provided using counts and percentages for subjects who meet the 
stopping rules as described below: 
• 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. 
8.7.2.1 Close Monitoring for Drug Discontinuation due to Elevated ALT/AST 
The following close observation guidelines applies to subjects that repeat assessments show 
persistent elevations of transaminases, but who do not meet drug discontinuation criteria, 
and for subjects who discontinue study drug due to ALT/AST elevations. 
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) 
Details related close monitoring is available in protocol section 10.2. 
A listing will be used to track and evaluate subjects that are part of the close observation 
guidelines. 
8.7.3 Clinical laboratory evaluations 
Summaries of clinical laboratory values and change from baseline will be performed using 
an 8-number summary by visit and treatment group. All subjects in the safety population 


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will be included in these summaries. Baseline is defined as the last value collected prior to 
first dose of study drug. 
The number and percentage of subjects with treatment-emergent laboratory abnormalities 
until the last dose of study drug will be summarized by treatment group. In addition, shift 
from baseline tables will be generated by visit and treatment group. 
For categorical tests: Treatment-emergent abnormal is defined as a change from normal at 
baseline to abnormal at any post-baseline 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 post- 
baseline. 
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 post-baseline 
Results will be reported according to any value less than the lower limit, any value 
less than 2x LLN and 3x LLN. 
All summary tables will include the abnormalities that occur during the treatment-free 
follow-up after the date of last dose. The denominator for these will include any subject 
who entered into the 4 week treatment-free follow-up phase. 
All laboratory data will be included in the data listings and all test values outside the 
normal range will be flagged as low or high. 
Separate listings will be provided for: Pregnancy test, FSH, HIV, HCV, and HBV along 
with biomarkers for NASH (Cytokeratin (CK)18, GLP-1 (glucagon-like peptide-1)). 
8.7.4 Vital signs 
Vital signs will include SBP (mmHg), DBP (mmHg), RR (breaths/min), HR (beats/min), 
and body temperature (°C). Observed values, change from baseline and percent change from 
baseline for vital signs will be summarized using an 8-number summary by visit and 
treatment group. In addition, the number and percentage of subjects with significant changes 
(per the criteria below) in vital signs from baseline will be summarized by treatment. 
Criteria for clinically significant changes in vital signs parameters. 
Pulse Rate 
• < 50 bpm 
• >120 bpm 
• 30 bpm increase from baseline 


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• 30 bpm decrease from baseline 
 
Blood Pressure 
• SBP > 150 mmHg or DBP > 100 mmHg 
• SBP > 200 mmHg or DBP > 110 mmHg 
Respiration Rate 
• < 8 breaths/min 
• 40 breaths/min 
Temperature 
• 38.3°C 
• 1.1°C increase from baseline (Baseline > 36.8°C) 
Change in Weight 
• 5% increase from baseline 
• 5% decrease from baseline 
A by-subject listing will be provided. 
8.7.5 Physical examinations 
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; Neurological; Breast; anorectal, and genital 
examinations will be performed when medically indicated. 
Physical examination data will be provided in data listings. 
8.7.6 Electrocardiograms (ECG) 
12-lead ECG measurements include (Heart Rate (bpm), QRS Duration (msec), PR Interval 
(msec), QT Interval (msec), RR Interval (msec) and QTcF (msec)) and will be summarized 
using an 8-number summary by visit and treatment for all safety subjects for observed values 
and changes from baseline. The overall ECG interpretation (Normal, Abnormal Not 
Clinically Significant, Abnormal Clinically Significant) will be summarized by presenting 
the number and percentage of subjects for each treatment group and time-point. 
In addition, the number and percentage of subjects meeting or exceeding the following 
categories will be summarized by treatment group. 
• Absolute QT/QTc interval prolongation 
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 


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• Change from baseline in QTc interval 
o QTc interval increases from baseline >30 
o QTc interval increase from baseline >60 
A by-subject listing will be provided. 
8.8 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
Analysis 
During the study, PK samples and PD samples for FGF19, C4 and bile acid will be collected 
as shown in the schedule of assessments. On day 1 and weeks 12, 36, and 72, a sample will 
be collected predose and two samples postdose; the first postdose sample will 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. 
8.8.1 Pharmacokinetic Analyses 
The PK analysis will use the pharmacokinetic population and will include only subjects in 
active treatment arms. 
The concentration data for EDP-305 and each metabolite collected according to schedule of 
events and will be summarized by active treatment arm, visit, and nominal time point. 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. If more than 50% of subjects have postdose 
concentration values below BLQ, descriptive statistics will not be presented except for 
maximum and BLQ will be displayed for mean and minimum. The number of observations, 
arithmetic mean, standard deviation (SD), % coefficient of variation (%CV), median, 
minimum, maximum, geometric mean, and %CV of the geometric mean (%GCV) will be 
displayed. 
Individual data will be presented in listing. 
8.8.2 Pharmacodynamic Analyses 
The PD analysis will be based on subjects’ randomized treatment assignment using all 
subjects belonging to the ITT population with available dosing data. This will include all 
treatment arms (active and placebo). 
A descriptive summary will be provided for the FGF19, C4, and bile acid endpoints 
including measured concentrations, change from baseline, and percentage change from 
baseline using the 8-number summary by visit, treatment group, and bin time midpoint. 
A by-subject listing will be provided for observed and derived variables. 
8.8.3 Pharmacokinetics/Pharmacodynamics (PK/PD) Analysis 
Scatter plots will be created using all subjects in the PK population. Plots for percentage 
change from baseline in each PD activity with EDP-305 concentration value will be 
generated for week 12 pre-dose. 
Additionally the following PK/PD plots will be created using all subjects in the PK 
population. Other PD plots will be created using all subjects in the efficacy population, 


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including placebo, as applicable. The following scatterplots will be generated: 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in ALT with EDP-305 concentration value 
(predose at Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in GGT with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with EDP-305 
concentration value (Predose Week 12) 
• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in MRI-PDFF with EDP-305 concentration value 
(Predose Week 12) 


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• Percentage change from Baseline in MRE with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in MRE with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in MRE with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in MRE with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in FGF19 (Predose Week 72) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in C4 (Predose Week 72) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in Bile Acid (Predose Week 72) 
• Percentage change from Baseline in ALT with EDP-305 concentration value 
(predose at Week 72) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in FGF19 (Predose Week 72) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in C4 (Predose Week 72) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in Bile Acid (Predose Week 72) 
• Percentage change from Baseline in GGT with EDP-305 concentration value 
(Predose Week 72) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in FGF19 (Predose Week 72) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in C4 (Predose Week 72) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in Bile Acid (Predose Week 72) 
• Percentage change from Baseline in Alkaline Phosphatase with EDP-305 
concentration value (Predose Week 72) 


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• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in FGF19 (Predose Week 72) 
• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in C4 (Predose Week 72) 
• Percentage change from Baseline in MRI-PDFF with the percentage change from 
Baseline in Bile Acid (Predose Week 72) 
• Percentage change from Baseline in MRI-PDFF with EDP-305 concentration value 
(Predose Week 72) 
• Percentage change from Baseline in MRE with the percentage change from 
Baseline in FGF19 (Predose Week 72) 
• Percentage change from Baseline in MRE with the percentage change from 
Baseline in C4 (Predose Week 72) 
• Percentage change from Baseline in MRE with the percentage change from 
Baseline in Bile Acid (Predose Week 72) 
• Percentage change from Baseline in MRE with EDP-305 concentration value 
(Predose Week 72) 
Box plot of EDP-305 and EP-022679 concentration (last predose) for subjects with adverse 
events occurring in at least 5% of the combined active subjects. 
Lastly, the analyses below will be carried out to provide additional data for better 
understanding of specific clinical events and manifestations during the course of the study. 
These analyses will be conducted for subjects with or without pruritus: 
PK and pruritus: 
• Summary of plasma concentration of EDP-305 and EP-022679 per time point and 
treatment group by visit for subjects with and without pruritus 
• Summary of PK parameters by treatment group by visit for subjects with and 
without pruritus 
• Boxplot of predose concentration at Week 2,4,8 and 12 for EDP-305 and EP- 
022679 by treatment group for subjects with and without pruritus 
• Listing of EDP-305 and EP-022679 concentration value for subjects with pruritus 
C4 and pruritus: 
• Summary of C4, change from baseline and percentage change from baseline by 
hour by visit for subjects with and without pruritus 
• Summary of AUC0-8 and AUC2-8 for C4, change from baseline and percentage 
change from baseline at Week 12 for subjects with and without pruritus 


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8.9 
Subgroup Analysis 
Subgroup analyses will be performed for the primary endpoint and the secondary endpoints 
to determine whether significant differences exist in primary and secondary endpoint results 
between subgroups. 
These subgroup analyses will be carried out using the subjects from the ITT and PP 
population. 
The list of potential subgroups (with applicable definitions in parentheses) includes the 
following: 
• Baseline Fibrosis score (2, 3), 
• MRE week 72 response: (<15% reduction vs ≥15% reduction in percentage of 
change from baseline), 
• MRI-PDFF week 72 response: (<30% reduction vs ≥30% reduction in percentage of 
change from baseline), 
• Both MRE week 72 response (≥15% reduction in percentage of change from 
baseline) and MRI-PDFF week 72 response (≥30% reduction in percentage of change 
from baseline) vs non-response. 
A logistic regression model will be used for categorical endpoints. The model will include 
the treatment group, diabetes status, use of Vitamin E and/or pioglitazone, subgroup and 
subgroup-by-treatment interaction as fixed effects and baseline NAS score as covariate. 
Odds ratios and 95% confidence intervals will be reported. 
For continuous endpoints an ANCOVA model with treatment group, diabetes status, use of 
Vitamin E and/or pioglitazone, subgroup and subgroup-by-treatment interaction as fixed 
effects and baseline NAS along with baseline parameter of interest as covariates. Least- 
squares means (using type III sum-of-squares), standard errors, p-value and 2-sided 95% 
confidence interval for treatment differences will be reported. 
For continuous endpoints that are repeated over visits a MMRM technique will be used. The 
model will include treatment, visit, subgroup and interaction effect of treatment, visit and 
subgroup as fixed effects and baseline NAS along with baseline parameter of interest as 
covariates. Least-squares means (using type III sum-of-squares), standard errors, p-value 
and 2-sided 95% confidence interval for treatment differences will be presented for each 
visit 
Forest plots will be presented for the sub group analysis mentioned above to describe the 
association using ITT and PP population. 


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8.10 Interim Analysis 
Two partially unblinded interim analyses (IA) are planned for this study. To protect study 
integrity, the IA will be performed by an independent statistician and statistical reporting 
group who are not involved in the clinical trial conduct and are not responsible for the final 
analysis of clinical trial data. Each interim analysis will be governed by a separate interim 
analysis charter. 
8.10.1 
Interim Analysis 1 (IA1) 
The first interim analysis will be conducted when approximately 75 subjects have completed 
the week 12 visit to review safety, tolerability. The key secondary endpoints in IA1 will be 
noninvasive tests (NITs): MRI-PDFF, MRE and non-invasive fibrosis markers. No analysis 
of the primary endpoint will be performed in IA1. PK, PD and PK/PD endpoints will be 
summarized as described in Section 8.8. 
The results to be submitted in IA1 will include all the displays for safety endpoints: treatment 
compliance, AEs, lab, ECG, vital signs, concomitant medications and physical examination; 
disposition and demographics results; and results for key secondary endpoints: MRI-PDFF, 
MRE and non-invasive fibrosis markers. 
Analysis for the liver MRI-PDFF, liver MRE and non-invasive markers is provided in 
Section 8.6.3.2.2, Section 8.6.3.2.3 and Section 8.6.4.1 respectively. 
8.10.2 
Interim Analysis 2 (IA2) 
The second interim analysis when approximately 35-40% of subjects have completed the 
week 72 biopsy. The analysis for the primary endpoint will be performed in IA2. A Lan- 
Demets alpha spending function with O’Brien-Fleming boundaries will be applied to control 
type I error at 0.025 significance level (two-sided) for each primary endpoint. Adjusted alpha 
obtained with this method will be used in second interim analysis. 
Each primary endpoint will be analysis using the logistic regression model given in Section 
8.6.2. A step-down sequential testing procedure will be used to control multiplicity in testing 
each dose vs placebo. 
PK, PD and PKPD endpoints will be summarized as described in Section 8.8. 


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8.11 COVID-19 Impact on Study 
Additional analysis will be performed to recognize and indicate the impact of participation 
of subjects by COVID-19. The impact of COVID-19 will be summarized by treatment group 
and overall by visit for all screened subjects. This table will present the subjects affected by 
COVID-19 in all aspects (e.g., missed visit and/or assessment due to COVID-19, remote 
visit due to COVID-19, modified assessment due COVID-19). In addition important 
protocol deviations related to COVID-19 using randomized subjects will be summarized. 
A by-subject listing will also be provided for all subjects that have their participation 
impacted by COVID-19. 




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10 
REFERENCES 
1. Clinical Study Protocol (Amendment 1.0) 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) 
2. Reboussin, D. M., DeMets, D. L., Kim, K. M., & Lan, K. K. (2000). Computations 
for group sequential boundaries using the Lan-DeMets spending function method. 
Control Clin Trials, 21(3), 190-207. 
3. Elman, S., Hynan, L. S., Gabriel, V., & Mayo, M. J. (2010). The 5-D itch scale: a 
new measure of pruritus. Br J Dermatol, 162(3), 587-593. doi:10.1111/j.1365- 
2133.2009.09586.x 
4. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – 
adopted March 1998). 
5. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf 
6. Agopian, V. G., Kaldas, F. M., Hong, J. C., Whittaker, M., Holt, C., Rana, A., . . 
Busuttil, R. W. (2012). Liver transplantation for nonalcoholic steatohepatitis: the 
new epidemic. Ann Surg, 256(4), 624-633. doi:10.1097/SLA.0b013e31826b4b7e. 




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SAS code for ANCOVA analysis 
PROC MIXED data = dataset method=type3; 
class trt01pn(ref=0) diab_st vitE_pio; 
model CHG = trt01pn diab_st vitE_pio baseline_NAS baseline_parameter /ddfm=KR; 
lsmeans trt01pn /pdiff ; 
ods output 
LSMEANS=lsm 
DIFFS=diff ; 
RUN; 
 
Note: 
1. Use data without any imputation. 
2. CHG: Change from baseline. 
3. diab_st: Baseline diabetes status 
4. vitE_pio: Use of Vitamin E and/or pioglitazone 
5. Baseline_NAS: Baseline value of NAS 
6. Baseline_parameter: Baseline value of the parameter to be analysed. 
7. Use numeric variables for treatment group 
8. Code trt01pn as Placebo=0, EDP 305 2 mg=1, EDP 305 1.5 mg=2 
 
SAS code for MMRM analysis 
PROC MIXED data = dataset method=type3; 
class trt01pn(ref=0) visitn usubjid ; 
model  CHG  =  trt01pn  visitn  trt01pn*visitn  baseline_NAS  baseline_parameter 
/ddfm=KR; 
repeated trt01pn / type = UN subject = usubjid; 
lsmeans trt01pn*avisitn /pdiff ; 
ods output 
LSMEANS=lsm 
DIFFS=diff 
RUN; 
 
Note: 
1. Use data without any imputation. 
2. CHG: Change from baseline. 
3. Baseline_NAS: Baseline value of NAS 
4. Baseline_parameter: Baseline value of the parameter to be analysed. 
5. Use numeric variables for visits and treatment group 
6. Code trt01pn as Placebo=0, EDP 305 2 mg=1, EDP 305 1.5 mg=2 
7. If model does not converge then use type=TOEPH 


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Appendix B – Scoring for Scales 
5D-itch scale 
5D-itch scale is developed by Elman (Elman, Hynan, Gabriel, & Mayo, 2010) and will be 
used to assess pruritus in subjects. The five dimensions (aka domains) assessed in 5D-itch 
scale are duration, degree, direction, disability, and distribution. 
The disability domain will be the highest score obtained from the daily activities of sleep, 
leisure/social activities, housework/errands, and work/school. The disability domain will 
only be calculated if at least 3 daily activities are documented. 
The distribution domain includes 16 locations of itch and is the categorized to a scale of 0 to 
5, based on the sum of the number of affected locations: sum of 0 to 2 = score of 1, sum of 
3 to 5 = score of 2, sum of 6 to 10 = score of 3, sum of 11 to 13 = score of 4, sum of 14 to 
16 = score of 5. 
The total 5D score is obtained by summing up the five domain scores and ranges between 5 
(no pruritus) and 25 (most severe pruritus). The total score will not be calculated if any of 
the domain scores is missing. 
 
Quality of Life scales - CLDQ-NASH 
CLDQ-NASH scale includes 36 items grouped into 6 domains: Abdominal Symptoms, 
Activity/Energy, Emotional Health, Fatigue, Systemic Symptoms, and Worry. This 
questionnaire is designed to find out how a subject had been feeling during the last two 
weeks Subject will be asked about their symptoms related to their fatty liver disease, how 
they have been affected in doing activities, and how their mood have been. 
In CLDQ-NASH, patients are asked about how frequently they experience certain problems 
or how they have been affected in doing activities impairing various aspects of their well- 
being; a 1-7 Likert scale is used for the responses such that the score of 1 corresponds to a 
problem is experienced “All of the time”, and the score of 7 to “None of the time”. 
The scores will be calculated separately for each domain as an average of the domain’s items. 
In all domains, greater scores reflect better health. The total CLDQ-NASH score will be 
obtained as the average of the domain scores. 
Cardiovascular risk score (ASCVD) 


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Data Derivation Details to Obtain Scale Scores for SF-36 
SF-36 questionnaire includes 8 domains with 36 items. This questionnaire designed to get 
idea about the subjects views about his/her health and to track of how the subject is feeling 
and if subject is able to do your usual activities. 
 
DERIVATION 
SF-36 PF scale score 
raw score = sum (items 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 
3J) 
PF = [ (raw score -10 )/20] * 100 
PF_Z = (PF – 83.29094) / 23.75883 
PF scale score = (PF_Z*10) + 50 
When calculating the raw score, if 5 or more of the items are 
non-missing then replace any missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. 
Substitute the mean for any missing scores. 
Otherwise, if less than 5 of the items are non-missing then PF 
scale score is missing. 
The response scale for each activity ranges from 1 to 3 where 
1=limited a lot, 2=limited a little, and 3=not limited at all. 
A higher PF scale score indicates better physical functioning. 


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DERIVATION 
SF-36 RP scale score 
raw score = sum (items 4A, 4B, 4C, and 4D ) 
RP = [(raw score -4)/16] * 100 
RP_Z = (RP – 82.50964) / 25.52028 
RP scale score = (RP_Z * 10) + 50 
When calculating the raw score, if 2 or more of the items are 
non-missing then replace any missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. 
Substitute the mean for any missing scores. 
Otherwise, if less than 2 of the items are non-missing then RP 
scale score is missing. 
The response scale for each item ranges from 1 to 5 where 
1=All of the time, 2=Most of the time, 3=Some of the time, 
4=A little of the time, and 5=None of the time. 
A higher RP 
scale score indicates better role-physical functioning. 


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SF-36 BP scale score 
raw score = sum (reversed item 7 and reversed item 8) 
BP = [ (raw score -2) / 10]*100 
BP_Z = (BP – 71.32527) / 23.66224 
BP scale score = (BP_Z * 10) + 50 
Reverse direction of Item 7 as follows if 
=1, set to 6 
if =2, set to 5.4 
if =3, set to 4.2 
if=4, set to 3.1 
if=5, set to 2.2 
if=6, set to 1 
Reverse direction of item 8 as follows: 
if =1 and original value of item 7=1, set to 6 
if =1 and original value of item 7>=2, set to 5 
if=2, set to 4 
if=3, set to 3 
if=4, set to 2 
if=5, set to 1 
If item 7 is answered and item 8 is missing, set 8 = reversed 
7 as defined above. 
If 8 is answered and 7 is missing, set 7 as reverse item 8 as 
follows 
if =1, set to 6 
if =2, set to 4.75 
if=3, set to 3.5 
if=4, set to 2.25 
if=5, set to 1 
If 1 or more questions were answered, calculate BP scale 
score as defined above. If neither question was answered 
then BP scale score is missing. 
The scale for Question 7, amount of bodily pain, ranges from 
1 to 6 where 1=None, 2=Very mild, 3=mild, 4=Moderate, 
5=Severe, and 6=Very severe. 
The scale for Question 8, the degree to which pain interfered 
with normal work, ranges from 1 to 5 where 1=Not at all, 
2=A little bit, 3=Moderately, 4=Quite a bit, and 
5=Extremely. 
A higher BP scale score indicates lack of bodily pain. 


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DERIVATION 
SF-36 GH scale score 
raw score = sum (reversed item 1, item 11A, reversed 11B, 
11C and reversed 11D) 
GH = [(raw score -5) / 20]*100 
GH_Z = (GH – 70.84570) / 20.97821 
GH scale score = (GH_Z * 10) + 50 
Reverse direction of Item 1 as follows: 
if =1, set to 5 
if =2, set to 4.4 
if =3, set to 3.4 
if =4, set to 2 
if =5, set to 1 
Reverse direction of item 11B and 11D by subtracting score 
from 6. 
When calculating the raw score, if 3 or more of the items are 
non-missing then replace any missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. Substitute 
the mean for any missing scores. 
Otherwise, if less than 3 of the items are non-missing then 
GH 
scale score is missing. 
Responses for Question 1, an assessment of self-perceived 
health status, range from 1 to 5 where 1=Excellent, 2=Very 
good, 3=Good, 4=Fair, and 5=Poor. 
Responses for the items in Question 11 range from 1 to 
5 where 1=Definitely true, 2=Mostly true, 3=Don’t know, 
4=Mostly false, and 5=Definitely false and reflect the 
subject’s perception of their relative health and expectations 
of their future health status. 
A higher GH scale score indicates better general health 
perceptions. 


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DERIVATION 
SF-36 VT scale score 
raw score = sum (reversed item 9a, reversed 9e, 9g and 9i) 
VT = [(raw score -4)/16] * 100 
VT_Z = (VT – 58.31411) / 20.01923 
VT scale score = (VT_Z * 10) + 50 
Reverse direction of Items 9a and 9e by subtracting score 
from 6. 
When calculating the raw score, if 2 or more of the items are 
non-missing then replace any missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. Substitute 
the mean for any missing scores. 
Otherwise, if less than 2 of the items are non-missing then 
VT 
scale score is missing. 
SF-36 SF scale score 
raw score = sum (reversed 6 and 10 ) 
SF = [(raw score -2) / 8] * 100 
SF_Z = (SF – 84.30250) / 22.91921 
SF scale score = (SF_Z * 10) + 50 
Reverse direction of score for item 6 by subtracting score 
from 6. 
When calculating the raw score, if 1 of the items is missing 
then substitute the missing score with the score on the 
non-missing item. If both items are missing then SF scale 
score is missing. 
Responses to Question 6, an assessment of the extent to 
which health/emotional problems interfered with social 
activities, range from 1 to 5 where 1=Not at all, 2=Slightly, 
3=Moderately, 4=Quite a bit, and 5=Extremely. 
Responses 
to Question 10 reflect the amount of time that 
health/emotional problems interfered with social activities 
and range from 1 to 5 where 1=All of the time, 2=Most of the 
time, 3=Some of the time, 4=A little of the time, and 5=None 
of the time. 
A higher SF scale score indicates better social functioning. 


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DERIVATION 
SF-36 RE scale score 
raw score = sum (items 5A, 5B, and 5C ) 
RE = [(raw score -3) / 12] * 100 
RE_Z = (RE – 87.39733) / 21.43778 
RE scale score = (RE_Z * 10) + 50 
When calculating the raw score, if 2 or more of the items are 
non-missing then replace any missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. Substitute 
the mean for any missing scores. 
Otherwise, if less than 2 of the items are non-missing then 
RE 
scale score is missing. 
Responses to the items in Question 5 range from 1 to 5 where 
1=All of the time, 2=Most of the time, 3=Some of the time, 
4=A little of the time, and 5=None of the time. A higher RE 
scale score indicates better role-emotional functioning. 


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DERIVATION 
SF-36 MH scale score 
raw score = sum (items 9B, 9C, reversed 9D, 9F and reversed 
9H) 
MH = [(raw score - 5 )/20]*100 
MH_Z = (MH – 74.98685) / 17.75604 
MH scale score = (MH_Z * 10) + 50 
Reverse direction of scores for 9D and 9H, by subtracting 
score from 6. 
If 3 or more of the items are non-missing then replace any 
missing values as follows: 
Calculate the mean of the answered questions, using the 
number of answered questions as the denominator. Substitute 
the mean for any missing scores. 
Otherwise, if less than 3 of the items are non-missing then 
MH scale score is missing. 
The scale for these items ranges from 1 to 5 where 1=All of 
the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, and 5=None of the time. A higher MH scale 
score indicates better mental health. 
SF-36 TR scale score 
raw score = item 2 
TR scale score = raw score 
The scale for this item ranges from 1 to 5 where 1=Much 
better now than one week ago, 2=Somewhat better now than 
one week ago, 3=About the same as one week ago, 
4=Somewhat worse now than one week ago, and 5=Much 
worse now than one week ago. A higher TR scale score 
indicates worse general health currently relative to one week 
previous. 


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DERIVATION 
SF-36 PCS score 
PCS score includes the 8 scales for GH, PF, 
RP, RE, SF, MH, BP, and VT. 
Raw Score = 
PF_Z *.42402 + RP_Z*.35119 + BP_Z*.31754 + 
GH_Z*.24954 + VT_Z*.02877 + SF_Z*-.00753 + RE_Z*- 
.19206 + MH_Z*-.22069 
PCS Summary Scale Score = (raw score *10) + 50 
Raw Score is missing if one of the component scale scores is 
missing. 
SF-36 MCS score 
MCS score includes the 8 scales for GH, 
PF, RP, RE, SF, MH, BP, and VT. 
Raw Score = 
PF_Z *-.22999 + RP_Z*-.12329 + BP_Z*-.09731 + GH_Z*- 
.01571 + VT_Z*.23534 + SF_Z*.26876 + RE_Z*.43407 + 
MH_Z*.48581 
MCS Summary Concept Score = (raw score *10) + 50 
Raw Score is missing if one of the component scale scores is 
missing. 


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Appendix C – Analysis Visit Windows 
For the purpose of conducting analyses, the visit windows noted below will be utilized for 
binning study visits. In the event that multiple visits fall within the same window, the 
scheduled visit will take precedence. If the scheduled visit was not attended, the closest 
visit to the target within the window will be utilized. If multiple visits are equidistant from 
the target date, the later of the two visits will be used. 
 
Nominal 
Visit 
Visit Window 
Lower Bound 
Visit Target 
(Days) 
Visit Window 
Upper Bound 
Screening 
N/A 
N/A 
-1 
Day 1 
1 
1 
1 
Day 7 
4 
7 
10 
Week 2 
11 
14 
20 
Week 4 
21 
28 
41 
Week 8 
42 
56 
69 
Week 12 
70 
84 
97 
Week 16 
98 
112 
125 
Week 20 
126 
140 
153 
Week 24 
154 
168 
181 
Week 28 
182 
196 
209 
Week 32 
210 
224 
237 
Week 36 
238 
252 
265 
Week 40 
266 
280 
293 
Week 44 
294 
308 
321 
Week 48 
322 
336 
363 
Week 56 
364 
392 
419 
Week 64 
420 
448 
475 
Week 72 
476 
504 
517 
Week 76 
518 
532 
N/A