Clinical trial NCT03812029
Conditions: Non-alcoholic Steatohepatitis
Keywords: EYP001 (vonafexor) Liver Diseases Non-alcoholic Fatty Liver Disease Non-alcoholic Steatohepatitis NASH
Sponsor: Enyo Pharma
Start date: 2019-01-30; Completion date: 2021-07-06
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effects of EYP001a (Vonafexor) with respect to safety, tolerability, pharmacokinetics and on markers of liver inflammation in patients with NASH

Detailed description:
This is a 2-part, randomized, double-blind, multicenter, placebo-controlled study to evaluate the safety and efficacy of Vonafexor in patients with NASH who likely have stage F2 to F3 fibrosis at approximately 50 global clinical sites. Overall, approximately 114 eligible patients will be enrolled: 24 patients in Part A (Safety Run-in Cohort), followed by 90 patients in Part B.

In Part A, 24 patients will be randomized on Day 1 to 1 of 4 parallel treatment groups: 100 mg Vonafexor twice daily (BID), 200 mg Vonafexor once daily (QD), 400 mg Vonafexor QD, or placebo BID. In Part B, 90 patients will be randomized on Day 1 to 1 of 3 parallel treatment groups: 100 mg Vonafexor QD, 200 mg Vonafexor QD, or placebo QD.

Arms: arm 1: Oral dose twice daily for 12 weeks (84 days) arm 2: Oral dose once daily for 12 weeks (84 days) arm 3: Oral dose once daily for 12 weeks (84 days) arm 4: Oral dose twice daily for 12 weeks (84 days) arm 5: Oral dose once daily for 12 weeks (84 days)
Interventions: intervention 1: Vonafexor intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2a, Randomized, Double-Blind, Multicenter, 
Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of EYP001a in Patients With 
Nonalcoholic Steatohepatitis 
 
Investigational Product: EYP001a 
Protocol Number: EYP001-202 
EudraCT Number: 2018-003119-22 
 
 
Sponsor: 
ENYO Pharma SA 
Bâtiment B - Bioserra 
60 Avenue Rockefeller, 69008 
Lyon, France 
Email: 202@enyopharma.com 
Telephone: +33 4 37 70 02 19 
 
 
 
Version Number: 5.0 
Original Protocol: 24 August 2018 
Amendment 1: 14 November 2018 
Amendment 2: 11 January 2019 
Amendment 3: 28 May 2019 
Amendment 4: 24 March 2020 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of ENYO Pharma SA except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for ENYO Pharma SA. You are 
allowed to disclose the contents of this document only to your Institutional Review Board or 
Independent Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to ENYO Pharma SA and that it may not be further disclosed to 
third parties. 


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SIGNATURE PAGE 
STUDY TITLE: A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo-Controlled 
Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in 
Patients With Nonalcoholic Steatohepatitis 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Pietro Scalfaro, MD 
Chief Medical Officer 
ENYO Pharma SA 
 
DocuSign Envelope ID: 59215D30-68AF-4F0E-BE7C-67CF162671F5
3/24/2020


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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by ENYO Pharma SA to study personnel under my supervision. I will discuss this material with 
them to ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential and proprietary to ENYO Pharma SA and that it 
may not be further disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by ENYO Pharma SA, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethics Committee regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE: A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to 
Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With 
Nonalcoholic Steatohepatitis 
PROTOCOL NUMBER: EYP001-202 
INVESTIGATIONAL PRODUCT: EYP001a 
PHASE: 2a 
INDICATION: Nonalcoholic steatohepatitis (NASH) 
OBJECTIVES: 
The primary objective is to determine the efficacy and safety profiles of EYP001a versus placebo 
on liver fat content (LFC) from baseline to Week 12 in patients with NASH. 
The secondary objectives are the following: 
 To explore the pharmacokinetics (PK) of EYP001a  
 To evaluate pharmacodynamic (PD) effects of EYP001a on bile acid-related markers as 
appropriate  
 To assess the effects of EYP001a on lipid and metabolic profiles 
 To assess the safety of EYP001a with statin coadministration  
 To assess the effects of EYP001a on noninvasive biomarkers of liver fibrosis and 
inflammation 
POPULATION: 
Inclusion Criteria 
A patient who meets all of the following criteria will be eligible to participate in the study: 
1. Provides signed written informed consent and agrees to comply with the study protocol. 
2. Is a male or female aged 18 years or older. 
3. Has a suspected diagnosis of NASH during the Screening Period (up to 12 weeks before 
dosing), defined as follows: 
a. Baseline serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
should be established by at least 2 samples obtained at least 4 weeks and no more than
12 weeks apart. One sample can be obtained from the patient’s medical history and 
1 sample can be obtained during the Screening Period, or both samples can be obtained 
during the Screening Period. If the values of ALT or AST in both samples are within 
normal ranges, the variability of the marker is assumed adequate for randomization. If the 
values of ALT or AST are higher than normal values, the patient will be eligible for 


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enrollment provided the increase from the first to second sample is 40%. If the values 
from sample 1 are higher than those from sample 2 (ie, there is a decrease), the patient will 
be eligible despite a >40% difference. A third sample can be collected if an increase from
sample 1 to sample 2 exceeds the 40% limit. If sample 3 exceeds the 40% limit (compared 
to sample 1), this increase shall prompt the search for clinical signs or symptoms of liver 
impairment, and the patient will not be eligible for enrollment. Baseline AST values should 
be >20 U/L. See Appendix I for central laboratory normal reference ranges. 
b. Normal average baseline levels of alkaline phosphatase (ALP). See Appendix I for central 
laboratory normal reference ranges. Total bilirubin (TBL) levels should be 22.2 mol/L 
(1.3 mg/dL). 
Note: Baseline serum ALP and TBL should be established by at least 2 samples obtained 
at least 4 weeks and no more than 12 weeks apart. One sample can be obtained from the 
patient’s medical history and 1 sample can be obtained during the Screening Period, or 
both samples can be obtained during the Screening Period. If the values of ALP or TBL in 
both samples are within normal ranges, the variability of the marker is assumed adequate 
for randomization. If the values of ALP or TBL are higher than normal values, the patient 
will be eligible for enrollment provided the increase from the first to second sample is
40%. If the values from sample 1 are higher than those from sample 2 (ie, there is a 
decrease), the patient will be eligible despite a >40% difference. A third sample can be 
collected if an increase from sample 1 to sample 2 exceeds the 40% limit. If sample 3
exceeds the 40% limit (compared to sample 1), this increase shall prompt the search for 
clinical signs or symptoms of liver impairment, and the patient will not be eligible for 
enrollment.  
c. Liver stiffness compatible with liver fibrosis stage F2 or F3 determined by FibroScan®
vibration-controlled transient elastography assessment cut-off value 8.5 kPa. 
d. FibroScan controlled attenuation parameter (CAP) for steatosis with cut-off values 
>300 dB/m. 
Note: Patients do not need to undergo a CAP assessment if their medical records indicate 
a magnetic resonance imaging (MRI)-proton density fat fraction (MRI-PDFF) LFC 10% 
within 12 months prior to screening. 
Note: Histology within 12 months prior to screening will supersede FibroScan entry 
criteria if the following criteria are met: NASH with fibrosis stage F2 to F3, defined as 
portal fibrosis with few septa (F2) or bridging septa between central and portal veins (F3), 
and nonalcoholic fatty liver disease (NAFLD) activity score 4, including a minimum of 
1 point each for ballooning and inflammation. However, if a patient participated in a 
previous study with a NASH investigational drug between 365 and 60 days prior to being 
screened for this study, the histology information will only be considered if the biopsy was 
performed after the end of the patient’s participation in the previous study. 
e. LFC 10% as measured by MRI-PDFF. 
4. Is not of childbearing potential (as defined in Inclusion Criterion 5) or, if of childbearing 
potential, is not pregnant as confirmed by a negative serum human chorionic gonadotropin test 
at screening and is not planning a pregnancy during the course of the study. 


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5. Women of childbearing potential and male patients with female partners must agree to use 
highly effective birth control throughout the duration of the study and for 90 days after 
stopping study drug. Patients who are using hormonal contraceptives or intrauterine devices 
should be instructed to use an additional barrier contraceptive measure during the study such
as a male or female condom with spermicide or diaphragm. Highly effective is defined as birth 
control methods that result in a failure rate of <1% per year when used consistently and 
correctly. Methods of highly effective birth control include the following: 
a. Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation. 
 Oral.  
 Intravaginal.  
 Transdermal.  
b. Progesterone-only hormonal contraception associated with inhibition of ovulation. 
 Oral.  
 Injectable.  
 Implantable.  
c. Intrauterine device.  
d. Intrauterine hormone-releasing system.  
e. Vasectomized partner (provided that the partner is the sole sexual partner of the woman of 
childbearing potential). 
f. Sexual abstinence (complete abstinence from sexual intercourse if this is the patient’s 
usual and preferred lifestyle). 
Note: A woman is considered of childbearing potential following menarche and until 
becoming postmenopausal unless permanently sterile. A postmenopausal state is defined as 
no menses for 12 consecutive months without an alternative medical cause. A 
follicle-stimulating hormone level in the postmenopausal range will be used to confirm a 
postmenopausal state in women 55 years of age. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from participation in the study:
1. Is an employee of a clinical research organization, vendor, or Sponsor involved with this study.
2. Has known non-NASH liver disease, including, but not limited to, alcoholic liver disease, 
autoimmune disease, human immunodeficiency virus, hepatitis B virus, active hepatitis C 
virus (HCV), Wilson’s disease, hemochromatosis, primary biliary cholangitis, primary 
sclerosing cholangitis, drug-induced liver injury, bile duct obstruction, or suspected or known 
liver cancer. 


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Note: HCV antibody (HCV Ab) positive individuals are not eligible, with the following 
2 exceptions: (a) Patients previously treated with a registered drug for viral hepatitis C with at 
least a 1-year period since documented sustained virologic response may be eligible if HCV 
ribonucleic acid (RNA) is below the limit of detection (LOD) and if all other eligibility criteria 
are met, and (b) patients with presence of HCV Ab if HCV RNA is below the LOD at 
screening without treatment (ie, spontaneous clearance) may be eligible if all other eligibility 
criteria are met. 
3. Has history of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or 
presence of esophageal varices. 
4. Has known history of alcohol abuse or daily heavy alcohol consumption (females: more than 
14 units of alcohol per week; males: more than 21 units of alcohol per week [1 unit of alcohol 
is equivalent to a half pint of beer {285 mL}, 1 measure of spirits {25 mL}, or 1 glass of wine 
{125 mL}]). Has an Alcohol Use Disorders Identification Test-Concise (AUDIT-C) score of 
3 points for men and women AND a full Alcohol Use Disorders Identification Test (AUDIT)
score of 8 points at screening.  
Note: Only patients with AUDIT-C scores 3 points at screening will receive the full AUDIT 
and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C scores 
<3 points will not receive the full AUDIT. 
5. Has Gilbert’s syndrome with direct bilirubin >1  upper limit of normal (ULN). 
6. Is pregnant or breastfeeding.  
7. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency 
conditions such as common variable hypogammaglobulinemia. 
8. Has a known preexisting medical or psychiatric condition that could interfere with the patient’s 
ability to provide informed consent or participate in study conduct, or that may confound study 
findings. 
9. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular 
disease within 90 days prior to the first study drug administration, including, but not limited 
to, myocardial infarction, acute coronary syndrome, revascularization (percutaneous coronary 
intervention or coronary artery bypass grafting) or ischemic stroke, or implanted defibrillator 
or pacemaker. 
10. Has participated in any drug study within 90 days prior to the first study drug administration 
in the current study. 
11. Has had major surgery within 90 days prior to the first study drug administration in the current 
study. 
12. Has a history of relevant drug and/or food allergies. The term “relevant” applies if any of the 
following allergy conditions are met: 
a. Has had several episodes of drug-induced urticaria or other immediate allergic signs 
(eg, rhinoconjunctivitis, respiratory) (2 in total at whatever time in medical history and 
with 1 or several drugs). 


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b. Has ongoing urticaria episodes (attributed to whatever allergen) or has other active history 
of immediate type reaction allergies (eg, allergic rhinoconjunctivitis, allergic asthma, or 
latex allergy). 
c. Has had a moderate or severe allergic reaction (Grade 2 per the World Allergy 
Organization reference table, ie, urticaria alone with a Grade 1 is not relevant). 
d. Has any allergic condition that might require an emergency epinephrine injection (similar 
to the EpiPen® Auto-Injector). 
13. Has a history of hypersensitivity to the study drug or to any of the excipients or placebo.  
14. Unable to undergo an MRI-PDFF due to: 
a. Contraindication to MRI examination. 
b. Severe claustrophobia impacting ability to perform MRI during the study, despite mild 
sedation/treatment with a short half-life (ie, <20 hours) anxiolytic. 
c. Body weight or girth exceeding the scanner capacities. 
15. Is using any of the following disallowed medications: 
a. Anticancer drug(s), immunomodulator(s), or immunosuppressant(s) within 90 days or 
5 half-lives prior to screening, whichever is longer, or any drug historically associated with 
NAFLD for >2 weeks in the year prior to screening (eg, amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those 
used for hormone replacement, anabolic steroids, or valproic acid or other known 
hepatotoxins at the Investigator or Medical Monitor’s discretion). 
b. Vitamin E (>400 IU/day), glitazones, glucagon-like peptide-1 receptor agonists, 
ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening. 
c. Agents (including herbal over-the-counter weight loss preparations) or medications known 
to significantly impact body weight within 90 days prior to screening (eg, sibutramine, 
phenetamine, and orlistat). 
d. Bile acid sequestrants (eg, cholestyramine) or lipid-modifying agents (eg, fibrates or
ezetimibe) other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, or 
lovastatin. 
e. Agents that are substrates for cytochrome P450 (CYP) 2C8 or CYP2C9 and have a narrow 
therapeutic index (eg, warfarin). 
16. Has prior or planned (during the study period) bariatric surgery (eg, gastroplasty or Roux-en-Y 
gastric bypass).  
17. Has type 1 diabetes mellitus. 
18. Has type 2 diabetes mellitus (T2DM) and hemoglobin A1c >9.5% or has not been on a stable 
dose of antidiabetic medication for at least 90 days prior to screening.  
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20. Has any of the following exclusionary laboratory results at screening:  
a. ALT >5  ULN, AST >5  ULN. 
b. International normalized ratio 1.3, unless on anticoagulant therapy. 
c. Platelet count <lower limit of normal. 
d. Estimated glomerular filtration rate <50 mL/min/1.73 m2 (the Modification of Diet in 
Renal Disease formula). 
e. Creatine kinase (CK) >ULN in patients on concomitant statin therapy and CK >3  ULN 
in all other patients. 
f. Thyroid-stimulating hormone >1.5  ULN or abnormal free triiodothyronine or free 
thyroxine. 
Note: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor if any of the above laboratory abnormalities are found. 
21. Has history of clinically significant gastrointestinal disease (especially: cholecystectomy prior
to age 25 years, peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, or
bariatric surgery); renal, hematologic, endocrine, oncologic, pulmonary, immunologic, or 
cardiovascular disease; neurologic or psychiatric disease (including any use of addictive
substances such as regular opioid treatment and/or any use of illicit drugs); or any other 
condition, which, in the opinion of the Investigator, would jeopardize the safety of the patient 
or impact the validity of the study results. 
22. Has a body mass index >45 kg/m2. 
STUDY DESIGN AND DURATION: 
This is a 2-part, randomized, double-blind, multicenter, placebo-controlled study to evaluate the 
safety and efficacy of EYP001a in patients with NASH who likely have stage F2 to F3 fibrosis at 
approximately 50 global clinical sites. Overall, approximately 114 eligible patients will be 
enrolled: 24 patients in Part A (Safety Run-in Cohort), followed by 90 patients in Part B. 
In Part A, 24 patients will be randomized on Day 1 to 1 of 4 parallel treatment groups: 100 mg 
EYP001a twice daily (BID), 200 mg EYP001a once daily (QD), 400 mg EYP001a QD, or placebo 
BID. In Part B, 90 patients will be randomized on Day 1 to 1 of 3 parallel treatment groups: 
100 mg EYP001a QD, 200 mg EYP001a QD, or placebo QD. 
Randomization will be stratified by statin use (yes, no) and T2DM status (yes, no) at screening in 
Part A, and by statin use (yes, no) and LFC (stratification factor with 3 categories: LFC<16%, 
16%LFC<22%, and 22%LFC) in Part B at screening. 
The following sequence of screening procedures will be applied to each patient who signs an 
informed consent form: 1) eligibility based on clinical and biological inclusion and exclusion 
criteria; 2) eligibility based on FibroScan criteria as described in Inclusion Criterion 3; and 
3) confirmation of eligibility based on MRI-PDFF results. A patient who is first designated as a 
screen failure prior to being randomized may be rescreened upon Sponsor or designee approval.
If the patient was screen failed after the MRI-PDFF was completed, the original MRI-PDFF scan 
may be utilized for rescreening, provided it was obtained within 1 month prior to rescreening. 


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Part A (Safety Run-in Cohort) 
Participation in Part A of the study will consist of a Screening Period (up to 12 weeks prior to 
Day 1), a 12-week Treatment Period, and a Follow-up Visit at Week 14; total study duration is up 
to 182 days. All eligibility criteria must be confirmed prior to dosing on Day 1.  
The 12-week Treatment Period in Part A will include 7 study visits on the following days: Days 1, 
7, 14, 21, 28, 56, and 84. Clinical, hematological, chemical, PD, and PK parameters will be 
assessed throughout the study. Intense PK/PD profiling on Days 1 and 14 will require 12-hour 
inpatient monitoring and 24-hour post-morning dose blood collection. Safety and tolerability 
assessments will include the monitoring of adverse events; adverse events of special interest 
(AESIs) (ie, pruritus, drug-induced liver injury, and all muscle-related adverse events); serious 
adverse events (SAEs); and findings from physical examinations, vital signs, electrocardiograms 
(ECGs), and clinical laboratory parameters. 
Throughout the study, all treatment-emergent adverse events (TEAEs), clinical assessments, and 
clinical laboratory parameters will be closely monitored against the criteria for drug-induced liver 
injury and muscle toxicity as detailed in the Clinical Safety Monitoring Plan (Appendix E). All 
adverse events will be assessed and reported using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 grading system. Additional safety 
measurements will be performed at the discretion of the Investigator (or delegate). Except during 
the Safety Run-in Period, plasma from blood samples will be collected at each visit and stored for 
protocol-related safety testing or exploratory analyses. 
Part B (Remaining Patients) 
Patients in Part B will be randomized on Day 1 to 1 of 3 parallel treatment groups: 100 mg 
EYP001a QD, 200 mg EYP001a QD, or placebo QD, with approximately 30 patients in each 
group. Pruritus-related tolerance issues will be addressed by a 2-step study drug titration strategy 
for the highest dose treatment group (ie, 200 mg QD): all patients randomized to an active 
treatment group will start with an initial dose of 100 mg QD for the first 2 weeks of treatment 
(Days 1 to 14). Patients randomized to the 200 mg QD treatment group will be uptitrated to 
200 mg QD starting Day 15 until Day 84, while patients randomized to the 100 mg QD treatment 
group will maintain a 100 mg QD dose throughout their participation. The study treatment 
assignment strategy will ensure that blind is maintained. 
Randomization will be stratified by statin use (yes, no) and LFC (stratification factor with 
3 categories: LFC<16%, 16%LFC<22%, and 22%LFC) at screening. 
Participation in Part B of the study will consist of a Screening Period (up to 12 weeks prior to
Day 1), a 12-week Treatment Period, and a Follow-up Visit at Week 14; total study duration is up
to 182 days. All eligibility criteria must be confirmed prior to dosing on Day 1. 
The 12-week Treatment Period in Part B will include 7 study visits on the following days: Days 1, 
14, 28, 42, 56, 70, and 84. Clinical, hematological, chemical, PD, and PK parameters will be 
assessed throughout the study. The safety and tolerability assessments will include the monitoring 
of adverse events; AESIs (ie, elevation of transaminases and all muscle-related adverse events); 
SAEs; and findings from physical examinations, vital signs, ECGs, and clinical laboratory 
parameters.  


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Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed 
in the Clinical Safety Monitoring Plan (Appendix E). All adverse events will be assessed and 
reported using the National Cancer Institute CTCAE Version 5.0 grading system. Additional 
safety measurements will be performed at the discretion of the Investigator (or delegate). At 
screening and on Days 1, 14, 28, 56, and 84; and at the End of Study (EOS) and Early Termination 
(ET) Visits, plasma from blood samples will be stored for protocol-related safety testing or 
exploratory analyses. 
Data Safety Monitoring Committee and Interim Analyses 
An external, independent Data Safety Monitoring Committee (DSMC) will review all available 
unblinded preliminary safety, PK, and PD results when any stopping rules are met, per the Clinical
Safety Monitoring Plan (Appendix E). In Part B, the DSMC will be promptly notified for further 
review if any patients experience ALT, AST, or bilirubin elevations 2  above baseline values.  
In addition, all available unblinded preliminary safety, PK, and PD results will be 
comprehensively reviewed during 2 interim analysis timepoints: 
 The first interim analysis will be performed at the end of the Safety Run-in Period, after the 
last of the 24 patients randomized in Part A has completed Day 28 (Week 4). It is anticipated 
that at the time of the first interim analysis, approximately 10 patients will have completed 
Day 84 (Week 12) of Part A.  
 A second interim analysis will be performed when 50% of patients in Part B have completed 
Day 56 (Week 8). 
The interim analyses will be performed on all available primary and secondary endpoints 
according to the DSMC charter, which describes the overall guidelines, composition, roles, and 
responsibilities of the independent DSMC for this study, including the selection of DSMC 
members, timing of meetings, methods of providing information to and from the DSMC, 
frequency and format of meetings, data analysis recommendations, and DSMC relationships with 
other parties participating in the conduct of this study. Patient accrual will continue throughout 
the period of DSMC review. The DSMC will advise on the accrual of the remaining patients per 
protocol or on any amendments that are necessary for safety reasons. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
EYP001a will be supplied as 100 and 200 mg immediate-release coated tablets for oral 
administration. 
Placebo tablets for oral administration will appear identical to EYP001a. 
EFFICACY VARIABLES:  
The primary efficacy variable is absolute change in LFC as measured by MRI-PDFF from baseline 
to Week 12. 
The secondary efficacy variables include the following: 
 Proportion of patients with 5% absolute reduction in LFC as measured by MRI-PDFF from 
baseline to Week 12 


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 Proportion of patients with 10% absolute reduction in LFC as measured by MRI-PDFF at 
Week 12 
 Proportion of patients with 20% absolute reduction in LFC as measured by MRI-PDFF at 
Week 12  
 Proportion of patients with a relative reduction in LFC 20% as measured by MRI-PDFF at 
Week 12 
 Proportion of patients with a relative reduction in LFC 30% as measured by MRI-PDFF at 
Week 12 
 Percent change (relative reduction) in LFC as measured by MRI-PDFF from baseline to 
Week 12 
 Change and percent change in imaging-derived mean iron-corrected T1 from baseline to 
Week 12 
 Change and percent change in waist to hip ratio from baseline to Week 12 (Part B only) 
 Change and percent change in waist to height ratio from baseline to Week 12 (Part B only) 
 Change in the following biomarkers of liver fibrosis and inflammation: ALT, AST, AST/ALT
ratio, adiponectin, high sensitivity C-reactive protein, interleukin 6, tumor necrosis factor 
alpha, cytokeratin-18, fibronectin, hyaluronic acid, procollagen type III N-terminal peptide, 
tissue inhibitor of metalloproteinases-1 (and derived enhanced liver fibrosis score), Pro-C3, 
and chitinase-3-like protein 1 (also known as YKL-40) from baseline to Week 4, Week 8, and 
Week 14/ET, as applicable 
PHARMACOKINETIC VARIABLES: 
In Part A, during the Safety Run-in Period, intense PK sampling will occur on Day 1 (1 day) and 
Day 14 (1 day) at the following timepoints: 0 (predose), 1, 2, 4, 6, 8, 10, 12, and 24 hours 
postdose; samples will be collected in the fasted state predose to 4 hours postdose, inclusive. 
Sparse PK samples will be collected for all other visits. Plasma samples to assess trough 
concentrations of EYP001a will be collected predose (fasting) in the morning and 2 hours postdose 
(an optional sample may also be collected at 6 hours postdose) at the following visits: Days 7, 21, 
28, 56, and 84. A sample will also be collected at the EOS and ET Visits. 
In Part B, sparse PK sampling will occur predose (fasting) at the following visits: Days 1, 14, 28, 
56, and 84. A sample will also be collected at the EOS and ET Visits. 
At the ET Visit (if applicable), the PK sample should be collected within 24 to 48 hours of last 
intake of study drug. The date and time of the PK draw and the last dose of study drug must be 
recorded in the electronic case report form (eCRF). 
Pharmacokinetic samples will be collected in a fasted state, defined as nothing by mouth except 
water for 6 hours, at all predose sampling timepoints (in Parts A and B) and at the 1- to 4-hour 
postdose timepoints (inclusive) on Days 1 and 14 of Part A. For BID dosing, PK timepoints will 
be based on the time of morning dosing. 


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PHARMACODYNAMIC VARIABLES:  
In Part A, intense PD sampling will occur on Day 1 (1 day) and Day 14 (1 day) at the following 
timepoints: 0 (predose, fasting), 4 (fasting), 6, 10, 12, and 24 hours postdose. Sparse PD sampling 
will also occur predose (fasting) and 2 hours postdose at the following visits: Days 28, 56, and 84. 
A sample will also be collected at the EOS and ET Visits. 
In Part B, sparse PD sampling will occur predose (fasting) at the following visits: Days 1, 14, 28,
56, and 84. A sample will also be collected at the EOS and ET Visits. 
At the ET Visit (if applicable), the PD sample should be collected within 24 to 48 hours of last 
intake of study drug. The date and time of the PD draw and the last dose of study drug must be 
recorded in the eCRF. 
Pharmacodynamic samples will be collected in a fasted state, defined as nothing by mouth except 
water for 6 hours, at all predose sampling timepoints (in Parts A and B) and at the 4-hour postdose 
timepoint on Days 1 and 14 in Part A. For BID dosing, PD sampling timepoints will be based on 
the time of morning dosing. 
Parameters will be measured in plasma samples using a validated method. Pharmacodynamic 
sampling will assess plasma levels of 7αhydroxy-4-cholesten-3-one; fibroblast growth factor 19; 
and total, primary, and secondary bile acids (such as chenodeoxycholic acid, deoxycholic acid, 
lithocholic acid, and/or others as appropriate). 
SAFETY VARIABLES: 
Safety and tolerability assessments will include the monitoring of adverse events; AESIs 
(ie, pruritus [Part A only], drug-induced liver injury [Part A only], elevation of transaminases 
[Part B only], and all muscle-related adverse events); SAEs; and findings from physical 
examinations, vital signs, ECGs, and clinical laboratory parameters.  
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed
in the Clinical Safety Monitoring Plan (Appendix E).  
All adverse events will be assessed and reported using the National Cancer Institute CTCAE 
Version 5.0 grading system. Additional safety measurements will be performed at the discretion 
of the Investigator (or delegate). 
STATISTICAL ANALYSES: 
Analysis Populations  
The Intent-to-Treat (ITT) Population includes all patients who are randomized and administered 
at least 1 dose of study drug. Patients without a Week 12 or end of treatment MRI-PDFF 
assessment will be imputed as nonresponders. 
The Safety Population is identical to the ITT Population. 
The modified ITT (mITT) Population includes patients from the ITT Population who have valid 
baseline and Week 12 MRI-PDFF measurements of LFC. 


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The Per-Protocol Population includes all patients from the mITT Population who finish the 
12-week Treatment Period without any major protocol violations. The analysis of LFC as 
measured by MRI-PDFF will be repeated on the Per-Protocol Population to test the robustness of 
results. 
Efficacy Analysis  
The efficacy analyses of LFC as measured by MRI-PDFF will be conducted on the ITT Population
and repeated on the mITT and Per-Protocol Populations. The analysis of other efficacy variables 
will be based on the ITT Population. 
For efficacy variables, observed data and change and/or percent change from baseline will be 
summarized using descriptive statistics and graphs per dose group and visit as appropriate. 
The primary efficacy analysis will be performed on the ITT Population. Missing MRI-PDFF 
values at Week 12 or ET will be imputed based on the missing at random assumption using 
multiple imputation. 
The primary efficacy analysis will be performed on the change in LFC as measured by MRI-PDFF
from baseline to Week 12 or ET using an analysis of covariance (ANCOVA) model with baseline 
fat fraction as a covariate and treatment, use of statin comedication at screening (stratification 
factor: use of statin [yes, no]), and T2DM status (yes, no) in Part A, and by statin use (yes, no) 
and LFC at screening (stratification factor with 3 categories: LFC<16%, 16%LFC<22%, and 
22%LFC) in Part B, as factors. Pairwise treatment comparisons between each EYP001a dose 
and placebo will be conducted from the ANCOVA model with least-square means, standard 
errors, 95% confidence intervals, and p-values being presented. To adjust the 3 tests (each 
EYP001a dose and placebo) for multiplicity in order to control the family-wise type I error at 
0.025 one-sided, the Bonferroni method will be used. 
The primary efficacy results will subsequently be analyzed by adding liver stiffness measurements
and CAP values at enrollment as additional factors. 
The statistical analysis of secondary efficacy variables based on change from baseline to Week 12 
will be conducted with a similar ANCOVA model, while secondary efficacy variables measured 
at multiple timepoints will be analyzed by mixed effect model repeated measures model. The 
responder (categorical) variables will be analyzed by a Cochran-Mantel-Haenszel test, stratified 
by statin comedication use and T2DM status at screening in Part A and statin comedication and 
LFC at screening in Part B. The analysis of the responder variables will be repeated using logistic 
regression models, adjusting for treatment, statin comedication at screening, and T2DM status at 
screening. Patients without a Week 12 or end of treatment MRI-PDFF assessment will be imputed 
as nonresponders. All secondary efficacy variables will be summarized using descriptive statistics.
In addition, the anticipated EYP001-202 efficacy results will serve as validation of an in silico 
NASH disease model, which was built based on public and expert knowledge and combined 
with the Phase 1 PK and PD EYP001 results. The model integrates 309 liver farnesoid X 
receptor-related biological variables and 1320 parameters and explores the effect of different 
EYP001 treatment regimens on NASH-relevant efficacy endpoints in a virtual population. 
Iterations of the model will support future explorations of development strategies with different 
EYP001 Phase 2 and 3 study designs. 


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Sensitivity Analysis  
Sensitivity analyses will be conducted by repeating the primary efficacy analysis based on: 
 The ITT Population with missing MRI-PDFF values at Week 12 or ET imputed using the 
multiple imputation with tipping point method based on the missing not at random assumption
 The mITT Population 
Pharmacodynamic Analysis 
Pharmacodynamic parameters, observed data, and change and/or percent change from baseline
will be summarized using descriptive statistics and graphs per dose group and visit, as appropriate.
Pharmacokinetic Analysis 
Plasma concentrations of EYP001a will be listed for all patients with available EYP001a plasma 
concentrations in treatment groups that include EYP001a or placebo. All concentrations below the 
limit of quantification will be labeled as such in the concentration data listings and will be treated 
as 0 in the summary statistics. 
Listings of individual patient plasma concentrations and actual blood sampling times and graphs 
of concentration versus time will be prepared by dose. Plasma concentrations will be summarized 
by and compared among different doses using descriptive statistics. 
Safety Analysis 
Baseline for physical examinations, all vital signs, 12-lead ECG measurements, pruritus 
questionnaire (Part A only), and clinical laboratory assessments will be defined as the last 
evaluation done before the first administration of study drug in each dose group on Day 1. 
Safety variables will be tabulated and presented for the Safety Population. 
The original terms used in the eCRF by Investigators to identify adverse events will be coded 
using the current version of the Medical Dictionary for Regulatory Activities. All adverse events 
will be assessed and reported using the National Cancer Institute CTCAE Version 5.0 grading 
system. A TEAE is defined as a new or worsening adverse event after the first dose of study drug. 
The percentage of patients with TEAEs will be summarized for each dose group by system organ 
class and preferred term. The study drug-related TEAEs and SAEs will be summarized in the same 
fashion. The TEAEs will also be summarized by system organ class, preferred term, and maximum 
severity. All SAEs and TEAEs leading to early discontinuation will be listed. 
The safety of EYP001a with statin coadministration will be assessed based on the difference in 
frequency of TEAEs between treatment groups.  
The clinical laboratory analytes, vital signs, and ECGs at each visit and their change from baseline 
will be summarized descriptively. Laboratory abnormalities based on predefined normal ranges 
will be tabulated by dose group showing patient counts and percentages. A listing of patients with 
any laboratory results outside the reference ranges will be provided if appropriate. 
SAMPLE SIZE DETERMINATION: 
The sample size of 114 randomized patients (n = 24 patients in Part A and n = 90 in Part B 
[n = 30 patients per treatment group]) is based on the efficacy endpoint: absolute change in LFC 
as measured by MRI-PDFF from baseline to Week 12, assuming that the treatment difference 


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between each active treatment group with placebo is at least 5.1% with a common standard 
deviation of 5.8%. 
With a 2-sample Z-test with the power of 0.8 and an overall family-wise 1-sided alpha of 0.025 
(or each active versus placebo alpha = 0.0125 after Bonferroni adjustment), 26 patients per 
treatment group will be needed to complete the Week 12 Visit. With the consideration of an 
approximately 13% dropout rate before Week 12, 30 patients will be randomized per treatment 
group in Part B. 
SITES: Approximately 50 global clinical sites  
SPONSOR: 
ENYO Pharma SA 
Bâtiment B - Bioserra 
60 Avenue Rockefeller, 69008 
Lyon, France  
Email: 202@enyopharma.com 
Telephone: +33 4 37 70 02 19 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 17 
List of Tables ................................................................................................................................ 22 
List of Figures ............................................................................................................................... 23 
List of Abbreviations and Definition of Terms............................................................................. 24 
1  Introduction and Background Information ............................................................................. 26 
1.1 
Rationale ........................................................................................................................ 26 
1.2 
Risk/Benefit ................................................................................................................... 30 
1.2.1  Phase 1 Experience in Healthy Subjects and Patients With Chronic Hepatitis 
B Virus Infection ............................................................................................... 30 
1.2.2  Experience in Nonalcoholic Steatohepatitis ...................................................... 30 
1.2.3  Overall Risk/Benefit .......................................................................................... 33 
2  Study Objectives ..................................................................................................................... 35 
2.1 
Primary Objective ......................................................................................................... 35 
2.2 
Secondary Objectives .................................................................................................... 35 
3  Study Description.................................................................................................................... 36 
3.1 
Summary of Study Design ............................................................................................ 36 
3.2 
Stopping Rules .............................................................................................................. 39 
3.3 
Study Indication ............................................................................................................ 40 
4  Selection and Withdrawal of Subjects .................................................................................... 41 
4.1 
Screening Strategy ......................................................................................................... 41 
4.2 
Inclusion Criteria ........................................................................................................... 41 
4.3 
Exclusion Criteria .......................................................................................................... 43 
4.4 
Withdrawal Criteria ....................................................................................................... 46 
5  Study Treatments .................................................................................................................... 47 
5.1 
Treatment Groups .......................................................................................................... 47 
5.2 
Rationale for Dosing ..................................................................................................... 47 
5.3 
Randomization and Blinding ......................................................................................... 49 
5.3.1  Stratification ...................................................................................................... 50 


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5.4 
Breaking the Blind ........................................................................................................ 50 
5.5 
Drug Supplies ................................................................................................................ 50 
5.5.1  Formulation and Packaging ............................................................................... 50 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 50 
5.5.3  Study Drug Administration ............................................................................... 51 
5.5.4  Treatment Compliance ...................................................................................... 51 
5.5.5  Storage and Accountability ............................................................................... 51 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 52 
5.6.1  Excluded Medications and/or Procedures ......................................................... 52 
5.6.2  Restricted Medications and/or Procedures ........................................................ 52 
5.6.3  Documentation of Prior and Concomitant Medication Use .............................. 53 
6  Study Procedures .................................................................................................................... 54 
6.1 
Informed Consent .......................................................................................................... 54 
6.2 
Screening Period (Parts A and B) (Weeks -12 to -1) .................................................... 54 
6.3 
Treatment Period (Weeks 0 to 12) ................................................................................ 55 
6.3.1  Part A: Safety Run-in Period (Weeks 0 to 4) .................................................... 55 
6.3.1.1  Day 1 (Week 0) ................................................................................... 55 
6.3.1.2  Day 7 (Week 1) ................................................................................... 56 
6.3.1.3  Day 14 (Week 2) ................................................................................. 56 
6.3.1.4  Day 21 (Week 3) ................................................................................. 57 
6.3.1.5  Day 28 (Week 4) ................................................................................. 58 
6.3.2  Part A: Continued Treatment Period (Weeks 5 to 12) ...................................... 58 
6.3.2.1  Day 56 (Week 8) ................................................................................. 58 
6.3.2.2  Day 84 (Week 12) ............................................................................... 59 
6.3.3  Part B: Treatment Period (Weeks 0 to 12) ........................................................ 60 
6.3.3.1  Day 1 (Week 0) ................................................................................... 60 
6.3.3.2  Day 14 (Week 2) ................................................................................. 61 
6.3.3.3  Day 28 (Week 4) ................................................................................. 61 
6.3.3.4  Day 42 (Week 6) ................................................................................. 62 
6.3.3.5  Day 56 (Week 8) ................................................................................. 62 
6.3.3.6  Day 70 (Week 10) ............................................................................... 63 
6.3.3.7  Day 84 (Week 12) ............................................................................... 63 


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6.4 
End of Study Follow-Up Visit (Parts A and B) (Week 14) .......................................... 64 
6.5 
Early Termination Visit and Withdrawal Procedures (Parts A and B) ......................... 65 
7  Efficacy Assessments .............................................................................................................. 67 
7.1 
Efficacy Variables ......................................................................................................... 67 
7.1.1  Primary Efficacy Variables ............................................................................... 67 
7.1.2  Secondary Efficacy Variables ........................................................................... 67 
8  Pharmacokinetic and Pharmacodynamic Assessments ........................................................... 68 
8.1 
Pharmacokinetic Variables ............................................................................................ 68 
8.2 
Pharmacodynamic Variables ......................................................................................... 68 
9  Safety Assessments ................................................................................................................. 69 
9.1 
Adverse Events .............................................................................................................. 69 
9.1.1  Adverse (Drug) Reaction .................................................................................. 70 
9.1.2  Unexpected Adverse Drug Reaction ................................................................. 70 
9.1.3  Assessment of Adverse Events by the Investigator .......................................... 70 
9.1.4  Adverse Events of Special Interest .................................................................... 71 
9.2 
Serious Adverse Events ................................................................................................. 72 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 73 
9.4 
Pregnancy Reporting ..................................................................................................... 73 
9.5 
Expedited Reporting ...................................................................................................... 74 
9.6 
Special Situation Reports .............................................................................................. 74 
9.7 
Medical History ............................................................................................................. 75 
9.8 
Clinical Laboratory Evaluations .................................................................................... 75 
9.9 
Vital Signs and Anthropometrics .................................................................................. 76 
9.10  Electrocardiograms ........................................................................................................ 76 
9.11  Physical Examinations .................................................................................................. 77 
9.12  Pruritus Assessments ..................................................................................................... 77 
9.12.1  Pruritus Management – Guidance to Investigators ........................................... 77 
9.13  Drug-Induced Liver Injury and Muscle Toxicity Monitoring ....................................... 78 
9.14  Diet and Lifestyle Counseling ....................................................................................... 78 
10  Statistics .................................................................................................................................. 79 
10.1  Analysis Populations ..................................................................................................... 79 
10.2  Statistical Methods ........................................................................................................ 79 


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10.2.1  Analysis of Efficacy .......................................................................................... 79 
10.2.1.1 Primary efficacy analysis .................................................................... 79 
10.2.1.2 Sensitivity analysis.............................................................................. 80 
10.2.1.3 Secondary efficacy analysis ................................................................ 80 
10.2.1.4 Validation of nonalcoholic steatohepatitis disease model .................. 80 
10.2.2  Pharmacodynamic Analysis .............................................................................. 80 
10.2.3  Pharmacokinetic Analysis ................................................................................. 80 
10.2.4  Analysis of Safety ............................................................................................. 81 
10.2.4.1 Adverse events .................................................................................... 81 
10.2.4.2 Laboratory values ................................................................................ 81 
10.2.4.3 Vital signs, anthropometrics, and electrocardiograms ........................ 81 
10.2.4.4 Prior and concomitant medications ..................................................... 81 
10.2.5  Demographic and Baseline Characteristics ....................................................... 81 
10.2.6  Interim Analysis ................................................................................................ 82 
10.2.7  Data and Safety Monitoring Committee ........................................................... 82 
10.2.8  Sample Size Determination ............................................................................... 82 
11  Data Management and Record Keeping ................................................................................. 84 
11.1  Data Management ......................................................................................................... 84 
11.1.1  Data Handling ................................................................................................... 84 
11.1.2  Computer Systems ............................................................................................. 84 
11.1.3  Data Entry ......................................................................................................... 84 
11.1.4  Medical Information Coding ............................................................................. 84 
11.1.5  Data Validation ................................................................................................. 84 
11.2  Record Keeping ............................................................................................................. 84 
11.3  End of Study .................................................................................................................. 85 
12  Investigator Requirements and Quality Control ..................................................................... 86 
12.1  Ethical Conduct of the Study ........................................................................................ 86 
12.2  Institutional Review Board/Independent Ethics Committee ......................................... 86 
12.3  Informed Consent .......................................................................................................... 86 
12.4  Patient Card ................................................................................................................... 86 
12.5  Study Monitoring Requirements ................................................................................... 87 
12.6  Disclosure of Data ......................................................................................................... 87 


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12.7  Retention of Records ..................................................................................................... 87 
12.8  Publication Policy ......................................................................................................... 88 
12.9  Financial Disclosure ...................................................................................................... 88 
12.10 Insurance and Indemnity ............................................................................................... 88 
12.11 Legal Aspects ................................................................................................................ 88 
13  Study Administrative Information .......................................................................................... 89 
13.1  Protocol Amendments ................................................................................................... 89 
14  References ............................................................................................................................... 90 
Appendix A: Schedule of Procedures ........................................................................................... 92 
Appendix B: Clinical Laboratory Analytes .................................................................................. 98 
Appendix C: 5-D Pruritus Scale ................................................................................................. 101 
Appendix D: Pruritus Visual Analog Scale ................................................................................ 102 
Appendix E: Clinical Safety Monitoring Plan ............................................................................ 103 
Appendix F: Alcohol Use Disorders Identification Test-Concise .............................................. 109 
Appendix G: The Alcohol Use Disorders Identification Test: Interview Version ..................... 111 
Appendix H: World Allergy Organization Grading System ....................................................... 112 
Appendix I: Central Laboratory Reference Ranges .................................................................... 114 


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LIST OF TABLES 
Table 1. 
Study Treatment Groups and Dosing Regimens – Part A .......................................... 47 
Table 2. 
Study Treatment Groups and Dosing Regimens – Part B........................................... 47 
Table 3. 
Study EYP001-202 Part A: Median PK Parameters at Day 1 and Day 14 ................. 48 
Table 4. 
Study EYP001-C01 Healthy: Median PK Parameters at Day 1 (SAD) and Day 14 
(MAD)......................................................................................................................... 48 
Table 5. 
Study EYP001-107: Median PK Parameters at Day 1 and Day 8 .............................. 48 
Table 6. 
Efficacy and Futility Boundaries for Part B ............................................................... 83 
Table 7. 
Schedule of Procedures – Part A ................................................................................ 92 
Table 8. 
Schedule of Procedures – Part B ................................................................................. 95 
Table 9. 
World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction 
Grading System ......................................................................................................... 112 


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LIST OF FIGURES  
Figure 1.  Effects of Food Intake on EYP001a Pharmacokinetic Parameters ............................. 27 
Figure 2.  Plasma C4 and FGF19 Concentrations From Day 27 – EYP001a 100 mg BID ........ 28 
Figure 3.  Plasma C4 and FGF19 Concentrations at Day 27 – EYP001a 200 mg QD ............... 28 
Figure 4.  Plasma C4 and FGF19 Concentrations From Day 27 – EYP001a 400 mg QD ......... 29 
Figure 5.  Pruritus Intensity Reported by Patient on the Visual Analogue Scale (0 to 10) Over 
the Treatment Period (AUC Integrated and Normalized) ........................................... 31 
Figure 6.  Pruritus Onset in Days for Intent-to-Treat Population ................................................ 32 
Figure 7.  Study Design ............................................................................................................... 36 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AESI 
Adverse event of special interest  
ALP 
Alkaline phosphatase 
ALT  
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
AST  
Aspartate aminotransferase  
AUC 
Area under the plasma concentration-time curve  
AUDIT 
Alcohol Use Disorders Identification Test 
AUDIT-C 
Alcohol Use Disorders Identification Test-Concise 
BID  
Twice daily 
BMI  
Body mass index  
C4 
7αhydroxy-4-cholesten-3-one 
CAP  
Controlled attenuation parameter 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
Cmax 
Maximum observed plasma concentration 
CRA  
Clinical Research Associate  
cT1 
Iron-corrected T1 
CTA  
Clinical trial authorization  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
EDC  
Electronic data capture  
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure in Utero  
EOS  
End of Study  
ET  
Early Termination  
FDA 
Food and Drug Administration  
FGF19 
Fibroblast growth factor 19 
FXR 
Farnesoid X receptor 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 


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Abbreviation 
Definition 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC  
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT  
Interactive Response Technology 
ITT 
Intent-to-Treat 
LDL-C 
Low-density lipoprotein cholesterol 
LFC 
Liver fat content 
LOD  
Limit of detection 
LSM 
Liver stiffness measurement  
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging-proton density fat fraction  
NAFLD 
Nonalcoholic fatty liver disease 
NASH  
Nonalcoholic steatohepatitis 
PD  
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
po 
Orally  
QD 
Once daily 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event  
SUSAR 
Suspected unexpected serious adverse reaction 
T2DM 
Type 2 diabetes mellitus 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach the maximum observed plasma concentration 
ULN 
Upper limit of normal  
VCTE 
Vibration-controlled transient elastography 
WHO  
World Health Organization 
WHR 
Waist to hip ratio 
WHtR 
Waist to height ratio 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disorder in western 
countries and involves steatosis, defined as liver fat content (LFC) >5%, leading to inflammation 
with hepatocyte injury. It is estimated that more than 5% of the population has advanced NASH. 
Its main consequence is liver fibrosis, which can progress to cirrhosis and hepatocellular 
carcinoma. Currently no registered drug therapy exists for this disease, which represents an 
important challenge.  
Clinical studies show evidence linking liver fat improvements in NASH with histological 
improvements. A study with ezetimibe for 24 weeks showed that histologic responders had 
approximately 30% relative LFC reduction on magnetic resonance imaging (MRI)-proton density 
fat fraction (MRI-PDFF) relative to a 2% increase for nonresponders.1 Findings in the FLINT 
study with farnesoid X receptor (FXR) agonist obeticholic acid showed that with reductions in 
LFC of 30%, there were greater odds of histologic response based on 2-point nonalcoholic fatty 
liver disease (NAFLD) activity score reduction.2  
A randomized, double-blind, placebo-controlled study with recombinant injected fibroblast 
growth factor 19 (FGF19) drug NGM282 for 12 weeks showed robust efficacy with -9.7% 
to -11.9% significant absolute LFC changes assessed via MRI-PDFF, as compared to -0.9% for 
placebo.3 An extension of this main study with a small group of patients (n = 22) who were 
assessed with paired MRI-PDFF and liver histology at baseline and Week 124 adds to the growing 
body of evidence showing how improvements in LFC may translate into histological changes. 
Improvements in liver histology are accepted surrogate endpoints for registration studies because 
they eventually translate to lower rates of liver transplant and liver disease progression. While 
there have not been enough studies conducted to demonstrate with scientific certainty that 
improvements in LFC assessed by noninvasive measurements, like MRI-PDFF, lead to clinically 
relevant outcomes, MRI-PDFF is an accepted endpoint of early stage proof-of-concept NASH 
studies.  
EYP001a is an agonist of the FXR, a key regulator of bile, lipid, and glucose metabolism, currently 
under clinical investigation as a new therapy for a functional cure of chronic hepatitis B virus 
(HBV) infection. In an experimental rodent model of NASH,5 EYP001a analogue def2572 has 
been shown to reduce liver steatosis, inflammation, apoptosis, and fibrosis. Moreover, FXR 
activation with the bile improved the histological features of NASH in patients with noncirrhotic 
NASH.2 
1.1 
Rationale 
The purpose of this Phase 2a study is to assess the effects of EYP001a compared with placebo on 
markers of LFC, inflammation, and fibrosis with respect to safety, tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD), and lipid/metabolic profiles in patients with NASH with likely 
stage F2 to F3 fibrosis. 
EYP001a Phase 1 data in healthy subjects showed that EYP001a was well tolerated after single 
and multiple oral administration from 30 to 800 mg (single ascending dose) and from 60 to 500 mg 
(multiple ascending dose). After single administration of EYP001a up to 500 mg, maximum 
observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) 
from time 0 to infinite time seemed linear, but increased less than proportionally at the single-dose 


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level of 800 mg. After multiple administrations, Cmax and AUC increased less than proportionally 
to the dose. In general, Cmax and AUC were lower after repeated administrations compared to 
single administration. EYP001a elimination was on average fast: apparent elimination half-life 
associated with the terminal slope of the semilogarithmic EYP001a concentration-time curve was 
around 2 to 3 hours, with a tendency for faster elimination after multiple dosing. In 11 patients 
with chronic HBV infection randomized to 4 cross-over single-dose oral treatment periods 
receiving 300 mg EYP001a fasted or fed, either in the morning or evening, the relative EYP001a 
bioavailability and FXR-related PD were assessed. EYP001a PK in HBV patients seemed to be 
slightly influenced by food, with a delay of a few hours (ie, time to reach Cmax [Tmax]) in the 
absorption process, leading to a lower Cmax. EYP001a exposure (ie, AUC) appeared to be higher 
under food conditions, but the variability of EYP001a PK and the small number of patients (n = 11) 
prevented a demonstration of bioequivalence on Cmax, AUC from time 0 to the time of the last 
quantifiable concentration, and AUC. Finally, for all dosing conditions, despite similar rapid 
EYP001a elimination, FGF19 and 7αhydroxy-4-cholesten-3-one (C4) showed a prolonged FXR 
target engagement over at least 24 hours, which was not influenced by fasting or fed condition or 
by morning or evening administration. 
Figure 1. Effects of Food Intake on EYP001a Pharmacokinetic Parameters  
 
AUC = area under the plasma concentration-time curve; AUClast = area under the plasma concentration-time curve from time 0 to 
the last quantifiable concentration; CI = confidence interval; Cmax = maximum observed plasma concentration; 
PK= pharmacokinetic; vs = versus. 
Population PK/PD models linking EYP001a and FGF19, and C4 plasma concentrations originating 
from Phase 1 data (Studies EYP001-C01, EYP001-102, EYP001-103, and EYP001-104) were 
built. The PK model reflects an absorption phase slowed down by food intake (an increase of Tmax 
and slight decrease of Cmax) but with similar bioavailability. Pharmacodynamic modeling for C4 
and FGF19 shows that C4 baseline production follows a circadian rhythm (periodicity = 12 hours) 
with no link with FGF19 production. An indirect response model with inhibition of C4 production 


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by EYP001a was simulated. The FGF19 baseline was impacted by meal intake. An indirect 
response model with stimulation of the FGF19 production by EYP001a was simulated.  
Figure 2. Plasma C4 and FGF19 Concentrations From Day 27 – EYP001a 100 mg BID 
Purple curves are simulated profiles with EYP001a administered 100 mg BID (red arrows indicate 7:00 am and 6:00 pm dosing) 
with food (blue arrows indicate meals). Black curves are placebo, ie, physiological changes. 
BID = twice daily; C4 = 7αhydroxy-4-cholesten-3-one; FGF19 = fibroblast growth factor 19; vs = versus. 
Figure 3. Plasma C4 and FGF19 Concentrations at Day 27 – EYP001a 200 mg QD 
Purple curves are simulated profiles with EYP001a administered 200 mg QD (red arrows indicate dosing at 7:00 am) with food 
(blue arrows indicate meals). Black curves are placebo, ie, physiological changes. 
C4 = 7αhydroxy-4-cholesten-3-one; FGF19 = fibroblast growth factor 19; QD = once daily; vs = versus. 


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Figure 4. Plasma C4 and FGF19 Concentrations From Day 27 – EYP001a 400 mg QD 
Purple curves are simulated profiles with EYP001a administered 400 mg QD (red arrows indicate dosing at 7:00 am) with food 
(blue arrows indicate meals). Black curves are placebo, ie, physiological changes. 
C4 = 7αhydroxy-4-cholesten-3-one; FGF19 = fibroblast growth factor 19; QD = once daily; vs = versus.  
The maximal reduction of PD biomarker C4 (approximate levels of 2 to 3 ng/mL) reflecting FXR 
engagement was already reached with 100 mg twice daily (BID) dosing and was not further 
decreased with higher doses. As expected, increasing the EYP001a dose increased PD biomarker 
FGF19 concentrations, but without having an additional substantial effect on C4 concentrations. 
Comparing a cumulative similar dose administered over 24 hours (ie, 400 mg once daily [QD] 
versus 200 mg BID), it appears that the dosing regimen of EYP001a decisively impacts C4 levels, 
with a return to baseline with both QD regimens. Fibroblast growth factor 19 response was, 
however, more impacted by the time of dosing (morning dosing versus evening dosing); the FGF19 
Cmax was the highest with 400 mg QD morning dosing. 
Based on the exploratory graphical EYP001a PK analysis of the effect of estimated glomerular 
filtration rate (eGFR) (computed from the Modification of Diet in Renal Disease [MDRD] 
formula6), an eGFR between 60 and 89 mL/min/1.73 m2 could potentially decrease the EYP001a 
apparent clearance by approximately 10%. Because the elimination pathway of EYP001a is mainly 
via liver metabolism, as investigated in animal and in vitro human hepatocyte studies and the 
known relative bioavailability dose-dependent 20% to 50% decrease after repeated 
administrations, an influence of a mild renal impairment on EYP001a elimination (corresponding 
to an eGFR reduction to 60 to 89 mL/min/1.73 m2) is considered minor and not clinically 
meaningful. Overall, in patients with mild renal impairment, the risk of observing any clinically 
relevant increase in exposure of EYP001a at the highest dose to be tested in this study (ie, 400 mg 
QD), is very unlikely. EYP001a was safe and well tolerated with a proportional increase up to 
500 mg QD. In this study, dosing up to 400 mg QD in patients with mild renal impairment is not 
expected to present a risk to patient safety and will contribute (via sparse PK sampling) to the 
existing population PK model, thus helping to refine PK profiling in patients with mild renal 
impairment. 
Taken together, the Phase 1 data combined with a PK/PD population simulation model support the 
doses and dosing regimen selected for this study. The results of this study are expected to support 
the conduct of a pivotal study to explore the efficacy of EYP001a for NASH for an a priori 
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1.2 
Risk/Benefit 
1.2.1 
Phase 1 Experience in Healthy Subjects and Patients With Chronic Hepatitis B Virus 
Infection 
Overall, in 4 Phase 1 studies, including 3 completed studies (EYP001-C01, EYP001-102, and 
EYP001-104) and in 1 study that is clinically complete but pending the clinical study report 
(EYP001-103; data as of 27 August 2018), EYP001a has been safe and well tolerated and showed 
engagement of FXR with pharmacology effects expected to be related to the hepatobiliary system 
and lipid metabolism. 
From the available data, no off-target effect has been demonstrated. In healthy human subjects and 
patients with chronic HBV infection, no clinically significant changes in safety laboratory 
parameters were observed with 15 days of repeated oral doses of EYP001a from 60 to 500 mg QD. 
Gastrointestinal adverse events (nausea, dyspepsia, diarrhea, and vomiting) were mostly seen with 
high doses, were short-lasting, and exclusively mild with few of moderate intensity. There were 
no clinically significant changes in vital signs or 12-lead electrocardiograms (ECGs). EYP001a 
showed no potential for QT prolongation in QT-EYP001a concentration analysis, performed per 
the recent International Council on Harmonisation (ICH) Guidance for concentration-response 
analysis.7  
Study EYP001-103 determined the safety and tolerability of 4-week oral administration of 
EYP001a in patients with chronic HBV infection when given as monotherapy (Part A) or in 
combination with pegylated interferon alpha-2a (Part B). Oral doses of 300 mg QD, 400 mg QD, 
200 mg BID, and 150 mg BID showed isolated increases in alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) (ie, without changes in bilirubin, alkaline phosphatase [ALP], 
or gamma-glutamyltransferase [GGT]) in 15 of 33 Part A patients and in 10 of 25 Part B patients. 
Grade 3/4 transient ALT/AST increases were observed in 3 patients: in 2 of these patients, the 
increases were attributed to hepatic flare; results in the third patient were not consistent with 
hepatic flare. Grade 1 increases in ALT/AST were observed in another 11 patients. Of the 10 of 
25 patients in Part B with elevated liver function test values, 3 patients were in the placebo plus 
pegylated interferon group, 3 patients were in the EYP001a 150 mg BID group, and 4 patients 
were in the EYP001a 300 mg QD group. Alanine aminotransferase/AST elevations occurred in 
patients with chronic HBV infection, and 8 patients in the study had values above the upper limit 
of normal (ULN) at screening or predose. They also occurred when starting antiviral therapy. 
Therefore, ALT/AST changes were expected in Study EYP001-103 and were not interpreted as a 
sign of liver toxicity. 
1.2.2 
Experience in Nonalcoholic Steatohepatitis 
After database lock of Part A of the current protocol, EYP001-202, an unscheduled interim 
analysis was performed on all endpoints collected on the 24 patients enrolled in the Safety Run-in 
Cohort. The review showed that EYP001a was safe in male and female NASH patients with stage 
F2 to F3 fibrosis. The most frequent (>20% in any treatment group) treatment-emergent adverse 
events (TEAEs) were pruritus and nausea. Nausea occurred in 2 of 6 (33.3%) patients in the 
400 mg QD dose group, nausea was not experienced by patients in other dose groups. Pruritus 
reported by Investigators occurred in 5 of 6 (83.3%) patients in the 100 mg BID dose group, 3 of 
5 (60.0%) patients in the 200 mg QD dose group, 5 of 6 (83.3%) patients in the 400 mg QD dose 
group, and no (0%) patients in the placebo group, although 4 of 7 (57.1%) patients in the placebo 


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group reported pruritus on the visual analog scale. Interestingly, patients receiving the 200 mg QD 
EYP001a dose reported less intense pruritus (Figure 5). 
Figure 5. Pruritus Intensity Reported by Patient on the Visual Analogue Scale (0 to 10) 
Over the Treatment Period (AUC Integrated and Normalized) 
 
AUC = area under the plasma concentration-time curve; BID = twice daily; ITT = Intent-to-Treat; LS = least square; NS = not 
significant; QD = once daily; SE = standard error.  
In the pooled analysis of all EYP001 subjects with pruritus, it appeared that NASH subjects who 
early-terminated their participation due to pruritus experienced pruritus during the first week, 
while NASH subjects who completed their participation experienced pruritus later (Figure 6). 


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Figure 6. Pruritus Onset in Days for Intent-to-Treat Population 
 
ITT = Intent-to-Treat; SD = standard deviation. 
A higher than expected pruritus rate in NASH subjects was observed during Part A of this study, 
compared to tolerability results from previous clinical studies of EYP001a in healthy subjects and 
patients with chronic HBV infection. This increased pruritus rate is explained by a higher than 
expected plasma exposure of EYP001a in NASH patients. Two reasons are imputed for this 
increased exposure. The first is the use of a new galenic tablet formulation with significantly higher 
bioavailability compared to the previously used capsules. The second is an approximately 25% 
higher exposure in NASH patients compared to healthy subjects, see Section 5.2. No unexpected 
or out of target organ TEAEs were observed. 
Two Grade 3 (1 in the 100 mg BID dose group and 1 in the 400 mg QD dose group) and 1 Grade 2 
(in the 100 mg BID dose group) elevations of transaminases were observed around Week 8 without 
signs of liver impairment (ie, no signs or symptoms of acute liver failure, protein synthesis, 
bilirubin, or glucose metabolism dysfunction) or drug-induced liver injury. Of note, 5 of 
7 (71.4%) subjects in the placebo group versus 3 of 5 (60.0%) subjects in the 200 mg QD EYP001 
group had ALT values >1  ULN. However, none of these subjects had elevations of transaminases 
defined as Grade 2 (or higher). Increases in ALT >3  ULN were seen in 4 of 24 (16.7%) subjects 
(1 in the placebo group) in Part A, which compares to a similar rate reported recently with other 
FXR agonists under development (eg, 11.8% in the Tropifexor Phase 2 study).8 Of note, 2 of 


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3 (66.7%) subjects with Grade 2 or 3 ALT increases had a body mass index (BMI) >40 kg/m2 
(55.2 and 40.5 kg/m2) and 1 had a BMI of 38.6 kg/m2 at screening. The nature of obesity-related 
health risks is similar in all populations, although the specific level of risk associated with a given 
level of obesity may vary with race/ethnicity, age, gender, and societal conditions. Disease risk for 
cardiovascular disease is highest in subjects with extreme obesity (Class III BMI 40 kg/m2). Body 
mass index correlates with total body fat on a population basis; however, it has limitations in 
predicting excess body fat associated with health risk on an individual basis. Overall the BMI 
upper limit of >45 kg/m2 leading to exclusion was, therefore, added to the enrollment criteria. 
In an ongoing Phase 1 study (EYP001-107), 10 NASH subjects were exposed over 9 days to the 
same EYP001a dose levels and formulation as those tested in Part A of this study (EYP001-202). 
The EYP001a formulation is detailed in Section 3.3, Drug Product, of the Investigator’s Brochure. 
Preliminary results indicate no changes in liver enzymes. 
No signs of muscle toxicity (creatine kinase [CK] increase) were observed, despite the finding that 
more than 50% of patients were on stable statin therapy during EYP001 therapy. This confirmed 
the Sponsor’s expectation that the coadministration of EYP001a with pravastatin, rosuvastatin, 
simvastatin, or atorvastatin, which are substrates for organic anion transporting polypeptides 1B1 
and 1B3, is appropriate for EYP001a, with no clinically meaningful drug-drug interactions to be 
expected.  
Finally, despite the small sample size of the Safety Run-in Part A Cohort, EYP001a met the 
primary endpoint with a significant and clinically meaningful LFC reduction (-6.3% absolute 
reduction and -35.3% relative reduction in the pooled analysis, driven by the 200 mg QD and 
400 mg QD doses). In addition, EYP001a significantly reduced weight and waist circumference, 
and improved liver biology (ALT from Week 1 to Week 4 and GGT throughout treatment) and the 
noninvasive imaging fibro-inflammatory biomarker (iron-corrected T1 [cT1]), all related to NASH 
severity. 
1.2.3 
Overall Risk/Benefit 
Overall, clinical data from Phase 1 and preliminary Phase 2 NASH studies showed that EYP001a 
was safe at oral doses up to 500 mg QD, administered over 2 (highest dose 500 mg QD) to 
12 weeks (highest dose 400 mg QD). Oral dosing with 400 mg QD and 100 mg, 150 mg, or 200 mg 
BID, however, led to a significant increase in pruritus episodes. NASH patients treated with the 
200 mg QD EYP001a dose interestingly reported less intense pruritus (Figure 5). 
Four Grade 3/4 transient ALT/AST increases were observed in HBV patients (2 were attributed to 
hepatic flares and 2 were consistent with changes expected in chronically infected HBV patients 
when starting antiviral therapy). In F2 to F3 NASH patients, 2 Grade 3 (1 in the 100 mg BID dose 
group and 1 in the 400mg QD dose group) and 1 Grade 2 (100 mg BID dose group) elevations of 
transaminases were observed. No elevation of transaminases was observed in the EYP001a 
200 mg QD dose group. Similar rates of elevations of transaminase were reported with other FXR 
agonists under development. Although such changes are known to occur in NASH patients, either 
due to an acute, transient, not identified toxin, like alcohol, or in connection with excessive eating 
associated with hepatocellular injury in obese patients,9 a causal relationship between 
investigational drug EYP001a and ALT/AST increase cannot be excluded. Therefore, patients will 
be carefully monitored every 2 weeks for clinical and liver laboratory assessments (AST, ALT, 
total bilirubin, and ALP) with the stopping rules applied as outlined in the Clinical Safety 


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Monitoring Plan (Appendix E). In Part B, the Data Safety Monitoring Committee (DSMC) will be 
promptly notified for further review if any patients experience ALT, AST, or bilirubin elevations 
2  above baseline values. 
In line and within the range of reported changes for other investigational FXR agonists, as well as 
the Food and Drug Administration (FDA) and European Medicines Agency-approved FXR agonist 
OCALIVA® (synthetic bile salt), EYP001a may modify lipid blood profiles. This appears to be a 
class effect with an unknown risk in the long term and requires monitoring in patients considered 
for chronic treatment with an FXR agonist. The potential risks of long-term high-density 
lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C) profile modifications 
need to be weighed against the possible therapy benefits – additional information from ongoing 
and future studies will be sought for a complete and accurate determination of this potential risk. 
Overall, based on available nonclinical and clinical data for EYP001a, prior knowledge with other 
FXR agonists showing favorable effect on liver growth and regeneration and prevention or 
resolution of liver fibrosis, and the preliminary safety and positive efficacy results from Part A of 
the study, the risk/benefit profile of EYP001a is judged as acceptable for further exploration in 
patients with NASH. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to determine the efficacy and safety profiles of EYP001a versus placebo 
on LFC from baseline to Week 12 in patients with NASH.  
2.2 
Secondary Objectives 
The secondary objectives are the following: 
 To explore the PK of EYP001a 
 To evaluate PD effects of EYP001a on bile acid-related markers as appropriate  
 To assess the effects of EYP001a on lipid and metabolic profiles 
 To assess the safety of EYP001a with statin coadministration 
 To assess the effects of EYP001a on noninvasive biomarkers of liver fibrosis and inflammation 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a 2-part, randomized, double-blind, multicenter, placebo-controlled study to evaluate the 
safety and efficacy of EYP001a in patients with NASH who likely have stage F2 to F3 fibrosis at 
approximately 50 global clinical sites. Overall, approximately 114 eligible patients will be 
enrolled: 24 patients in Part A (Safety Run-in Cohort), followed by 90 patients in Part B. 
In Part A, 24 patients will be randomized on Day 1 to 1 of 4 parallel treatment groups: 100 mg 
EYP001a BID, 200 mg EYP001a QD, 400 mg EYP001a QD, or placebo BID. In Part B, 90 patients 
will be randomized on Day 1 to 1 of 3 parallel treatment groups: 100 mg EYP001a QD, 200 mg 
EYP001a QD, or placebo QD. 
Randomization will be stratified by statin use (yes, no) and type 2 diabetes mellitus (T2DM) status 
(yes, no) at screening in Part A, and by statin use (yes, no) and LFC (stratification factor with 
3 categories: LFC <16%, 16%LFC<22%, and 22%LFC) in Part B at screening. 
The following sequence of screening procedures will be applied to each patient who signs an 
informed consent form (ICF): 1) eligibility based on clinical and biological inclusion and exclusion 
criteria; 2) eligibility based on FibroScan criteria as described in Inclusion Criterion 3; and 
3) confirmation of eligibility based on MRI-PDFF results. A patient who is first designated as a 
screen failure prior to being randomized may be rescreened upon Sponsor or designee approval. If 
the patient was screen failed after the MRI-PDFF was completed, the original MRI-PDFF scan 
may be utilized for rescreening, provided it was obtained within 1 month prior to rescreening.  
For a schematic of the study design, see Figure 7. 
Figure 7. Study Design 
 
BID = twice daily; D = Day; DSMC = Data Safety Monitoring Committee; QD = once daily; Wk = Week.  
This study will consist of 2 parts: Part A will include a Safety Run-in Period during the Treatment 
Period. Screening for Part B will begin after completion of data review on the Safety Run-in Period 


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of Part A and recommendation from the DSMC. The first 24 eligible patients (approximately 
6 randomized patients in each group) will be assessed during the Safety Run-in Period with a 
frequent monitoring schedule (weekly visits during the first month of treatment and visits every 
4 weeks thereafter during the remainder of the Treatment Period) and intense PK profiling on 
Days 1 and 14. Sparse PK sampling will be performed during all other study visits.  
Part A (Safety Run-in Cohort) 
Participation in Part A of the study will consist of a Screening Period (up to 12 weeks prior to 
Day 1), a 12-week Treatment Period, and a Follow-up Visit at Week 14; total study duration is up 
to 182 days. All eligibility criteria must be confirmed prior to dosing on Day 1.  
The 12-week Treatment Period in Part A will include 7 study visits on the following days: Days 1, 
7, 14, 21, 28, 56, and 84. Clinical, hematological, chemical, PD, and PK parameters will be 
assessed throughout the study. Intense PK/PD profiling on Days 1 and 14 will require 12-hour 
inpatient monitoring and 24-hour post-morning dose blood collection. Safety and tolerability 
assessments will include the monitoring of adverse events; adverse events of special interest 
(AESIs) (ie, pruritus, drug-induced liver injury, and all muscle-related adverse events); serious 
adverse events (SAEs); and findings from physical examinations, vital signs, ECGs, and clinical 
laboratory parameters.  
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed 
in the Clinical Safety Monitoring Plan (Appendix E). All adverse events will be assessed and 
reported using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 grading system. Additional safety measurements will be performed at the 
discretion of the Investigator (or delegate). Except during the Safety Run-in Period, plasma from 
blood samples will be collected at each visit and stored for protocol-related safety testing or 
exploratory analyses. 
Part B (Remaining Patients) 
Patients in Part B will be randomized on Day 1 to 1 of 3 parallel treatment groups: 100 mg 
EYP001a QD, 200 mg EYP001a QD, or placebo QD, with approximately 30 patients in each 
group. Pruritus-related tolerance issues will be addressed by a 2-step study drug titration strategy 
for the highest dose treatment group (ie, 200 mg QD): all patients randomized to an active 
treatment group will start with an initial dose of 100 mg QD for the first 2 weeks of treatment 
(Days 1 to 14). Patients randomized to the 200 mg QD treatment group will be uptitrated to 200 mg 
QD starting Day 15 until Day 84, while patients randomized to the 100 mg QD treatment group 
will maintain a 100 mg QD dose throughout their participation. The study treatment assignment 
strategy will ensure that blind is maintained. 
Randomization will be stratified by statin use (yes, no) and LFC (stratification factor with 
3 categories: LFC<16%, 16%LFC<22%, and 22%LFC) at screening. 
Participation in Part B of the study will consist of a Screening Period (up to 12 weeks prior to 
Day 1), a 12-week Treatment Period, and a Follow-up Visit at Week 14; total study duration is up 
to 182 days. All eligibility criteria must be confirmed prior to dosing on Day 1. 
The 12-week Treatment Period in Part B will include 7 study visits on the following days: Days 1, 
14, 28, 42, 56, 70, and 84. Clinical, hematological, chemical, PD, and PK parameters will be 


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assessed throughout the study. The safety and tolerability assessments will include the monitoring 
of adverse events; AESIs (ie, elevation of transaminases and all muscle-related adverse events); 
SAEs; and findings from physical examinations, vital signs, ECGs, and clinical laboratory 
parameters.  
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed 
in the Clinical Safety Monitoring Plan (Appendix E). All adverse events will be assessed and 
reported using the National Cancer Institute CTCAE Version 5.0 grading system. Additional 
safety measurements will be performed at the discretion of the Investigator (or delegate). At 
screening and on Days 1, 14, 28, 56, and 84; and at the End of Study (EOS) and Early Termination 
(ET) Visits, plasma from blood samples will be stored for protocol-related safety testing or 
exploratory analyses. 
Data Safety Monitoring Committee and Interim Analyses 
An external, independent DSMC will review all available unblinded preliminary safety, PK, and 
PD results when any stopping rules are met, per the Clinical Safety Monitoring Plan (Appendix E). 
In Part B, the DSMC will be promptly notified for further review if any patients experience ALT, 
AST, or bilirubin elevations 2  above baseline values. 
In addition, all available unblinded preliminary safety, PK, and PD results will be comprehensively 
reviewed during 2 interim analysis timepoints: 
 The first interim analysis will be performed at the end of the Safety Run-in Period, after the 
last of the 24 patients randomized in Part A has completed Day 28 (Week 4). It is anticipated 
that at the time of the first interim analysis, approximately 10 patients will have completed 
Day 84 (Week 12) of Part A.  
 A second interim analysis will be performed when 50% of patients in Part B have completed 
Day 56 (Week 8). 
The interim analyses will be performed on all available primary and secondary endpoints 
according to the DSMC charter, which describes the overall guidelines, composition, roles, and 
responsibilities of the independent DSMC for this study, including the selection of DSMC 
members, timing of meetings, methods of providing information to and from the DSMC, frequency 
and format of meetings, data analysis recommendations, and DSMC relationships with other 
parties participating in the conduct of this study. Patient accrual will continue throughout the 
period of DSMC review. The DSMC will advise on the accrual of the remaining patients per 
protocol or on any amendments that are necessary for safety reasons. 
Efficacy Assessments 
Liver fat content will be assessed by MRI-PDFF using a standardized imaging acquisition 
calibration protocol10 and central readings will be performed at screening (as baseline value) and 
Week 12. The ET assessment will be performed only for patients on study drug for 4 weeks. 
Imaging for cT1 will be assessed centrally; T1 mapping allows in vivo tissue characterization, and 
measurements can be adjusted for the iron level, as high iron levels in the presence of fibrosis can 
lead to “pseudo-normal” T1, yielding an unbiased cT1. This noninvasive test has shown good 
correlation with histological liver fibrosis in a cohort of patients with mixed liver disease etiologies 


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undergoing clinically indicated liver biopsy11 and has been shown to correlate with 
fibro-inflammatory disease and predict clinical outcomes in patients with chronic liver disease.12 
Harrison et al showed that cT1 correlated with NAFLD activity score (p=0.514, p<0.001) and 
accurately identified patients with steatosis, stratified those with NASH or simple steatosis, and 
reliably excluded clinically significant liver disease with superior negative predictive value 
(83.3%) to liver stiffness (42.9%) and enhanced liver fibrosis score (57.1%). Furthermore, the 
experimental NASH drug NGM282 was recently reported to correlate histological NASH 
improvement with cT1 readout and improve fibrosis and NASH-related histology in 12 weeks in 
patients with biopsy-confirmed NASH, which is preceded by significant decreases in hepatic 
steatosis, liver transaminases, and fibrosis markers at 6 weeks.13 See Banerjee et al for further 
support of the relevance of T1 mapping technique for ﬁbrosis.14  
The anticipated EYP001-202 efficacy results will serve as validation of an in silico NASH disease 
model, which was built based on public and expert knowledge and combined with the Phase 1 PK 
and PD EYP001 results.15 The model integrates 309 liver FXR-related biological variables and 
1320 parameters and explores the effect of different EYP001 treatment regimens on 
NASH-relevant efficacy endpoints in a virtual population. Iterations of the model will support 
future explorations of development strategies with different EYP001 Phase 2 and 3 study designs. 
3.2 
Stopping Rules  
Dosing of a patient may be discontinued for any of the following events:  
 One occurrence of an SAE assessed to be definitely or probably related to dosing with the 
study drug. See Section 9.1.3. 
 Confirmation of any of the study drug discontinuation criteria as described in the Clinical 
Safety Monitoring Plan (Appendix E). 
 CK 5  ULN. 
 Signs/symptoms of acute coronary syndrome. 
 Confirmed cardiac troponin I concentration increase (performed centrally) from baseline and 
>ULN. 
 Occurrence of any condition that, in the opinion of the Investigator, significantly jeopardizes 
the wellbeing and safety of the patient and is assessed to be probably related to dosing with the 
study drug. 
 Clinically significant changes in vital signs or ECGs (such as arrhythmias) or in the safety 
laboratory tests assessed to be probably (ie, no alternative explanation likely) related to dosing 
with the study drug. A “possible” relationship is not considered to require a suspension of 
treatment. 
If 2 or more patients meet study drug stopping criteria, dosing should be suspended or terminated 
for the remaining patients. The DSMC must review all safety data and provide clearance prior to 
dosing any additional patients.  
For clinical sites in the United Kingdom or European Union, in the case of study halt, the study 
may only be restarted after Medicines & Healthcare Products Regulatory Agency or National 
Competent Authority approval, respectively, via a substantial protocol amendment. 


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If a patient experiences a Grade 5 CTCAE toxicity, or if more than 2 patients develop a Grade 3 
CTCAE toxicity in the same category, the study will be paused and safety reports will be submitted 
to the DSMC for review and clearance prior to dosing any additional patients. 
Reinitiation of study drug may be considered after consultation with the Medical Monitor.  
3.3 
Study Indication 
The indication for this study is the treatment of patients with NASH.  


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 
Screening Strategy 
The following sequence of screening procedures will be applied to each patient who signs an ICF: 
1) eligibility based on clinical and biological inclusion and exclusion criteria; 2) eligibility based 
on FibroScan criteria as described in Inclusion Criterion 3; and 3) confirmation of eligibility 
based on MRI-PDFF results.  
A patient who is first designated as a screen failure prior to being randomized may be rescreened 
upon Sponsor or designee approval. If the patient was screen failed after the MRI-PDFF was 
completed, the original MRI-PDFF scan may be utilized for rescreening, provided it was obtained 
within 1 month prior to rescreening. 
4.2 
Inclusion Criteria 
A patient who meets all of the following criteria will be eligible to participate in the study: 
1. Provides signed written informed consent and agrees to comply with the study protocol. 
2. Is a male or female aged 18 years or older.  
3. Has a suspected diagnosis of NASH during the Screening Period (up to 12 weeks before 
dosing), defined as follows:16,17  
a. Baseline serum ALT and AST should be established by at least 2 samples obtained at least 
4 weeks and no more than 12 weeks apart. One sample can be obtained from the patient’s 
medical history and 1 sample can be obtained during the Screening Period, or both samples 
can be obtained during the Screening Period. If the values of ALT or AST in both samples 
are within normal ranges, the variability of the marker is assumed adequate for 
randomization. If the values of ALT or AST are higher than normal values, the patient will 
be eligible for enrollment provided the increase from the first to second sample is 40%. 
If the values from sample 1 are higher than those from sample 2 (ie, there is a decrease), 
the patient will be eligible despite a >40% difference. A third sample can be collected if an 
increase from sample 1 to sample 2 exceeds the 40% limit. If sample 3 exceeds the 
40% limit (compared to sample 1), this increase shall prompt the search for clinical signs 
or symptoms of liver impairment, and the patient will not be eligible for enrollment. 
Baseline AST values should be >20 U/L. See Appendix I for central laboratory normal 
reference ranges. 
b. Normal average baseline levels of ALP. See Appendix I for central laboratory normal 
reference ranges. Total bilirubin (TBL) levels should be 22.2 mol/L (1.3 mg/dL). 
Note: Baseline serum ALP and TBL should be established by at least 2 samples obtained 
at least 4 weeks and no more than 12 weeks apart. One sample can be obtained from the 
patient’s medical history and 1 sample can be obtained during the Screening Period, or 
both samples can be obtained during the Screening Period. If the values of ALP or TBL in 
both samples are within normal ranges, the variability of the marker is assumed adequate 
for randomization. If the values of ALP or TBL are higher than normal values, the patient 
will be eligible for enrollment provided the increase from the first to second sample is 
40%. If the values from sample 1 are higher than those from sample 2 (ie, there is a 
decrease), the patient will be eligible despite a >40% difference. A third sample can be 


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collected if an increase from sample 1 to sample 2 exceeds the 40% limit. If sample 3 
exceeds the 40% limit (compared to sample 1), this increase shall prompt the search for 
clinical signs or symptoms of liver impairment, and the patient will not be eligible for 
enrollment. 
c. Liver stiffness compatible with liver fibrosis stage F2 or F3 determined by FibroScan 
vibration-controlled transient elastography assessment cut-off value 8.5 kPa. 
d. FibroScan controlled attenuation parameter (CAP) for steatosis with cut-off values 
>300 dB/m. 
Note: Patients do not need to undergo a CAP assessment if their medical records indicate 
an MRI-PDFF LFC 10% within 12 months prior to screening. 
Note: Histology within 12 months prior to screening will supersede FibroScan entry criteria 
if the following criteria are met: NASH with fibrosis stage F2 to F3, defined as portal 
fibrosis with few septa (F2) or bridging septa between central and portal veins (F3), and 
NAFLD activity score 4, including a minimum of 1 point each for ballooning and 
inflammation. However, if a patient participated in a previous study with a NASH 
investigational drug between 365 and 60 days prior to being screened for this study, the 
histology information will only be considered if the biopsy was performed after the end of 
the patient’s participation in the previous study. 
e. LFC 10% as measured by MRI-PDFF. 
4. Is not of childbearing potential (as defined in Inclusion Criterion 5) or, if of childbearing 
potential, is not pregnant as confirmed by a negative serum human chorionic gonadotropin 
(hCG) test at screening and is not planning a pregnancy during the course of the study. 
5. Women of childbearing potential and male patients with female partners must agree to use 
highly effective birth control throughout the duration of the study and for 90 days after stopping 
study drug. Patients who are using hormonal contraceptives or intrauterine devices should be 
instructed to use an additional barrier contraceptive measure during the study such as a male 
or female condom with spermicide or diaphragm. Highly effective is defined as birth control 
methods that result in a failure rate of <1% per year when used consistently and correctly. 
Methods of highly effective birth control include the following: 
a. Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation. 
 Oral.  
 Intravaginal.  
 Transdermal.  
b. Progesterone-only hormonal contraception associated with inhibition of ovulation. 
 Oral.  
 Injectable.  
 Implantable.  
c. Intrauterine device.  


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d. Intrauterine hormone-releasing system.  
e. Vasectomized partner (provided that the partner is the sole sexual partner of the woman of 
childbearing potential). 
f. Sexual abstinence (complete abstinence from sexual intercourse if this is the patient’s usual 
and preferred lifestyle). 
Note: A woman is considered of childbearing potential following menarche and until becoming 
postmenopausal unless permanently sterile. A postmenopausal state is defined as no menses 
for 12 consecutive months without an alternative medical cause. A follicle-stimulating 
hormone level in the postmenopausal range will be used to confirm a postmenopausal state in 
women 55 years of age. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
4.3 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from participation in the study: 
1. Is an employee of a clinical research organization, vendor, or Sponsor involved with this study. 
2. Has known non-NASH liver disease, including, but not limited to, alcoholic liver disease, 
autoimmune disease, human immunodeficiency virus (HIV), HBV, active hepatitis C virus 
(HCV), Wilson’s disease, hemochromatosis, primary biliary cholangitis, primary sclerosing 
cholangitis, drug-induced liver injury, bile duct obstruction, or suspected or known liver 
cancer. 
Note: HCV antibody (HCV Ab) positive individuals are not eligible, with the following 
2 exceptions: (a) Patients previously treated with a registered drug for viral hepatitis C with at 
least a 1-year period since documented sustained virologic response may be eligible if HCV 
ribonucleic acid (RNA) is below the limit of detection (LOD) and if all other eligibility criteria 
are met, and (b) patients with presence of HCV Ab if HCV RNA is below the LOD at screening 
without treatment (ie, spontaneous clearance) may be eligible if all other eligibility criteria are 
met.  
3. Has history of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or 
presence of esophageal varices. 
4. Has known history of alcohol abuse or daily heavy alcohol consumption (females: more than 
14 units of alcohol per week; males: more than 21 units of alcohol per week [1 unit of alcohol 
is equivalent to a half pint of beer {285 mL}, 1 measure of spirits {25 mL}, or 1 glass of wine 
{125 mL}]). Has an Alcohol Use Disorders Identification Test-Concise (AUDIT-C) score of 
3 points for men and women AND a full Alcohol Use Disorders Identification Test (AUDIT) 
score of 8 points at screening.  
Note: Only patients with AUDIT-C scores 3 points at screening will receive the full AUDIT 
and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C scores 
<3 points will not receive the full AUDIT. 
5. Has Gilbert’s syndrome with direct bilirubin >1  ULN. 
6. Is pregnant or breastfeeding.  


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7. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency 
conditions such as common variable hypogammaglobulinemia. 
8. Has a known preexisting medical or psychiatric condition that could interfere with the patient’s 
ability to provide informed consent or participate in study conduct, or that may confound study 
findings. 
9. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular 
disease within 90 days prior to the first study drug administration, including, but not limited 
to, myocardial infarction, acute coronary syndrome, revascularization (percutaneous coronary 
intervention or coronary artery bypass grafting) or ischemic stroke, or implanted defibrillator 
or pacemaker. 
10. Has participated in any drug study within 90 days prior to the first study drug administration 
in the current study. 
11. Has had major surgery within 90 days prior to the first study drug administration in the current 
study. 
12. Has a history of relevant drug and/or food allergies. The term “relevant” applies if any of the 
following allergy conditions are met: 
a. Has had several episodes of drug-induced urticaria or other immediate allergic signs 
(eg, rhinoconjunctivitis, respiratory) (2 in total at whatever time in medical history and 
with 1 or several drugs). 
b. Has ongoing urticaria episodes (attributed to whatever allergen) or has other active history 
of immediate type reaction allergies (eg, allergic rhinoconjunctivitis, allergic asthma, or 
latex allergy). 
c. Has had a moderate or severe allergic reaction (Grade 2 per the World Allergy 
Organization reference table, ie, urticaria alone with a Grade 1 is not relevant). 
d. Has any allergic condition that might require an emergency epinephrine injection (similar 
to the EpiPen® Auto-Injector). 
13. Has a history of hypersensitivity to the study drug or to any of the excipients or placebo.  
14. Unable to undergo an MRI-PDFF due to: 
a. Contraindication to MRI examination. 
b. Severe claustrophobia impacting ability to perform MRI during the study, despite mild 
sedation/treatment with a short half-life (ie, <20 hours) anxiolytic. 
c. Body weight or girth exceeding the scanner capacities. 
15. Is using any of the following disallowed medications:  
a. Anticancer drug(s), immunomodulator(s), or immunosuppressant(s) within 90 days or 
5 half-lives prior to screening, whichever is longer, or any drug historically associated with 
NAFLD for >2 weeks in the year prior to screening (eg, amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those 
used for hormone replacement, anabolic steroids, or valproic acid or other known 
hepatotoxins at the Investigator or Medical Monitor’s discretion). 


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b. Vitamin E (>400 IU/day), glitazones, glucagon-like peptide-1 receptor agonists, 
ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening. 
c. Agents (including herbal over-the-counter weight loss preparations) or medications known 
to significantly impact body weight within 90 days prior to screening (eg, sibutramine, 
phenetamine, and orlistat). 
d. Bile acid sequestrants (eg, cholestyramine) or lipid-modifying agents (eg, fibrates or 
ezetimibe) other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, or 
lovastatin. 
e. Agents that are substrates for cytochrome P450 (CYP) 2C8 or CYP2C9 and have a narrow 
therapeutic index (eg, warfarin). 
16. Has prior or planned (during the study period) bariatric surgery (eg, gastroplasty or Roux-en-Y 
gastric bypass).  
17. Has type 1 diabetes mellitus. 
18. Has T2DM and hemoglobin A1c >9.5% or has not been on a stable dose of antidiabetic 
medication for at least 90 days prior to screening. 
19. Has had total body weight loss of >5% within 6 months or since a liver biopsy, if applicable. 
20. Has any of the following exclusionary laboratory results at screening:  
a. ALT >5  ULN, AST >5  ULN. 
b. International normalized ratio 1.3, unless on anticoagulant therapy. 
c. Platelet count <lower limit of normal. 
d. eGFR <50 mL/min/1.73 m2 (MDRD formula6).  
e. CK >ULN in patients on concomitant statin therapy and CK >3  ULN in all other patients. 
f. Thyroid-stimulating hormone >1.5  ULN or abnormal free triiodothyronine or free 
thyroxine. 
Note: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor if any of the above laboratory abnormalities are found. 
21. Has history of clinically significant gastrointestinal disease (especially: cholecystectomy prior 
to age 25 years, peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, or 
bariatric surgery); renal, hematologic, endocrine, oncologic, pulmonary, immunologic, or 
cardiovascular disease; neurologic or psychiatric disease (including any use of addictive 
substances such as regular opioid treatment and/or any use of illicit drugs); or any other 
condition, which, in the opinion of the Investigator, would jeopardize the safety of the patient 
or impact the validity of the study results. 
22. Has a BMI >45 kg/m2. 


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4.4 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
 Patient withdrawal of consent or request of discontinuation from the study for any reason 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol 
 Patient meeting any of the stopping rules 
 Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient 
 Pregnancy 
 Requirement of prohibited concomitant medication 
 Patient failure to comply with protocol requirements or study-related procedures 
 Termination of the study by the Sponsor or the regulatory authority 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
ET Visit. The reason for patient withdrawal must be documented in the electronic case report form 
(eCRF). 
In the case of patients lost to follow-up, multiple attempts to contact the patient must be made and 
documented in the patient’s medical records before a patient can be registered as being lost to 
follow-up. Multiple attempts are considered 3 telephone calls. If the patient does not respond, a 
letter must be sent to the patient. If no response is received a month after the letter was sent, the 
patient can be registered as lost to follow-up. 
In general, withdrawn patients will not be replaced during the study. However, during the Safety 
Run-in Period in Part A, withdrawn patients will be replaced if less than 16 of the planned 
24 patients complete the Day 28 Visit. In such a situation, the withdrawn patients will be replaced 
with an appropriate number of new patients to ensure that between 16 and 24 patients complete 
the Day 28 Visit of Part A (ie, complete the Safety Run-in Period).  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Approximately 114 eligible patients with NASH will be randomized. In Part A, 24 patients will be 
randomized into 4 parallel treatment groups as outlined in Table 1. In Part B, 90 patients will be 
randomized into 3 parallel treatment groups as outlined in Table 2.  
Table 1. 
Study Treatment Groups and Dosing Regimens – Part A 
Treatment Group 
Morning Regimen: 2 Tablets [1] 
Evening Regimen: 1 Tablet [2] 
Placebo 
2 tablets of placebo
1 tablet of placebo 
100 mg BID 
1 tablet of 100 mg EYP001a and 1 tablet of 
placebo 
1 tablet of 100 mg EYP001a 
200 mg QD 
2 tablets of 100 mg EYP001a
1 tablet of placebo 
400 mg QD 
2 tablets of 200 mg EYP001a
1 tablet of placebo 
1. 
With breakfast, except during intense PK/PD sampling on Days 1 and 14 of Part A, when dosing will occur with water 
only.  
2. 
With dinner.  
BID = twice daily; PD = pharmacodynamic(s); PK = pharmacokinetic(s); QD = once daily. 
 
Table 2. 
Study Treatment Groups and Dosing Regimens – Part B 
Treatment Group 
Morning Regimen: 1 Tablets [1] 
Placebo 
1 tablet of placebo
100 mg QD 
1 tablet of 100 mg EYP001a 
200 mg QD 
1 tablet of 100 mg EYP001a from Day 1 to Day 14 
1 tablet of 200 mg EYP001a from Day 15 to Day 84 
1. 
With breakfast.  
QD = once daily.  
5.2 
Rationale for Dosing 
EYP001a Phase 1 data in healthy subjects showed that EYP001a was well tolerated after single 
and multiple oral administrations from 30 to 800 mg (single ascending dose) and from 60 to 
500 mg (multiple ascending dose). For all dosing conditions, despite similar rapid EYP001a 
elimination, FGF19 and C4 showed a prolonged FXR target engagement up to at least 24 hours, 
which was not influenced by fasting or fed condition or by morning or evening administration 
(Study EYP001-102). EYP001a was safe in HBV subjects treated over 4 weeks with doses of 
EYP001a 100 mg QD, 150 mg BID, 200 mg QD, 200 mg BID, 300 mg QD, and 400 mg QD. The 
most frequent TEAEs were headache, pruritus, abdominal pain, and diarrhea. Pruritus was mostly 
seen with BID administration and was of mild or moderate intensity and lasted for 5 to 36 days. In 
addition, the QD doses showed better tolerance with few pruritus TEAEs. 
Population PK/PD simulations for C4 and FGF19, based on preliminary modeling, support the 
doses and dosing regimens selected for Part A of this study: 100 mg BID versus 200 mg QD and 
400 mg QD. The expected differences in C4 and FGF19 (AUC at 24 hours) at steady state between 
EYP001a and placebo treatments were assessed in simulations in healthy subjects and in patients 
with chronic HBV infection. The selected regimen and doses suggest that, in NASH patients, 
relevant C4 and FGF19 changes (C4 decrease and FGF19 increase) will occur. Patients with 
NASH were expected to have values that fell between those simulated in healthy subjects and in 
subjects with HBV. 


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The preliminary and unblinded analysis of Part A of the current study, EYP001-202, showed that 
EYP001a was safe in 24 male and female patients with stage F2 to F3 NASH. A higher than 
expected pruritus rate (60% for patients treated with the 200 mg QD dose and 83% for patients 
treated with the 100 mg BID and 400 mg QD doses) was observed. Patients who received 200 mg 
QD EYP001a interestingly reported less intense pruritus as compared to other dose groups (Figure 
5, Section 1.2.2). Also, NASH subjects who early-terminated their participation due to pruritus 
experienced pruritus during the first week, while NASH subjects who completed their participation 
experienced pruritus later (Figure 6, Section 1.2.2). These observations support an EYP001a 
uptitration strategy to improve tolerance of pruritus. 
The higher pruritus occurrence was explained by an unexpected substantially higher EYP001a 
plasma exposure compared to the exposure previously observed in healthy subjects (Table 3 and 
Table 4). This difference can be explained by a different formulation of study drug, with the current 
tablet formulation leading to a higher bioavailability compared to the previously used capsule 
formulation. In addition, an approximately 50% to 79% higher exposure in NASH patients 
compared to healthy subjects was also noted in an ongoing Phase 1 trial (EYP001-107), which can 
be explained by a slower elimination in NASH subjects compared to healthy subjects (Table 5).  
Table 3. 
Study EYP001-202 Part A: Median PK Parameters at Day 1 and Day 14 
PK Visit 
Day 1 
Day 14 
Arm 
Cmax 
(ng/mL)
Tmax 
(h)
AUC0-24h 
(ng.h/mL)
Cmax 
(ng/mL)
Tmax 
(h) 
AUC0-24h 
(ng.h/mL)
200 mg QD NASH (n=5 & 2) 
2220 
4.00
11,983
2875
2.50 
8459
400 mg QD NASH (n=6 & 4) 
3565 
2.00
16,495
2055
1.50 
6897
NOTE: Because of data inconsistencies in the 100 mg BID dosing history, the PK data could not be estimated. 
AUC0-24h = area under the plasma concentration-time curve from time 0 to 24 hours; BID = twice daily; Cmax = maximum 
observed plasma concentration; NASH = nonalcoholic steatohepatitis; PK = pharmacokinetic; QD = once daily; Tmax = time to 
reach the maximum observed plasma concentration.
 
Table 4. 
Study EYP001-C01 Healthy: Median PK Parameters at Day 1 (SAD) and Day 14 
(MAD) 
PK Visit 
Day 1 
Day 14 
Arm 
Cmax 
(ng/mL)
Tmax 
(h)
AUCInf 
(ng.h/mL)
Cmax 
(ng/mL)
Tmax 
(h) 
AUCInf 
(ng.h/mL)
250 mg QD HV (n=6) 
1440 
2.25
5540
946
2.75 
2738
500 mg QD HV (n=6) 
2790 
2.50
10,182
1700
2.50 
5619
AUCInf = area under the plasma concentration-time curve from time 0 to infinite time; Cmax = maximum observed plasma 
concentration ; HV = healthy volunteer; MAD = multiple ascending dose; PK = pharmacokinetic; QD = once daily; 
SAD = single ascending dose; Tmax = time to reach the maximum observed plasma concentration. 
 
Table 5. 
Study EYP001-107: Median PK Parameters at Day 1 and Day 8 
PK Visit 
Day 1 
Day 8 
Arm 
Cmax 
(ng/mL)
Tmax 
(h)
AUC0-24h 
(ng.h/mL)
Cmax 
(ng/mL)
Tmax 
(h) 
AUC0-24h 
(ng.h/mL)
200 mg QD NASH (n=3) 
2350 
4.00
10,365
983
2.00 
4012
400 mg QD NASH (n=4) 
2085 
5.00
20,830
1800
3.13 
9239
400 mg QD HV (n=4) 
2175 
2.03
11,614
1870
3.00 
6115
AUC0-24h = area under the plasma concentration-time curve from time 0 to 24 hours; Cmax = maximum observed plasma 
concentration ; HV = healthy volunteer; NASH = nonalcoholic steatohepatitis; PK = pharmacokinetic; QD = once daily; 
Tmax = time to reach the maximum observed plasma concentration.


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Finally, the PK profile of EYP001a in NASH patients confirmed the known decrease in exposure 
at Day 14: Day 14/Day 1 AUC ratio was 0.4 to 0.7 for the 200 mg QD and 400 mg QD dose 
groups, respectively, and Cmax ratio was 0.6 to 1.3 for the 200 mg QD and 400 mg QD dose groups, 
respectively. No accumulation was noted. A similar decrease in exposure over time was also 
previously seen in healthy subjects (Table 3, Table 4, and Table 5) and in patients with chronic 
HBV infection.  
The safety profiling in Part A showed 2 Grade 3 (1 in the 100 mg BID dose group and 1 in the 
400 mg QD dose group) and 1 Grade 2 (in the 100 mg BID dose group) elevations of transaminases 
around Week 8 without signs of liver impairment (ie, no signs or symptoms of acute liver failure, 
protein synthesis, bilirubin, or glucose metabolism dysfunction) or drug-induced liver injury. Of 
note, 5 of 7 (71.4%) patients in the placebo group versus 3 of 5 (60.0%) patients in the 200 mg QD 
EYP001 dose group had ALT values >1  ULN. However, none of these patients had elevations 
of transaminases defined as Grade 2 (or higher). In Part A, increases in ALT >3  ULN were seen 
in 4 of 24 (16.7%) patients (1 in the placebo group), which compares to a similar rate reported 
recently with other FXR agonists under development (eg, 11.8% in the Tropifexor Phase 2 study).8 
Importantly, in the Part A Safety Run-in Cohort, EYP001a met the primary endpoint with a 
significant and clinically meaningful -6.3% absolute liver fat reduction. EYP001a also 
significantly reduced weight and waist circumference, and improved liver biology (ALT initially, 
and GGT) and the fibro-inflammatory biomarker (cT1), all known to relate to NASH severity. 
Interestingly, the noninvasive biomarker for liver fibro-inflammation (cT1) showed the largest 
improvement in the 200 mg QD EYP001a dose group (-116 msec versus -69 and -43 msec in the 
100 mg BID and 400 mg QD EYP001a dose groups, respectively).  
Overall, the 200 mg QD dose and a new lower 100 mg QD dose will be further tested in Part B of 
this study because they are expected to optimally balance risk/benefit. Pruritus-related tolerance 
issues will be addressed by a 2-step study drug titration strategy for the highest dose treatment 
group (ie, 200 mg QD): all patients randomized to an active treatment group will start with an 
initial dose of 100 mg QD for the first 2 weeks of treatment (Days 1 to 14). Patients randomized 
to the 200 mg QD treatment group will be uptitrated to 200 mg QD starting Day 15 until Day 84, 
while patients randomized to the 100 mg QD treatment group will maintain a 100 mg QD dose 
throughout their participation. The study treatment assignment strategy will ensure that blind is 
maintained. The 100 mg BID and 400 mg QD dose levels will be discontinued. 
5.3 
Randomization and Blinding 
This study follows a randomized, double-blind, placebo-controlled design. Patients in Part A will 
be randomized via the Interactive Response Technology (IRT) system to 1 of 4 parallel treatment 
groups on Day 1 in a 1:1:1:1 ratio. However, prerandomization will occur within the IRT system 
at least 7 days prior to randomization. Patients in Part B will be randomized via the IRT system to 
1 of 3 parallel treatment groups on Day 1 in a 1:1:1 ratio. Prerandomization is not applicable in 
Part B. 
Both EYP001a and placebo will be provided as tablets for oral administration and will be identical 
in appearance. 
Prerandomization/randomization information will be concealed from the Investigators and the 
patients until the end of the study, with the exception of an emergency situation involving a patient 
that required unblinding of the treatment assignment. 


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5.3.1 
Stratification  
Randomization will be stratified by statin use (yes, no) and T2DM status (yes, no) in Part A, and 
by statin use (yes, no) and LFC (stratification factor with 3 categories: LFC<16%, 
16%LFC<22%, and 22%LFC) in Part B at screening. Randomization can occur after eligibility 
check on Day -3, at the earliest, and prior to dosing on Day 1 at the latest. 
5.4 
Breaking the Blind 
Until formal conclusion of the study, patients, Investigators, and all clinical site personnel will 
remain blinded to treatment allocation, except in the event of a medical emergency that necessitates 
unblinding. In the event of a medical emergency, when knowledge of the patient’s treatment 
assignment would influence the patient’s clinical care, the clinical site will be able to unblind the 
patient via the IRT system. In the case of unblinding, the IRT system will send a blinded 
notification to study team members to let them know that a patient was unblinded.  
In preparation for the DSMC meeting, Part A data were unblinded and analyzed by an independent 
statistician and presented to the DSMC. The study team remained blinded during this analysis. 
Due to the DSMC decision to update dosing arms, all Part A data were locked and unblinded data 
were sent to the unblinded Sponsor statistician.  
When 50% of patients have completed the Week 8 visit in Part B, the DSMC will review all 
available primary and secondary endpoints according to the DSMC charter. The conclusions and 
recommendations of the DSMC will be shared blindly with the clinical sites. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The drug product will be supplied as immediate-release coated tablets for oral administration. 
Excipients include lactose monohydrate, microcrystalline cellulose, crospovidone, sodium lauryl 
sulfate, silicon dioxide, and magnesium stearate. Placebo tablets will appear identical to EYP001a.  
For Part A, all study drug (EYP001a and placebo) will be packaged in blister packs and wallets. 
One wallet will contain 2 weeks of study drug (ie, 14 days of EYP001a or placebo) as per the 
randomization schedule. Morning and evening tablets will be clearly labeled. 
For Part B, all study drug (EYP001a and placebo) will be packaged in blister packs and carton 
boxes. One box will contain 3 weeks of study drug (ie, 3 blister strips or 21 days of EYP001a or 
placebo) as per the randomization schedule. 
5.5.2 
Study Drug Preparation and Dispensing 
For Part A, study drug will be dispensed as 100 and 200 mg tablets for oral administration at 
Weeks 0, 2, 4, and 8 by blinded clinical site personnel. Patients will receive enough study drug to 
last until the next visit.  
For Part B, study drug will be dispensed as 100 and 200 mg tablets for oral administration at 
Weeks 0, 2, 4, 6, 8, and 10 by blinded clinical site personnel. Patients will receive enough study 
drug to last until the next visit. 


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5.5.3 
Study Drug Administration 
EYP001a is only available for oral administration. The study drug should be administered with 
noncarbonated water. 
For Part A, patients will take 2 tablets in the morning during breakfast and 1 tablet in the evening 
during dinner.  
For Part B, patients will take 1 tablet in the morning during breakfast. 
On study visit days, patients should come fasted to the clinical site and take their morning dose 
during breakfast at the clinical site, following blood sample collection, except during intense 
PK/PD sampling on Days 1 and 14 of Part A, when dosing will occur with water only. 
5.5.4 
Treatment Compliance 
In Part A, patient diaries will be reviewed to assess compliance throughout the study. In Parts A 
and B, the quantity of study drug dispensed to and returned by the patient will be counted. If the 
patient is not compliant with study drug intake, the Investigator should discuss this with the patient. 
If study drug compliance drops below 80% at any given time during the Treatment Period, the 
Investigator or designee should discuss compliance with the patient and counsel the patient 
appropriately. Noncompliance includes missed doses in addition to taking the wrong dose. The 
Investigator must encourage compliance with the study drug and with the study procedures at all 
times. 
5.5.5 
Storage and Accountability 
Study drug should be stored in a cool, dry place (15°C to 25°C or 59°F to 77°F) (stable from 5°C 
to 40°C, with 75% relative humidity). 
The Investigator or appropriately trained designee will maintain an accurate record of the receipt 
of the study drug shipment, including the date and quantity received. Refer to the Pharmacy 
Manual for further information. 
In addition, an accurate drug dispensing record will be kept that specifies the amount of study drug 
dispensed to each patient and the date of dispensing.  
A drug accountability inventory record to account for all dispensing and return of any used and 
unused study drug must be maintained and available by the clinical site staff for inspection at any 
time. At the end of the study, the study drug will be reconciled, and copies of the complete record 
of study drug accountability will be provided to the Sponsor. 


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5.6 
Prior and Concomitant Medications and/or Procedures 
Unless medically warranted, all concomitant medications should remain stable from screening 
through the EOS Visit. 
5.6.1 
Excluded Medications and/or Procedures 
Excluded medications and procedures include the following:  
 Anticancer drugs, immunomodulators, and immunosuppressants within 90 days or 5 half-lives 
prior to screening, whichever is longer 
 Drugs historically associated with NAFLD for >2 weeks in the year prior to screening 
(eg, amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens 
at doses greater than those used for hormone replacement, anabolic steroids, or valproic acid 
or other known hepatotoxins at the Investigator or Medical Monitor’s discretion) 
 Vitamin E (>400 IU/day), glitazones, glucagon-like peptide-1 receptor agonists, 
ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening  
 Agents (including herbal over-the-counter weight loss preparations) or medications known to 
significantly impact body weight within 90 days prior to screening (eg, sibutramine, 
phenetamine, and orlistat) 
 Bile acid sequestrants (eg, cholestyramine) or lipid-modifying agents (eg, fibrates or 
ezetimibe) other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, or 
lovastatin 
 Agents that are substrates for CYP2C8 or CYP2C9 and have a narrow therapeutic index 
(eg, warfarin) 
 Prior or planned (during the study period) bariatric surgery (eg, gastroplasty or Roux-en-Y 
gastric bypass) 
 Major surgery within 90 days prior to the first study drug administration  
5.6.2 
Restricted Medications and/or Procedures 
Patients receiving statin therapy (rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, or 
lovastatin are the only allowable statins) need to be on stable therapy for at least 90 days prior to 
the first administration of study drug. If LDL-C increases >10 mg/dL at Week 2, the statin dose 
may be increased and titrated up at the following visit if the LDL-C remains 5% above the baseline 
value.  
For patients without statin therapy at baseline, if LDL-C increases 25% from Day 1 to Day 14, 
rosuvastatin 20 mg QD will be introduced and titrated up to 40 mg QD at the following visit if 
LDL-C remains 5% above the baseline value. 
Patients receiving other lipid-lowering treatments need to be on stable therapy for at least 90 days 
prior to the first study drug administration and must agree to remain on a stable regimen for their 
entire participation in the study. Patients with T2DM should be on a stable dose of antidiabetic 
medication for at least 90 days prior to screening and must agree to remain on a stable regimen for 
their entire participation in the study. 


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Close monitoring is required for comedication agents that are substrates for CYP2C8 or CYP2C9. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
All concomitant medications must be recorded in the eCRF. Any medication taken on or after the 
date the patient signs informed consent will be recorded in the eCRF. Any changes to concomitant 
medication dosing during the study will be captured in the eCRF and closely monitored. 


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6 
STUDY PROCEDURES 
Blood sample collection will be prioritized starting with the safety sample.  
All blood samples should be collected while the patient is in a fasted state, defined as nothing by 
mouth except water for 6 hours. 
A 3-day window is acceptable for all visits during the Treatment Period, except for Days 1 and 14 
in Part A, when the window is 1 day. 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any 
protocol-specific procedures are performed. 
6.2 
Screening Period (Parts A and B) (Weeks -12 to -1) 
The following procedures will be performed during the Screening Period (Weeks -12 to -1): 
 Obtain informed consent.  
 Evaluate inclusion/exclusion criteria. 
 Obtain demographics and medical history. 
 Record prior and concomitant medications. 
 Perform complete physical examination. 
 Measure height and body weight and calculate BMI. 
 Measure waist circumference (Part A only). 
 Measure waist and hip circumferences (Part B only). 
 Calculate waist to hip ratio (WHR) and waist to height ratio (WHtR) (Part B only). 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws.  
 Administer the AUDIT-C test. Patients with AUDIT-C scores 3 points at screening will 
receive the full AUDIT and will be excluded if they score 8 points on the full AUDIT. Patients 
with AUDIT-C scores <3 points will not receive the full AUDIT. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following:  
o Anti-HCV, anti-HIV, and anti-HBV status and HCV RNA reflexive testing, except if viral 
serology data are already available in the patient’s medical history/records and obtained 
within 90 days prior to screening. 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Serum pregnancy test (only for women of childbearing potential).  


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o Follicle-stimulating hormone test (only for women 55 years of age, to confirm 
postmenopausal state). 
o Plasma storage. 
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG. 
 Perform FibroScan.  
 Perform MRI-PDFF and cT1 imaging if FibroScan values (liver stiffness measurement [LSM] 
and CAP) are within eligibility range.  
 Assess adverse events. 
6.3 
Treatment Period (Weeks 0 to 12) 
6.3.1 
Part A: Safety Run-in Period (Weeks 0 to 4) 
6.3.1.1 
Day 1 (Week 0) 
The following procedures will be performed on Day 1 (Week 0): 
 Review inclusion/exclusion criteria and confirm patient eligibility.  
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Intense PD profile (predose [fasting] and 4 [fasting], 6, 10, 12, and 24 hours postdose). 
o Liver fibrosis and inflammation. 
o Intense PK profile (predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose [samples will 
be collected in the fasted state predose to 4 hours postdose, inclusive]). 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test.  
 Randomize eligible patients prior to dosing.  
 Assess pruritus. 
 Assess adverse events. 


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 Dispense patient diary. 
 Dispense study drug and provide dosing instructions. 
6.3.1.2 
Day 7 (Week 1) 
The following procedures will be performed on Day 7 (Week 1): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Liver fibrosis and inflammation. 
o Sparse PK profile (predose [fasting] and 2 hours postdose; optional sample at 6 hours 
postdose). 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess pruritus.  
 Assess adverse events. 
6.3.1.3 
Day 14 (Week 2) 
The following procedures will be performed on Day 14 (Week 2): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 


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 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Intense PD profile (predose [fasting] and 4 [fasting], 6, 10, 12, and 24 hours postdose). 
o Intense PK profile (predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose [samples will 
be collected in the fasted state predose to 4 hours postdose, inclusive]). 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess pruritus.  
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance.  
 Dispense new study drug and provide dosing instructions. 
6.3.1.4 
Day 21 (Week 3) 
The following procedures will be performed at Day 21 (Week 3): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Liver fibrosis and inflammation. 
o Sparse PK (predose [fasting] and 2 hours postdose; optional sample at 6 hours postdose). 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess pruritus.  
 Assess adverse events. 


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6.3.1.5 
Day 28 (Week 4) 
The following procedures will be performed at Day 28 (Week 4): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD profile (predose [fasting] and 2 hours postdose). 
o Liver fibrosis and inflammation. 
o Sparse PK profile (predose [fasting] and 2 hours postdose; optional sample at 6 hours 
postdose). 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess pruritus. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 
 Dispense new study drug and provide dosing instructions.  
6.3.2 
Part A: Continued Treatment Period (Weeks 5 to 12) 
6.3.2.1 
Day 56 (Week 8) 
The following procedures will be performed on Day 56 (Week 8): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 


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 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD profile (predose [fasting] and 2 hours postdose). 
o Liver fibrosis and inflammation. 
o Sparse PK profile (predose [fasting] and 2 hours postdose; optional sample at 6 hours 
postdose). 
o Plasma storage. 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess pruritus. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 
 Dispense new study drug and provide dosing instructions. 
6.3.2.2 
Day 84 (Week 12) 
The following procedures will be performed on Day 84 (Week 12): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD profile (predose [fasting] and 2 hours postdose). 


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o Sparse PK profile (predose [fasting] and 2 hours postdose; optional sample at 6 hours 
postdose). 
o Plasma storage.  
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Perform MRI-PDFF and cT1 imaging. 
 Perform FibroScan vibration-controlled transient elastography (VCTE) (optional). 
 Assess pruritus.  
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 
6.3.3 
Part B: Treatment Period (Weeks 0 to 12) 
6.3.3.1 
Day 1 (Week 0) 
The following procedures will be performed at Day 1 (Week 0): 
 Review inclusion/exclusion criteria and confirm patient eligibility.  
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist and hip circumferences. 
 Calculate WHR and WHtR. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD (predose [fasting]). 
o Liver fibrosis and inflammation. 
o Sparse PK (predose [fasting]). 
o Plasma storage.  
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test.  
 Randomize eligible patients prior to dosing.  


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 Assess adverse events. 
 Dispense study drug and provide dosing instructions.  
6.3.3.2 
Day 14 (Week 2) 
The following procedures will be performed at Day 14 (Week 2): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist and hip circumferences. 
 Calculate WHR and WHtR. 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD (predose [fasting]). 
o Sparse PK (predose [fasting]). 
o Plasma storage. 
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance.  
 Dispense new study drug and provide dosing instructions.  
6.3.3.3 
Day 28 (Week 4) 
The following procedures will be performed at Day 28 (Week 4): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist and hip circumferences.  
 Calculate WHR and WHtR. 


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 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD (predose [fasting]). 
o Liver fibrosis and inflammation. 
o Sparse PK (predose [fasting]). 
o Plasma storage.  
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance.  
 Dispense new study drug and provide dosing instructions. 
6.3.3.4 
Day 42 (Week 6) 
The following procedures will be performed at Day 42 (Week 6): 
 Record changes in concomitant medications. 
 Collect blood sample for the following: 
o Chemistry for assessment of ALT, AST, ALP, GGT, and total bilirubin. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 
 Dispense new study drug and provide dosing instructions. 
6.3.3.5 
Day 56 (Week 8) 
The following procedures will be performed at Day 56 (Week 8): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist and hip circumferences. 
 Calculate WHR and WHtR. 


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 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD (predose [fasting]). 
o Liver fibrosis and inflammation. 
o Sparse PK (predose [fasting]). 
o Plasma storage.  
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance.  
 Dispense new study drug and provide dosing instructions. 
6.3.3.6 
Day 70 (Week 10) 
The following procedures will be performed at Day 70 (Week 10): 
 Record changes in concomitant medications. 
 Collect blood sample for the following: 
o Chemistry for assessment of ALT, AST, ALP, GGT, and total bilirubin. 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance.  
 Dispense new study drug and provide dosing instructions. 
6.3.3.7 
Day 84 (Week 12) 
The following procedures will be performed at Day 84 (Week 12): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist and hip circumferences. 
 Calculate WHR and WHtR. 


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 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o Sparse PD (predose [fasting]). 
o Sparse PK (predose [fasting]). 
o Plasma storage.  
 Collect urine sample for urinalysis and pregnancy test. If the pregnancy test is positive, perform 
serum hCG test. 
 Perform 12-lead ECG. 
 Perform MRI-PDFF and cT1 imaging. 
 Perform FibroScan VCTE (optional). 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 
6.4 
End of Study Follow-Up Visit (Parts A and B) (Week 14) 
The following procedures will be performed at the EOS Follow-up Visit at Day 98 (Week 14): 
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference (Part A only). 
 Measure waist and hip circumferences (Part B only). 
 Calculate WHR and WHtR (Part B only). 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o PD. 
o Serum pregnancy test. 


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o Liver fibrosis and inflammation. 
o PK. 
o Plasma storage. 
 Collect urine sample for urinalysis. 
 Perform 12-lead ECG. 
 Assess pruritus (Part A only).  
 Assess adverse events. 
6.5 
Early Termination Visit and Withdrawal Procedures (Parts A and B) 
The end of treatment for patients completing the study is Day 84 (Week 12).  
Patients who discontinue early from the study for any reason before completion of the Treatment 
Period will be requested to return to the clinic for an ET Visit within a maximum of 48 hours after 
their last intake of study drug, regardless of how many days they participated in the study. 
Patients who discontinue early from the study for any reason after completion of the Treatment 
Period and before the EOS Follow-up Visit will be requested to return to the clinic for an ET Visit 
as soon as possible and no later than the planned EOS Follow-up Visit. 
For patients who are withdrawn from the study prior to completion, all ET procedures will be 
performed at an ET Visit. These procedures include the following:  
 Record changes in concomitant medications. 
 Perform brief physical examination. 
 Measure body weight and calculate BMI. 
 Measure waist circumference (Part A only). 
 Measure waist and hip circumferences (Part B only). 
 Calculate WHR and WHtR (Part B only). 
 Collect vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature) with the patient in the sitting position after 5 minutes of rest and before any blood 
draws. 
 Administer the AUDIT-C test. 
 Counsel on diet/lifestyle. 
 Collect blood sample for the following: 
o Chemistry, hematology, coagulation, and lipid and metabolic profile. 
o PD (preferably within 24 to 48 hours of last intake of study drug). 
o Liver fibrosis and inflammation. 
o Serum pregnancy test.  


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o PK (preferably within 24 to 48 hours of last intake of study drug). 
o Plasma storage.  
 Collect urine sample for urinalysis.  
 Perform 12-lead ECG. 
 Perform MRI-PDFF and cT1 imaging only for patients on study drug 4 weeks.  
 Perform FibroScan VCTE (optional). 
 Assess pruritus (Part A only). 
 Assess adverse events. 
 Collect returned used/unused study drug and assess compliance. 


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7 
EFFICACY ASSESSMENTS 
In addition to the efficacy assessments listed below, this study plans to validate an in silico NASH 
disease model that predicts responders and nonresponders to EYP001a.  
7.1 
Efficacy Variables  
7.1.1 
Primary Efficacy Variables  
The primary efficacy variable is absolute change in LFC as measured by MRI-PDFF from baseline 
to Week 12. 
7.1.2 
Secondary Efficacy Variables  
The secondary efficacy variables include the following:  
 Proportion of patients with 5% absolute reduction in LFC as measured by MRI-PDFF from 
baseline to Week 12 
 Proportion of patients with 10% absolute reduction in LFC as measured by MRI-PDFF at 
Week 12 
 Proportion of patients with 20% absolute reduction in LFC as measured by MRI-PDFF at 
Week 12  
 Proportion of patients with a relative reduction in LFC 20% as measured by MRI-PDFF at 
Week 12 
 Proportion of patients with a relative reduction in LFC 30% as measured by MRI-PDFF at 
Week 12 
 Percent change (relative reduction) in LFC as measured by MRI-PDFF from baseline to 
Week 12  
 Change and percent change in imaging-derived mean cT1 from baseline to Week 12 
 Change and percent change in WHR from baseline to Week 12 (Part B only) 
 Change and percent change in WHtR from baseline to Week 12 (Part B only) 
 Change in the following biomarkers of liver fibrosis and inflammation: ALT, AST, AST/ALT 
ratio, adiponectin, high sensitivity C-reactive protein, interleukin 6, tumor necrosis factor 
alpha, cytokeratin-18, fibronectin, hyaluronic acid, procollagen type III N-terminal peptide, 
tissue inhibitor of metalloproteinases-1 (and derived enhanced liver fibrosis score), Pro-C3, 
and chitinase-3-like protein 1 (also known as YKL-40) from baseline to Week 4, Week 8, and 
Week 14/ET, as applicable 


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8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS  
Pharmacokinetic (EYP001a concentrations) and PD (C4 and FGF19 concentrations) data will be 
added to the current PK/PD database, and population PK/PD models will be reassessed to 
investigate potential influence of NASH on PK/PD relationships. 
8.1 
Pharmacokinetic Variables  
In Part A, during the Safety Run-in Period, intense PK sampling will occur on Day 1 (1 day) and 
Day 14 (1 day) at the following timepoints: 0 (predose), 1, 2, 4, 6, 8, 10, 12, and 24 hours 
postdose; samples will be collected in the fasted state predose to 4 hours postdose, inclusive. 
Sparse PK samples will be collected for all other visits. Plasma samples to assess trough 
concentrations of EYP001a will be collected predose (fasting) in the morning and 2 hours postdose 
(an optional sample may also be collected at 6 hours postdose) at the following visits: Days 7, 21, 
28, 56, and 84. A sample will also be collected at the EOS and ET Visits. 
In Part B, sparse PK sampling will occur predose (fasting) at the following visits: Days 1, 14, 28, 
56, and 84. A sample will also be collected at the EOS and ET Visits. 
At the ET Visit (if applicable), the PK sample should be collected within 24 to 48 hours of last 
intake of study drug. The date and time of the PK draw and the last dose of study drug must be 
recorded in the eCRF. 
Pharmacokinetic samples will be collected in a fasted state, defined as nothing by mouth except 
water for 6 hours, at all predose sampling timepoints (in Parts A and B) and at the 1- to 4-hour 
postdose timepoints (inclusive) on Days 1 and 14 of Part A. For BID dosing, PK timepoints will 
be based on the time of morning dosing. 
8.2 
Pharmacodynamic Variables 
In Part A, intense PD sampling will occur on Day 1 (1 day) and Day 14 (1 day) at the following 
timepoints: 0 (predose, fasting), 4 (fasting), 6, 10, 12, and 24 hours postdose. Sparse PD sampling 
will also occur predose (fasting) and 2 hours postdose at the following visits: Days 28, 56, and 84. 
A sample will also be collected at the EOS and ET Visits. 
In Part B, sparse PD sampling will occur predose (fasting) at the following visits: Days 1, 14, 28, 
56, and 84. A sample will also be collected at the EOS and ET Visits. 
At the ET Visit (if applicable), the PD sample should be collected within 24 to 48 hours of last 
intake of study drug. The date and time of the PD draw and the last dose of study drug must be 
recorded in the eCRF. 
Pharmacodynamic samples will be collected in a fasted state, defined as nothing by mouth except 
water for 6 hours, at all predose sampling timepoints (in Parts A and B) and at the 4-hour postdose 
timepoint on Days 1 and 14 in Part A. For BID dosing, PD sampling timepoints will be based on 
the time of morning dosing. 
Parameters will be measured in plasma samples using a validated method. Pharmacodynamic 
sampling will assess plasma levels of C4; FGF19; and total, primary, and secondary bile acids 
(such as chenodeoxycholic acid, deoxycholic acid, lithocholic acid, and/or others as appropriate).18  


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9 
SAFETY ASSESSMENTS 
Safety and tolerability assessments will include the monitoring of adverse events; AESIs 
(ie, pruritus [Part A only], drug-induced liver injury [Part A only], elevation of transaminases 
[Part B only], and all muscle-related adverse events); SAEs; and findings from physical 
examinations, vital signs, ECGs, and clinical laboratory parameters.  
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed 
in the Clinical Safety Monitoring Plan (Appendix E). 
All adverse events will be assessed and reported using the National Cancer Institute CTCAE 
Version 5.0 grading system. Additional safety measurements will be performed at the discretion 
of the Investigator (or delegate). 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until the EOS Visit. Patients should be instructed 
to report any adverse event that they experience to the Investigator, whether or not they think the 
event is due to study drug. Beginning at the time of informed consent, Investigators should make 
an assessment for adverse events and record the event on the appropriate adverse event eCRF. 
Beginning with receipt of first dose of study drug, any adverse event that occurs during the 
Treatment Period will be recorded as a TEAE on the appropriate eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself.  
Any medical condition already present at screening should be recorded as medical history and not 
be reported as an adverse event unless the medical condition or signs or symptoms present at 
baseline changes in severity, frequency, or seriousness at any time during the study. In this case, 
it should be reported as an adverse event: worsening of preexisting condition. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at screening and significantly worsen during the study 
should be reported as adverse events, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 


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are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an adverse event. Laboratory abnormalities or other abnormal clinical findings 
(eg, ECG abnormalities) should be reported as an adverse event if any of the following are 
applicable: 
 If an intervention is required as a result of the abnormality (such as a re-test being made more 
than 1 time) 
 If action taken with the study drug is required as a result of the abnormality 
 Based on the clinical judgment of the Investigator 
9.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
9.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For EYP001a, the reference safety 
information is included in the Investigator’s Brochure currently in force. The reference safety 
information will be reviewed yearly and the periodicity of the review will be harmonized with the 
reporting period of the Development Safety Update Report. 
9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess all adverse events using the National Cancer Institute CTCAE 
Version 5.0 grading system. 
Causality Assessment 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 Definite: An adverse event that is consistent with the suspected type of reaction known for the 
drug, in line with the reasonable temporal order after treatment, and is alleviated or disappears 
upon discontinuation of the study drug. 
 Probable: An adverse event that is consistent with the suspected type of reaction known for the 
drug, in line with the reasonable temporal order after treatment, alleviates or disappears upon 
discontinuation of the study drug, but could also be caused by the clinical conditions of the 
study patient or other factors. 
 Possible: An adverse event that is consistent with the suspected type of reaction known for the 
drug, not in line with the reasonable temporal order after treatment, and could also be caused 
by the clinical conditions of the study patient or other factors. 
 Improbable: An adverse event that is inconsistent with the suspected type of reaction known 
for the drug, not in line with the reasonable temporal order after treatment, and could also be 
caused by the clinical conditions of the study patient or other factors. 


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 Not related: An adverse event that is inconsistent with the suspected type of reaction known 
for the drug, not in line with the reasonable temporal order from administration of the study 
drug, or that can be easily explained by other factors, such as underlying diseases, 
complication, concomitant drugs, and concurrent treatment. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
 Concomitant drug- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
 Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the patient and provide a logical 
and better explanation for the event. 
 The pharmacology and PK of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
See Section 4.4 for withdrawal criteria.  
9.1.4 
Adverse Events of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence for predefined 
AESIs throughout the patient’s participation in this study.  
In Part A, events of pruritus, drug-induced liver injury, and all muscle-related adverse events will 
be monitored as AESIs during this study; the Investigator will assess and record these events on a 
separate AESI form. Pruritus will be assessed using a visual analog scale and 5-D questionnaire 
(degree, duration, direction, disability, and distribution) itch scale at each study visit after 
screening. See Appendix C and Appendix D.  
In Part B, events of elevation of transaminases and all muscle-related adverse events will be 
monitored as AESIs during this study; the Investigator will assess and record these events on a 
separate AESI form. 


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During the course of the study, additional AESIs may be identified by the Sponsor; the Investigator 
will assess and record in detail any additional information on AESIs on an SAE form (whether or 
not the event meets seriousness criteria in Section 9.2), to be submitted within 24 hours of 
awareness of the event.  
Adverse events of special interest must be recorded on the eCRF and sent to the ENYO safety 
designee via fax or email within 24 hours. 
Safety Contact Information 
PharmaLex 
Telephone: +34 976 204 400 
Fax: +34 976 204 402 
Email: EnyoSafety@pharmalex.com  
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death. 
 A life-threatening adverse event. 
o Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
 Requires hospitalization or prolongation of existing hospitalizations. 
o Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will 
not be recorded as an SAE under this criterion, nor will hospitalization for a procedure 
scheduled or planned before signing of informed consent, or elective treatment of a 
preexisting condition that did not worsen from baseline. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective surgery 
should be recorded as adverse events and assessed for seriousness. Admission to the 
hospital for social or situational reasons (ie, no place to stay, live too far away to come for 
hospital visits, respite care) will not be considered inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 An important medical event. 
o Note: Important medical events that do not meet any of the above criteria may be 
considered an SAE when, based upon appropriate medical judgment, they may jeopardize 
the patient and may require medical or surgical intervention to prevent 1 of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalizations, or the development of drug dependency. 


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9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until 14 days following the last 
administration of study drug must be reported to ENYO Pharma SA (hereinafter, ENYO) and its 
safety designee within 24 hours of the knowledge of the occurrence. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study and also complete and submit the SAE form to the safety vendor. When the 
form is completed, ENYO safety personnel and its safety designee will be notified electronically 
by the EDC system that an event has been added. If the event meets serious criteria and it is not 
possible to access the EDC system, send an email to the ENYO safety designee or call the ENYO 
safety designee SAE reporting line (contact information listed below), and fax/email the completed 
paper SAE form to the ENYO safety designee within 24 hours of awareness. When the EDC 
system becomes available, the SAE information must be entered within 24 hours of the system 
becoming available. 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to the ENYO safety designee via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
Safety Contact Information 
PharmaLex 
Telephone: +34 976 204 400 
Fax: +34 976 204 402 
Email: EnyoSafety@pharmalex.com  
9.4 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within the safety follow-up period defined in the 
protocol, the Investigator is to stop dosing with study drug(s) immediately and the patient should 
be withdrawn from the study. Early termination procedures should be implemented at that time.  
A pregnancy is not considered to be an adverse event or SAE; however, it must be reported to the 
ENYO safety designee within 24 hours of knowledge of the event (contact information listed in 
Section 9.3) The ENYO safety designee will then provide the Investigator/clinical site the 
Exposure in Utero (EIU) form for completion. The Investigator/clinical site must complete the 
EIU form and fax/email it back to the ENYO safety designee.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period defined in the protocol, the Investigator should notify the 
ENYO safety designee and ENYO safety personnel as described above.  


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The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the follow-up EIU form should be faxed/emailed to the 
ENYO safety designee and ENYO safety personnel. If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (ie, postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the 
procedures for reporting an SAE. 
9.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about suspected unexpected serious 
adverse reactions (SUSARs) that are fatal or life-threatening as soon as possible to the FDA, 
applicable competent authorities in all the countries concerned, and to the Central Ethics 
Committee, and in any case no later than 7 days after knowledge by the Sponsor/designee of such 
a case. Relevant follow-up information will subsequently be communicated within an additional 
8 days.  
All other SUSARs will be reported to the FDA, applicable competent authorities concerned, and 
to the Central Ethics Committee concerned as soon as possible but within a maximum of 15 days 
of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to an investigational medicinal product. 
9.6 
Special Situation Reports 
Special situation reports include reports of EYP001a or statin overdose, misuse, abuse, and 
medication error.  
 Overdose: Refers to the administration of a quantity of EYP001a or statin given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the patient has taken additional dose(s) or the Investigator has reason to suspect that 
the patient has taken additional dose(s).  
 Misuse: Refers to situations where EYP001a or statin is intentionally and inappropriately used 
in a way that is not in accordance with the protocol instructions or local prescribing information 
and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is persistent or sporadic, intentional excessive use of EYP001a or statin, which is 
accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of EYP001a or statin by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors. Cases of patients missing doses of study 
drug are not considered reportable as medication error. 


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All special situation events as described above must be documented and captured in the eCRF. All 
adverse events associated with these special situation reports should be reported as adverse events 
or SAEs as well as recorded on the adverse event eCRF and/or the SAE report form. Details of the 
signs and symptoms, clinical management, and outcome should be provided, when available. 
9.7 
Medical History  
Medical history, including information on prior and concomitant medication, will be collected for 
all patients at screening. Data from previous liver biopsies are not a prerequisite for enrollment but 
should be collected if available in the patient’s medical record. 
9.8 
Clinical Laboratory Evaluations 
Clinical safety laboratory parameters will be measured or calculated at study visits specified in 
Appendix A. Profiles for hematology, coagulation, serum chemistry, lipid and metabolic 
parameters, and urinalysis will be evaluated from samples collected after 6 hours of fasting 
(nothing by mouth except water). Further analysis of urine sediment or urine microscopy will be 
performed when there are any abnormalities on any of the following 3 dipstick results: leukocyte 
esterase, blood, or nitrite, and if judged clinically significant by the Investigator. See Appendix B 
for a complete list of laboratory analytes. 
For women of childbearing potential, a serum hCG test will be performed at screening and the 
EOS and ET Visits. Urine hCG testing will be performed at visits specified in Appendix A. If a 
urine hCG test is positive, a serum hCG test will be performed. 
Follicle-stimulating hormone level will be measured at screening to confirm postmenopausal state 
in women 55 years of age. 
Anti-HBV, anti-HCV, and anti-HIV will be assessed at screening, and HCV RNA will be 
reflexively tested. Samples will be collected for central laboratory analysis except if viral serology 
data is already available in patient’s medical history/records and obtained within 90 days prior to 
screening. 
Plasma from blood samples obtained at screening and at study visits specified in Appendix A, 
including EOS and ET Visits, will be stored for protocol-related safety testing or exploratory 
analyses. 
Blood sampling procedures, including information on blood volume, collection tubes, sample 
processing, storage, and shipping are provided in the Laboratory Manual.  
The safety of statin coadministration will be assessed at study visits specified in Appendix A by 
monitoring CK levels. 
Technical details on laboratory parameters (methods and commercial kit[s]) will be specified in 
the Laboratory Manual. 


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Additional laboratory testing may be required in response to adverse events and laboratory findings 
as described in the Clinical Safety Monitoring Plan (Appendix E). Laboratory abnormalities 
should be reported as an adverse event if any of the following is applicable: 
 If an intervention is required as a result of the abnormality (such as a re-test being performed 
more than 1 time) 
 If action taken with the study drug is required as a result of the abnormality 
9.9 
Vital Signs and Anthropometrics 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature) 
and anthropometrics (height, body weight, BMI, waist circumference, hip circumference [Part B 
only], WHR [Part B only], and WHtR [Part B only]) will be assessed as specified in Appendix A.  
Blood pressure will be measured using a standardized process: 
 Clinical site staff will assess blood pressure with the patient in the sitting position after 
5 minutes of rest and before any blood draws. 
 Clinical site staff will use a mercury sphygmomanometer or automatic blood pressure device 
with an appropriately sized cuff with the bladder centered over the brachial artery. 
 Clinical site staff will record the arm used for the measurement and use the same arm 
throughout the study.  
 Clinical site staff will measure and record the blood pressure. 
Blood pressure will be recorded to the nearest 2 mmHg mark on the manometer or to the nearest 
whole number on an automatic device. A blood pressure reading will be repeated 1 to 2 minutes 
later, and the second reading will also be recorded to the nearest 2 mmHg mark.  
Waist circumference will be measured using a standardized process: 
 Measure the waist circumference at the end of several consecutive natural breaths, at a level 
parallel to the floor, midpoint between the top of the iliac crest and the lower margin of the last 
palpable rib in the mid axillary line. The tape should be placed around the abdomen at the level 
of this midway point and a reading taken when the tape is snug but does not compress the 
skin.19 
Hip circumference will be measured using a standardized process: 
 Measure the hip circumference at a level parallel to the floor, at the largest circumference of 
the buttocks. The tape should be placed around the hips and a reading taken when the tape is 
snug but does not compress the skin.  
9.10 
Electrocardiograms 
Single 12-lead ECGs will be performed at screening; on Days 7 (Part A only), 14, 21 (Part A only), 
28, 56, and 84; and at the EOS and ET Visits after the patient has been resting in the supine position 
for at least 10 minutes. The ECG will include 12 standard leads and will be recorded at a paper 
speed of 25 mm/sec. QT interval corrected for heart rate using Fridericia’s formula will be 
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In case of evident bad quality of the tracing (eg, muscle tremor), the ECG will be repeated. 
See Appendix A. 
9.11 
Physical Examinations 
A complete physical examination (including general appearance; eyes, ears, nose, and throat; head 
and neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; lymphatic; dermatological; 
neurological systems; mental status; and extremities) will be performed at screening. Brief, 
symptom-directed physical examinations will be performed in Part A at each study visit after 
screening and in Part B on Days 1, 14, 28, 56, and 84; and at the EOS and ET Visits. 
See Appendix A. 
9.12 
Pruritus Assessments 
In Part A, the pruritus visual analog scale and 5-D questionnaire (degree, duration, direction, 
disability, and distribution) itch scale will be assessed at each study visit after screening. 
See Appendix A.  
In Part B, pruritus will be reported as any other adverse event. If a patient reports pruritus, the 
visual analog scale and the 5-D questionnaire (degree, duration, direction, disability, and 
distribution) itch scale will be administered. 
9.12.1 
Pruritus Management – Guidance to Investigators 
Mostly mild to moderate pruritus has been observed in clinical trials with EYP001a and has also 
been reported with other FXR agonists and in patients with NASH. Pruritus is also part of the 
natural disease symptomatology of NASH and independent of any pharmacological treatment. 
Tolerance to pruritus may develop over continuous, uninterrupted dosing or after a short (few 
days) interruption of EYP001a (empirical observations). 
The following 3-level therapeutic approach to pruritus should be applied: 
1. Topical non-pharmacological or over-the-counter interventions to improve pruritus may be 
tried and can be advised to patients. These include application of moisturizers, cooling agents, 
and antihistamines; or taking cool showers/showering in the morning, using clear/gentle soaps 
and laundry detergents, application of cold packs or fabric strips soaked in cold water, 
avoidance of wool or other irritating fabrics, and wearing loose-fitting clothing. 
2. In the case of no improvement of pruritus, a drug holiday of 2 days to a maximum of 5 days 
may be implemented. 
3. In the case pruritus prevails and requires systemic oral pharmacological treatment, it is 
encouraged to seek advice from the Medical Monitor. Recommended possible comedications 
for pruritus are: naltrexone (25 to 50 mg/day orally [po]), ondansetron (4 to 24 mg/day po), 
hydroxyzine (25 to 75 mg/day po), sertraline (25 to 75 mg/day po), and gabapentin 300 mg/day 
po). 
Note: Bile acid sequestrants are excluded medications, the concomitant use of naltrexone with 
gabapentin is disallowed. 


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9.13 
Drug-Induced Liver Injury and Muscle Toxicity Monitoring 
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will be 
closely monitored against the criteria for drug-induced liver injury and muscle toxicity as detailed 
in the Clinical Safety Monitoring Plan (Appendix E). The Clinical Safety Monitoring Plan 
describes the actions with regard to the study drug that are required upon clinical findings and 
confirmation of laboratory abnormalities suggestive of muscle toxicity or liver injury of varying 
degrees as a function of baseline findings. 
9.14 
Diet and Lifestyle Counseling 
Diet and lifestyle counseling will occur as per standard of care. Diet and lifestyle counseling will 
be performed in Part A at each study visit and in Part B at screening and on Days 1, 14, 28, 56, 
and 84; and at the EOS and ET Visits. High-level dietary and physical activity guidelines will be 
provided and documented in the eCRF.  


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10 
STATISTICS 
10.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population includes all patients who are randomized and administered 
at least 1 dose of study drug. Patients without a Week 12 or end of treatment MRI-PDFF 
assessment will be imputed as nonresponders unless otherwise specified. 
The Safety Population is identical to the ITT Population. 
The modified ITT (mITT) Population includes patients from the ITT Population who have valid 
baseline and Week 12 MRI-PDFF measurements of LFC. 
The Per-Protocol Population includes all patients from the mITT Population who finish the 
12-week Treatment Period without any major protocol violations. The analysis of LFC as 
measured by MRI-PDFF will be repeated on the Per-Protocol Population to test the robustness of 
results. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
The primary and secondary efficacy analyses are described in the sections below. The efficacy 
analyses of LFC as measured by MRI-PDFF will be conducted on the ITT Population and repeated 
on the mITT and Per-Protocol Populations. The analysis of other efficacy variables will be based 
on the ITT Population. 
For efficacy variables, observed data and change and/or percent change from baseline will be 
summarized using descriptive statistics and graphs per dose group and visit as appropriate. 
10.2.1.1 
Primary efficacy analysis 
The primary efficacy analysis will be performed on the ITT Population. Missing MRI-PDFF 
values at Week 12 or ET will be imputed based on the missing at random assumption using 
multiple imputation. 
The primary efficacy analysis will be performed on the change in LFC as measured by MRI-PDFF 
from baseline to Week 12 or ET using an analysis of covariance (ANCOVA) model with baseline 
fat fraction as a covariate and treatment, use of statin comedication at screening (stratification 
factor: use of statin [yes, no]), and T2DM status (yes, no) in Part A, and by statin use (yes, no) and 
LFC at screening (stratification factor with 3 categories: LFC<16%, 16%LFC<22%, and 
22%LFC) in Part B, as factors. Pairwise treatment comparisons between each EYP001a dose and 
placebo will be conducted from the ANCOVA model with least-square means, standard errors, 
95% confidence intervals, and p-values being presented. To adjust the 3 tests (each EYP001a dose 
and placebo) for multiplicity in order to control the family-wise type I error at 0.025 one-sided, 
the Bonferroni method will be used. 
The primary efficacy results will subsequently be analyzed by adding LSMs and CAP values at 
enrollment as additional factors. 


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10.2.1.2 
Sensitivity analysis  
Sensitivity analyses will be conducted by repeating the primary efficacy analysis based on:  
 The ITT Population with missing MRI-PDFF values at Week 12 or ET imputed using the 
multiple imputation with tipping point method based on the missing not at random assumption 
 The mITT Population 
10.2.1.3 
Secondary efficacy analysis 
The statistical analysis of secondary efficacy variables based on change from baseline to Week 12 
will be conducted with a similar ANCOVA model, while secondary efficacy variables measured 
at multiple timepoints will be analyzed by mixed effect model repeated measures model. 
The responder (categorical) variables will be analyzed by a Cochran-Mantel-Haenszel test, 
stratified by statin comedication use and T2DM status at screening in Part A and statin 
comedication and LFC at screening in Part B. The analysis of the responder variables will be 
repeated using logistic regression models, adjusting for treatment, statin comedication at 
screening, and T2DM status at screening. Patients without a Week 12 or end of treatment 
MRI-PDFF assessment will be imputed as nonresponders. All secondary efficacy variables will be 
summarized using descriptive statistics. 
10.2.1.4 
Validation of nonalcoholic steatohepatitis disease model 
The anticipated EYP001-202 efficacy results will serve as validation of an in silico NASH disease 
model, which was built based on public and expert knowledge and combined with the Phase 1 PK 
and PD EYP001 results.15 The model integrates 309 liver FXR-related biological variables and 
1320 parameters and explores the effect of different EYP001 treatment regimens on 
NASH-relevant efficacy endpoints in a virtual population. Iterations of the model will support 
future explorations of development strategies with different EYP001 Phase 2 and 3 study designs. 
10.2.2 
Pharmacodynamic Analysis  
Pharmacodynamic parameters, observed data, and change and/or percent change from baseline 
will be summarized using descriptive statistics and graphs per dose group and visit, as appropriate. 
10.2.3 
Pharmacokinetic Analysis  
Plasma concentrations of EYP001a will be listed for all patients with available EYP001a plasma 
concentrations in treatment groups that include EYP001a or placebo. All concentrations below the 
limit of quantification will be labeled as such in the concentration data listings and will be treated 
as 0 in the summary statistics.  
Listings of individual patient plasma concentrations and actual blood sampling times and graphs 
of concentration versus time will be prepared by dose. Plasma concentrations will be summarized 
by and compared among different doses using descriptive statistics. 


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10.2.4 
Analysis of Safety 
Baseline for physical examinations, all vital signs, 12-lead ECG measurements, pruritus 
questionnaire (Part A only), and clinical laboratory assessments will be defined as the last 
evaluation done before the first administration of study drug in each dose group on Day 1. 
Safety variables will be tabulated and presented for the Safety Population. 
10.2.4.1 
Adverse events 
The original terms used in the eCRF by Investigators to identify adverse events will be coded using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA). All adverse 
events will be assessed and reported using the National Cancer Institute CTCAE Version 5.0 
grading system. A TEAE is defined as a new or worsening adverse event after the first dose of 
study drug. The percentage of patients with TEAEs will be summarized for each dose group by 
system organ class and preferred term. The study drug-related TEAEs and SAEs will be 
summarized in the same fashion. The TEAEs will also be summarized by system organ class, 
preferred term, and maximum severity. All SAEs and TEAEs leading to early discontinuation will 
be listed.  
The safety of EYP001a with statin coadministration will be assessed based on the difference in 
frequency of TEAEs between treatment groups. 
10.2.4.2 
Laboratory values  
The clinical laboratory analytes at each visit and change from baseline will be summarized 
descriptively. Abnormalities based on predefined normal ranges will be tabulated by dose group 
showing patient counts and percentages. A listing of patients with any laboratory results outside 
the reference ranges will be provided if appropriate. 
10.2.4.3 
Vital signs, anthropometrics, and electrocardiograms 
Vital signs, anthropometrics, and ECGs at each visit assessed and change from baseline will be 
summarized descriptively. 
10.2.4.4 
Prior and concomitant medications  
Prior and concomitant medications will be coded with the World Health Organization (WHO) 
Drug Dictionary. A prior medication is defined as any medication taken by the patient before the 
first dose of study drug. A concomitant medication is defined as any medication taken by the 
patient at the same time or after the first dose of study drug. Number and frequency of patients 
taking prior and concomitant medications will be tabulated and listed. 
10.2.5 
Demographic and Baseline Characteristics 
For all patients who receive at least 1 dose of study drug, descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) will be performed for age, gender, race and ethnicity, 
BMI, waist circumference, WHR (Part B only), WHtR (Part B only), body weight, and height. 


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10.2.6 
Interim Analysis 
All available unblinded preliminary safety, PK, and PD results will be comprehensively reviewed 
during 2 interim analysis timepoints: 
 The first interim analysis will be performed at the end of the Safety Run-in Period, after the 
last of the 24 patients randomized in Part A has completed Day 28 (Week 4). It is anticipated 
that at the time of the first interim analysis, approximately 10 patients will have completed 
Day 84 (Week 12) of Part A.  
 A second interim analysis will be performed when 50% of patients in Part B have completed 
Day 56 (Week 8). 
The interim analyses will be performed on all available primary and secondary endpoints 
according to the DSMC charter. The conclusions and recommendations of the DSMC will be 
shared blindly with the Sponsor and clinical sites. 
10.2.7 
Data and Safety Monitoring Committee 
An external, independent DSMC will review all available unblinded preliminary safety, PK, and 
PD results when any stopping rules are met and in accordance with the interim analysis timepoints 
described in Section 10.2.6. In Part B, the DSMC will be promptly notified for further review if 
any patients experience ALT, AST, or bilirubin elevations 2  above baseline values.  
The interim analyses will be performed on all available primary and secondary endpoints 
according to the DSMC charter, which describes the overall guidelines, composition, roles, and 
responsibilities of the independent DSMC for this study, including the selection of DSMC 
members, timing of meetings, methods of providing information to and from the DSMC, frequency 
and format of meetings, data analysis recommendations, and DSMC relationships with other 
parties participating in the conduct of this study. Patient accrual will continue throughout the 
period of DSMC review. The DSMC will advise on the accrual of the remaining patients per 
protocol or on any amendments that are necessary for safety reasons. 
10.2.8 
Sample Size Determination 
The sample size of 114 randomized patients (n = 24 patients in Part A and n = 90 in Part B 
[n = 30 patients per treatment group]) is based on the efficacy endpoint: absolute change in LFC 
as measured by MRI-PDFF from baseline to Week 12, assuming that the treatment difference 
between each active treatment group with placebo is at least 5.1% with a common standard 
deviation of 5.8%.  
With a 2-sample Z-test with the power of 0.8 and an overall family-wise 1-sided alpha of 0.025 
(or each active versus placebo alpha = 0.0125 after Bonferroni adjustment), 26 patients per 
treatment group will be needed to complete the Week 12 Visit. With the consideration of an 
approximately 13% dropout rate before Week 12, 30 patients will be randomized per treatment 
group in Part B. 
A Lan-DeMets alpha spending function will be used for this group sequential design. Nonbinding 
O’Brien-Fleming efficacy boundaries and futility boundaries will be calculated using 
EAST 6.4 software. The efficacy and futility boundaries are described in Table 6. 


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At the time of the interim analysis, if the test-statistic is equal to or less than the futility boundary, 
the Sponsor can decide to stop the study due to lack of efficacy. 
Table 6. 
Efficacy and Futility Boundaries for Part B 
Look 
Week 8 
Number 
of 
Patients 
Week 12 
Number 
of 
Patients 
Information
Fraction 
Cumulative 
Alpha 
Spent 
Cumulative 
Beta Spent
Z 
Efficacy 
Boundary
Z Futility 
Boundary 
p-value 
Efficacy 
Boundary
p-value 
Futility 
Boundary
#1 
(interim 
analysis) 
45 
23 
0.25 
<0.0001 
0.0113 
-4.7604 
0.6966 
<0.0001 
0.7570 
#2 (final 
analysis) 
90 
 
1 
0.0125 
0.1962 
-2.2414 
-2.2414 
0.0125 
0.0125 


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the clinical site on eCRFs and reviewed by the Clinical Research Associate 
(CRA) during monitoring visits. The CRAs will verify data recorded in the EDC system with 
source documents for completeness and accuracy. Data reported in the eCRFs that are derived 
from source documents should be consistent with the source documents or the discrepancies should 
be explained. All corrections or changes made to any study data in the EDC system will be 
appropriately tracked in an audit trail. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system that adheres to Title 21 of the US Code 
of Federal Regulations (21 CFR Part 11) compliance. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All clinical site personnel 
must log into the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with 21 CFR Part 11 and other appropriate 
international regulations. All passwords will be strictly confidential. 
11.1.4 
Medical Information Coding 
For medical information, the latest versions of the following thesauri will be used: 
 MedDRA for medical history and adverse events 
 WHO Drug Dictionary for prior and concomitant medications 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the clinical site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study drug, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the clinical site. Source data is defined as all information in original 
records and certified copies of original records of clinical findings, observations, or other activities 
in a clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer 


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or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.  
11.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last patient in the study.  
 


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
12.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
12.2 
Institutional Review Board/Independent Ethics Committee 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of patients. 
The study will only be conducted at clinical sites where IRB/IEC approval has been obtained. The 
protocol, Investigator’s Brochure, ICF, advertisements (if applicable), written information given 
to the patients, safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB/IEC by the Investigator. 
Federal regulations and ICH Guidelines require that approval be obtained from an IRB/IEC prior 
to participation of patients in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for patient recruitment, and any other written 
information regarding this study to be provided to a patient or patient’s legal guardian must be 
approved by the IRB/IEC. 
No drug will be released to a clinical site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. 
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator or designee (where locally 
permitted) will obtain written informed consent from each patient before any study-specific 
activity is performed and should document in the source documentation that consent was obtained 
prior to enrollment in the study. The original signed copy of the ICF must be maintained by the 
Investigator and is subject to inspection by a representative of the Sponsor, their representatives, 
auditors, the IRB/IEC and/or regulatory agencies. A copy of the signed ICF will be given to the 
patient. 
12.4 
Patient Card  
On enrollment in the study, the patient will receive a patient card to be carried at all times. The 
patient card will state that the patient is participating in a clinical research study and contact details 
in case of an emergency. 


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12.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC for clinical sites in the European Union, applicable 
regulatory requirements, and the Declaration of Helsinki and that valid data are entered into the 
eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and clinical site personnel the following documents: protocol, Investigator’s 
Brochure, eCRFs and procedures for their completion, informed consent process, and the 
procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the clinical site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the clinical site by signature and date on the study-specific monitoring log. 
12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/IEC as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 


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If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
12.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
12.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under US 21 CFR Part 54. In addition, Investigators must commit 
to promptly updating this information if any relevant changes occur during the study and for a 
period of 1 year after the completion of the study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who give their consent to the clinical study.  
12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable ethics 
opinion have been received. 


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by the Sponsor 
or their designee. All protocol amendments will undergo the same review and approval process as 
the original protocol. 
Written verification of IRB/IEC and Competent Authority approval will be obtained before any 
amendment is implemented that affects patient safety or the evaluation of safety, and/or efficacy. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC and 
Competent Authority approvals; however, the IRB/IEC and Competent Authority will be notified 
about an administrative change if required by local regulations. 
A protocol amendment may be implemented after it has been approved by the IRB/IEC and 
Competent Authority, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported according to the local 
regulations. 


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14 
REFERENCES 
1. 
Patel J, Bettencourt R, Cui J, et al. Association of noninvasive quantitative decline in 
liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. 
Therp Adv Gastroenterol. 2016;9(5):692-701. DOI: 10.1177/1756283X16656735.  
 
2.  
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor 
ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a 
multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
DOI: 10.1016/S0140-6736(14)61933-4. 
3.  
Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of 
non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, 
placebo-controlled, phase 2 trial. Lancet. 2018;391(10126):1174-1185. 
DOI: 10.1016/S0140-6736(18)30474-4. 
4. 
Harrison SA, Rossi SJ, Bashir MR, et al. NGM282 improves fibrosis and NASH-related 
histology in 12 weeks in patients with biopsy-confirmed NASH, which is preceded by 
significant decreases in hepatic steatosis, liver transaminases and fibrosis markers at 
6 weeks. Paper presented at: The EASL Congress. April 14, 2018. Paris, France. 
5. 
ENYO Pharma rodent NASH model internal report (Study Ref#SLMN089-1703-9-1).  
6. 
MDRD formula in Food and Drug Administration. Guidance for Industry: 
Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data 
Analysis, and Impact on Dosing and Labeling. 2010 March. 
7.  
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-Antiarrhythmic Drugs – Questions and Answers (R3) Guidance for Industry. 
June 2017. Available from: https://www.fda.gov/downloads/Drugs/Guidance 
ComplianceRegulatoryInformation/Guidances/UCM073161.pdf. 
8. 
Lucas KJ, Lopez P, Lawitz EJ, et al. Tropifexor, a highly potent FXR agonist, produces 
robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase 
in patients with fibrotic NASH after 12 weeks of therapy: Flight-FXR Part C interim 
results. American Association for the Study of Liver Diseases – 2019 Late-breaking 
abstracts. https://www.aasld.org/sites/default/files/2019-10/2019-TLM-
LateBreakingAbstracts.pdf. Accessed [02-March-2020].  
9. 
Lelli L, Castellini G, Gabbani T, et al. Associations between liver enzymes, 
psychopathological and clinical features in eating disorders. Eur Eat Disord Rev. 
2014;22(6):443-447. DOI: 10.1002/erv.2317.  
10. 
Caussy C, Reeder SB, Sirlin CB, et al. Non-invasive, quantitative assessment of liver fat 
by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018;Jan 21. 
DOI: 10.1002/hep.29797. 
11. 
Pavlides M, Banerjee R, Sellwood J, et al. Multiparametric magnetic resonance imaging 
predicts clinical outcomes in patients with chronic liver disease. J Hepatol. 
2016;64(2):308-315. DOI: https://doi.org/10.1016/j.jhep.2015.10.009.  
12. 
Banerjee R, Pavlides M, Tunnicliffe EM, et al. Multiparametric magnetic resonance for 
the non-invasive diagnosis of liver disease. J Hepatol. 2014;60(1):69-77. 
DOI: 10.1016/j.jhep.2013.09.002. 
13. 
Harrison S, Wilman H, Kelly M, et al. Prevalence and stratification of NAFLD/NASH in 
a UK and US cohort using non-invasive multiparametric MRI. J Hepatol. 
2018;(68)Supp.1:s550. DOI: 10.1016/S0168-8278(18)31359-X. 
 
 


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14.  
Banerjee R, Kelly M, Wilman H, et al. Imaging endpoints for non-alcoholic 
steatohepatitis (NASH) therapeutic trials: A growing role for multiparametric MRI? 
J Heptol. 2018;May 16. DOI: 10.1016/j.jhep.2018.04.022. 
15. 
NOVADISCOVERY: EYP001 In Silico Project Stage 5 Results. 31 May 2018. 
ENYO Pharma Internal Report Code EYP001SIL002. 
16.  
Patel YA, Imperial JC, Muir AJ, et al. Baseline parameters in clinical trials for 
nonalcoholic steatohepatitis: recommendations from the liver forum. Gastroenterology. 
2017;153(3):621-625.e7. DOI: 0.1053/j.gastro.2017.07.024. 
17.  
Siddiqui MS, Harrison SA, Abdelmalek MF, et al. Case definitions for inclusion and 
analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of 
regulatory science. Hepatology. 2018;67(5):2001-2012. DOI: 10.1002/hep.29607. 
18.  
Puri P, Daita K, Joyce A, et al. The presence and severity of nonalcoholic steatohepatitis 
is associated with specific changes in circulating bile acids. Hepatology. 2017;July 11. 
DOI: 10.1002/hep.29359. 
19. 
Obesity: preventing and managing the global epidemic. Report of a WHO consultation. 
World Health Organ Tech Rep Ser. 2000;894:i-xii, 1-253. 


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92
APPENDIX A: SCHEDULE OF PROCEDURES 
Table 7. 
Schedule of Procedures – Part A 
 
Screeninga
Treatment Period 
EOS FUP 
Visit  
 
 
 
ET Visitc 
Safety Run-In Period 
Continued Treatment 
Period 
Study Week  
-12 to -1 
0 
1 
2 
3 
4 
8 
12 
14 
Study Dayb 
Assessment 
-84 to -3 
Day 1  
Day 7 
Day 14 
Day 21 
Day 28 
Day 56 
Day 84 
Day 98 
Informed consent 
X 
 
Eligibility criteria 
X 
Xd
 
Demographics 
X 
 
Medical history  
X 
 
Prior/concomitant medicationse 
X 
X
X
X
X
X 
X
X
X
X
Height and body weightf 
X 
X
X
X
X
X 
X
X
X
X
BMI calculationg 
X 
X
X
X
X
X 
X
X
X
X
Waist circumferenceh 
X 
X
X
X
X
X 
X
X
X
X
Physical examinationi 
X 
X
X
X
X
X 
X
X
X
X
Vital signsj 
X 
X
X
X
X
X 
X
X
X
X
AUDIT-Ck 
X 
X
X
X 
X
X
X
Randomizationl 
 
X
 
Pruritus assessmentm 
 
X
X
X
X
X 
X
X
X
X
Adverse event monitoring 
X 
X
X
X
X
X 
X
X
X
X
Viral serologyn 
X 
 
Chemistry, hematology, 
coagulation, and lipid and 
metabolic profileo 
X 
X
X
X
X
X 
X
X
X
X
Urinalysisp 
X 
X
X
X
X
X 
X
X
X
X
Pregnancy testq 
X 
X
X
X
X
X 
X
X
X
X
12-Lead ECGr 
X 
X
X
X
X 
X
X
X
X
FibroScans 
X 
 
X
X
MRI-PDFF and cT1 imagingt 
X 
 
X
Xu
Diet/lifestyle counselingv 
X 
X
X
X
X
X 
X
X
X
X
PD biomarker samplingw 
 
X
X
X 
X
X
X
Xx 
Liver fibrosis and 
inflammation samplingy 
 
X
X
X
X 
X
X
X


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Table 7. 
Schedule of Procedures – Part A (Continued) 
 
Screeninga
Treatment Period 
EOS FUP 
Visit  
 
 
 
ET Visitc 
Safety Run-In Period 
Continued Treatment 
Period 
Study Week  
-12 to -1 
0 
1 
2 
3 
4 
8 
12 
14 
Study Dayb 
Assessment 
-84 to -3 
Day 1  
Day 7 
Day 14 
Day 21 
Day 28 
Day 56 
Day 84 
Day 98 
PK samplingz 
 
Xz
X
Xz
X
X 
X
X
X
Xx
Blood sampling for plasma 
storageaa 
X 
 
 
 
 
 
X
X
X
X
Dispense patient diary 
 
X
 
Dispense EYP001a or placebo 
 
Xbb
Xbb
X 
X
Collect used/unused study drug 
and assess compliance 
 
 
 
X
X 
X
X
 
X
Blood sample collection will be prioritized starting with the safety sample. All blood samples should be collected while the patient is in a fasted state, defined as nothing by 
mouth except water for 6 hours. Additional details on fasting during PK and PD sampling are provided in footnotes w and z, respectively. 
a. 
The Screening Period may be up to 12 weeks in duration. A patient who is first designated as a screen failure prior to being randomized may be rescreened upon Sponsor 
or designee approval. If the patient was screen failed after the MRI-PDFF was completed, the original MRI-PDFF scan may be utilized for rescreening, provided it was 
obtained within 1 month prior to rescreening. Patients will be prerandomized into the study once all eligibility criteria are confirmed.  
b. 
A 3-day window is acceptable for all visits during the Treatment Period, except for Days 1 and 14 of Part A, when the window is 1 day. 
c. 
Patients who discontinue early from the study for any reason prior to completion of the Treatment Period will be requested to return to the clinic for an ET Visit within a 
maximum of 48 hours after their last intake of study drug, regardless of how many days they participated in the study. Patients who discontinue early from the study for 
any reason after completion of the Treatment Period and before the EOS FUP Visit will be requested to return to the clinic for an ET Visit as soon as possible and no later 
than the planned EOS FUP Visit. 
d. 
Perform prior to dosing. 
e. 
Authorized medications per exception list and on a case-by-case basis, as documented by written approval from the Sponsor, are acceptable.  
f. 
Height assessed only at screening.  
g. 
Use screening height for BMI calculation. 
h. 
Measure the waist circumference at the end of several consecutive natural breaths, at a level parallel to the floor, midpoint between the top of the iliac crest and the lower 
margin of the last palpable rib in the mid axillary line. The tape should be placed around the abdomen at the level of this midway point and a reading taken when the tape 
is snug but does not compress the skin.  
i. 
A complete physical examination (including general appearance; eyes, ears, nose, and throat; head and neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; 
lymphatic; dermatological; neurological systems; mental status; and extremities) will be performed at screening. Brief, symptom-directed physical examinations will be 
performed on Days 1, 7, 14, 21, 28, 56, 84, and at the EOS and ET Visits. 
j. 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature and will be performed with the patient in the sitting position after 
5 minutes of rest and before any blood draws. Clinical site staff will use a mercury sphygmomanometer or automatic blood pressure device with an appropriately sized cuff 
with the bladder centered over the brachial artery. Clinical site staff will record the arm used for the measurement and use the same arm throughout the study. Clinical site 
staff will measure and record the blood pressure. Blood pressure will be recorded to the nearest 2 mmHg mark on the manometer or to the nearest whole number on an 
automatic device. A blood pressure reading will be repeated 1 to 2 minutes later, and the second reading will also be recorded to the nearest 2 mmHg mark. 
k. 
Patients with AUDIT-C scores 3 points at screening will receive the full AUDIT and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C 
scores <3 points will not receive the full AUDIT. 
l. 
Can occur after eligibility check on Day -3 at the earliest and prior to dosing on Day 1 at the latest. 


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m. Assess using a visual analog scale and 5-D questionnaire (degree, duration, direction, disability, and distribution) itch scale. 
n. 
Anti-HCV, anti-HIV, and anti-HBV status will be assessed, and HCV RNA will be reflexively tested. Samples will be collected for central laboratory analysis except if 
viral serology data is already available in patient’s medical history/records and obtained within 90 days prior to screening. 
o. 
Collected after 6 hours of fasting. See Appendix B for the complete list of clinical laboratory parameters. 
p. 
Urinalysis will be evaluated from samples collected after 6 hours of fasting. Further analysis of urine sediment or urine microscopy will be performed when there are any 
abnormalities on any of the following 3 dipstick results: leukocyte esterase, blood, or nitrite, and if judged clinically significant by the Investigator. 
q. 
For women of childbearing potential, a serum hCG test will be performed at screening and the EOS and ET Visits. Urine hCG testing will be performed at all other visits. 
If a urine hCG test is positive, a serum hCG test will be performed. Follicle-stimulating hormone level will be measured at screening to confirm postmenopausal state in 
women 55 years of age. 
r. 
Single 12-lead ECGs will be performed at screening; on Days 7, 14, 21, 28, 56, and 84; and at the EOS and ET Visits after the patient has been resting in the supine 
position for at least 10 minutes. In case of evident bad quality of the tracing (eg, muscle tremor), the ECG will be repeated. QT interval corrected for heart rate using 
Fridericia’s formula will be measured. 
s. 
FibroScan with the use of a probe appropriate for the patient’s stature for VCTE assessment of LSM for fibrosis and CAP for steatosis with cut-off values LSM 8.5 kPa 
and CAP >300 dB/m, respectively. Patients do not need to undergo a CAP assessment if their medical records indicate an MRI-PDFF LFC 10% within the 12 months 
prior to screening. Assessments at Day 84 and ET Visits are optional. 
t. 
Perform if FibroScan values (LSM and CAP) are within eligibility range; MRI-PDFF using standardized imaging acquisition calibration protocol and central reading to be 
performed at screening (as baseline value) and Week 12 or ET. 
u. 
Perform only for patients on study drug for 4 weeks.  
v. 
Diet/lifestyle counseling will occur as per standard of care at each study visit. High-level dietary and physical activity guidelines will be provided and documented in the 
eCRF. 
w. Intense PD sampling will occur on Day 1 (1 day) and Day 14 (1 day) of Part A at the following timepoints: 0 (predose, fasting), 4 (fasting), 6, 10, 12, and 24 hours 
postdose. Sparse PD sampling will also occur predose (fasting) and 2 hours postdose at the following visits: Days 28, 56, and 84. A sample will also be collected at the 
EOS and ET Visits. For BID dosing, PD sampling timepoints will be based on the time of morning dosing. Pharmacodynamic sampling will assess plasma levels of C4; 
FGF19; and total, primary, and secondary bile acids (such as CDCA, DCA, LCA, and/or others as appropriate). 
x. 
At the ET Visit (if applicable), a PK/PD sample should be collected, preferably within 24 to 48 hours of last intake of study drug. The date and time of the PK/PD draw 
and the last dose of study drug must be recorded in the eCRF. 
y. 
Liver fibrosis and inflammation parameters include ALT, AST, AST/ALT ratio, adiponectin, high sensitivity C-reactive protein, interleukin 6, tumor necrosis factor alpha, 
cytokeratin-18, fibronectin, hyaluronic acid, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases-1 (and derived enhanced liver fibrosis score), 
Pro-C3, and chitinase-3-like protein 1 (also known as YKL-40). 
z. 
Intense PK sampling will occur on Day 1 (1 day) and Day 14 (1 day) of Part A at the following timepoints: 0 (predose), 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; 
samples will be collected in the fasted state predose to 4 hours postdose, inclusive. Sparse PK samples will be collected for all other visits. Plasma samples to assess trough 
concentrations of EYP001a will be collected predose (fasting) in the morning and 2 hours postdose (an optional sample may also be collected at 6 hours postdose) at the 
following visits: Days 7, 21, 28, 56, and 84. A sample will also be collected at the EOS and ET Visits. For BID dosing, PK timepoints will be based on the time of morning 
dosing. 
aa. Plasma from blood samples will be stored for protocol-related safety testing or exploratory analyses. 
bb. During intense PK/PD sampling on Days 1 and 14 of Part A, dosing will occur with water only; blood sampling timepoints are fixed during this period. The start of meal 
times must be captured and can vary with meal times in the morning and evening – limited up to 3 main meals per 24 hours with 2-hour variability. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUDIT = Alcohol Use Disorders Identification Test; AUDIT-C = Alcohol Use Disorders Identification 
Test-Concise; BID = twice daily; BMI = body mass index; C4 = 7αhydroxy-4-cholesten-3-one; CAP = controlled attenuation parameter; CDCA = chenodeoxycholic acid; 
cT1 = iron-corrected T1; DCA = deoxycholic acid; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End of Study; ET = Early Termination; 
FGF19 = fibroblast growth factor 19; FUP = Follow-up; HBV = hepatitis B virus; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; LCA = lithocholic acid; LFC = liver fat content; LSM = liver stiffness measurement; MRI-PDFF = magnetic resonance imaging proton density fat 
fraction; PD = pharmacodynamic; PK = pharmacokinetic; RNA = ribonucleic acid; VCTE = vibration-controlled transient elastography.


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Table 8. 
Schedule of Procedures – Part B 
 
Screeninga 
Treatment Period  
EOS FUP 
Visit  
 
 
ET Visitc 
Study Week  
-12 to -1 
0 
2 
4 
6 
8 
10 
12 
14 
Study Dayb 
Assessment 
-84 to -3 
Day 1  
Day 14 
Day 28 
Day 42 
Day 56 
Day 70 
Day 84  
Day 98 
Informed consent 
X
 
Eligibility criteria 
X
Xd
 
Demographics 
X
 
Medical history 
Xe
 
Prior/concomitant medicationsf 
X
X
X
X
X
X
X
X
X
X
Height and body weightg 
X
X
X
X
X
X
X
X
BMI calculationh 
X
X
X
X
X
X
X
X
Waist and hip circumferencei 
X
X
X
X
X
X
X
X
WHR and WHtR calculationsh 
X
X
X
X
X
X
X
X
Physical examinationj 
X
X
X
X
X
X
X
X
Vital signsk 
X
X
X
X
X
X
X
X
AUDIT-Cl 
X
X
X
X
X
Randomizationm 
 
X
 
Adverse event monitoringe 
X
X
X
X
X
X
X
X
X
X
Viral serologyn 
X
 
Chemistry, hematology, and 
coagulationo 
X
X
X
X
Xp
X
Xp
X
X
X
Lipid and metabolic profileo 
X
X
X
X
X
X
X
X
Urinalysisq 
X
X
X
X
X
X
X
X
Pregnancy testr 
X
X
X
X
X
X
X
X
12-Lead ECGs 
X
X
X
X
X
X
X
FibroScant 
X
 
X
X
MRI-PDFF and cT1 imagingu 
X
 
X
Xv
Diet/lifestyle counselingw 
X
X
X
X
X
X
X
X
PD biomarker samplingx 
 
X
X
X
X
X
X
Xy
Liver fibrosis and inflammation 
samplingz 
 
X
X
X
X
X
PK samplingaa 
 
X
X
X
X
X
X
Xy
 
 


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Table 8. 
Schedule of Procedures – Part B (Continued) 
 
Screeninga 
Treatment Period  
EOS FUP 
Visit  
 
 
ET Visitc 
Study Week  
-12 to -1 
0 
2 
4 
6 
8 
10 
12 
14 
Study Dayb 
Assessment 
-84 to -3 
Day 1  
Day 14 
Day 28 
Day 42 
Day 56 
Day 70 
Day 84  
Day 98 
Blood sampling for plasma 
storagebb 
X 
X
X
X
X
X
X
X
Dispense EYP001a or placebo 
 
X
X
X
X
X
X
Collect used/unused study 
drug and assess compliance 
 
 
Xcc
Xcc
X
Xcc
Xcc
Xcc
 
X
Blood sample collection will be prioritized starting with the safety sample. All blood samples should be collected while the patient is in a fasted state, defined as nothing by 
mouth except water for 6 hours.  
a. 
The Screening Period may be up to 12 weeks in duration. A patient who is first designated as a screen failure prior to being randomized may be rescreened upon Sponsor 
or designee approval. If the patient was screen failed after the MRI-PDFF was completed, the original MRI-PDFF scan may be utilized for rescreening, provided it was 
obtained within 1 month prior to rescreening.  
b. 
A 3-day window is acceptable for all visits during the Treatment Period.  
c. 
Patients who discontinue early from the study for any reason prior to completion of the Treatment Period will be requested to return to the clinic for an ET Visit within a 
maximum of 48 hours after their last intake of study drug, regardless of how many days they participated in the study. Patients who discontinue early from the study for 
any reason after completion of the Treatment Period and before the EOS FUP Visit will be requested to return to the clinic for an ET Visit as soon as possible and no later 
than the planned EOS FUP Visit. 
d. 
Perform prior to dosing. 
e. 
If pruritus is reported, assess using a visual analog scale and 5-D questionnaire (degree, duration, direction, disability, and distribution) itch scale. 
f. 
Authorized medications per exception list and on a case-by-case basis, as documented by written approval from the Sponsor, are acceptable.  
g. 
Height assessed only at screening.  
h. 
Use screening height for BMI and WHtR calculations. 
i. 
Measure the waist circumference at the end of several consecutive natural breaths, at a level parallel to the floor, midpoint between the top of the iliac crest and the lower 
margin of the last palpable rib in the mid axillary line. The tape should be placed around the abdomen at the level of this midway point and a reading taken when the tape 
is snug but does not compress the skin. Measure the hip circumference at a level parallel to the floor, at the largest circumference of the buttocks. The tape should be 
placed around the hips and a reading taken when the tape is snug but does not compress the skin. Waist to hip ratio (WHR) and (WHtR) will be calculated at each visit in 
which assessed. 
j. 
A complete physical examination (including general appearance; eyes, ears, nose, and throat; head and neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; 
lymphatic; dermatological; neurological systems; mental status; and extremities) will be performed at screening. Brief, symptom-directed physical examinations will be 
performed on Days 1, 14, 28, 56, 84, and at the EOS and ET Visits. 
k. 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature and will be performed with the patient in the sitting position after 
5 minutes of rest and before any blood draws. Clinical site staff will use a mercury sphygmomanometer or automatic blood pressure device with an appropriately sized cuff 
with the bladder centered over the brachial artery. Clinical site staff will record the arm used for the measurement and use the same arm throughout the study. Clinical site 
staff will measure and record the blood pressure. Blood pressure will be recorded to the nearest 2 mmHg mark on the manometer or to the nearest whole number on an 
automatic device. A blood pressure reading will be repeated 1 to 2 minutes later, and the second reading will also be recorded to the nearest 2 mmHg mark. 
l. 
Patients with AUDIT-C scores 3 points at screening will receive the full AUDIT and will be excluded if they score 8 points on the full AUDIT. Patients with AUDIT-C 
scores <3 points will not receive the full AUDIT. 
m. Can occur after eligibility check on Day -3 at the earliest and prior to dosing on Day 1 at the latest. 


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n. 
Anti-HCV, anti-HIV, and anti-HBV status will be assessed, and HCV RNA will be reflexively tested. Samples will be collected for central laboratory analysis except if 
viral serology data is already available in patient’s medical history/records and obtained within 90 days prior to screening. 
o. 
Collected after 6 hours of fasting. See Appendix B for the complete list of clinical laboratory parameters.  
p. 
On Days 42 and 70 only ALT, AST, ALP, GGT, and total bilirubin will be measured. 
q. 
Urinalysis will be evaluated from samples collected after 6 hours of fasting. Further analysis of urine sediment or urine microscopy will be performed when there are any 
abnormalities on any of the following 3 dipstick results: leukocyte esterase, blood, or nitrite, and if judged clinically significant by the Investigator. 
r. 
For women of childbearing potential, a serum hCG test will be performed at screening and the EOS and ET Visits. Urine hCG testing will be performed at all other visits. 
If a urine hCG test is positive, a serum hCG test will be performed. Follicle-stimulating hormone level will be measured at screening to confirm postmenopausal state in 
women 55 years of age. 
s. 
Single 12-lead ECGs will be performed at screening; on Days 14, 28, 56, and 84; and at the EOS and ET Visits after the patient has been resting in the supine position for 
at least 10 minutes. In case of evident bad quality of the tracing (eg, muscle tremor), the ECG will be repeated. QT interval corrected for heart rate using Fridericia’s 
formula will be measured. 
t. 
FibroScan with the use of a probe appropriate for the patient’s stature for VCTE assessment of LSM for fibrosis and CAP for steatosis with cut-off values LSM 8.5 kPa 
and CAP >300 dB/m, respectively. Patients do not need to undergo a CAP assessment if their medical records indicate an MRI-PDFF LFC 10% within the 12 months 
prior to screening. Assessments at Day 84 and ET Visits are optional. 
u. 
Perform if FibroScan values (LSM and CAP) are within eligibility range; MRI-PDFF using standardized imaging acquisition calibration protocol and central reading to be 
performed at screening (as baseline value) and Week 12 or ET. 
v. 
Perform only for patients on study drug for 4 weeks. 
w. Diet/lifestyle counseling will occur as per standard of care at screening and on Days 1, 14, 28, 56, and 84; and at the EOS and ET Visits. High-level dietary and physical 
activity guidelines will be provided and documented in the eCRF. 
x. 
Sparse PD sampling will occur predose (fasting) at the following visits: Days 1, 14, 28, 56, and 84. A sample will also be collected at the EOS and ET Visits. 
Pharmacodynamic sampling will assess plasma levels of C4; FGF19; and total, primary, and secondary bile acids (such as CDCA, DCA, LCA, and/or others as 
appropriate). 
y. 
At the ET Visit (if applicable), a PK/PD sample should be collected, preferably within 24 to 48 hours of last intake of study drug. The date and time of the PK/PD draw 
and the last dose of study drug must be recorded in the eCRF. 
z. 
Liver fibrosis and inflammation parameters include ALT, AST, AST/ALT ratio, adiponectin, high sensitivity C-reactive protein, interleukin 6, tumor necrosis factor alpha, 
cytokeratin-18, fibronectin, hyaluronic acid, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases-1 (and derived enhanced liver fibrosis score), 
Pro-C3, and chitinase-3-like protein 1 (also known as YKL-40). 
aa. Sparse PK sampling will occur predose (fasting) at the following visits: Days 1, 14, 28, 56, and 84. A sample will also be collected at the EOS and ET Visits. 
bb. At screening and on Days 1, 14, 28, 56, and 84; and at the EOS and ET Visits, plasma from blood samples will be stored for protocol-related safety testing or exploratory 
analyses. 
cc. On Days 14, 28, 42, 56, 70, and 84, compliance will be assessed and study drug will be returned. In addition, on Days 14, 28, 42, 56, and 70 new study drug will be 
dispensed and dosing instructions provided.  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUDIT = Alcohol Use Disorders Identification Test; AUDIT-C = Alcohol Use Disorders Identification 
Test-Concise; BMI = body mass index; C4 = 7αhydroxy-4-cholesten-3-one; CAP = controlled attenuation parameter; CDCA = chenodeoxycholic acid; cT1 = iron-corrected T1; 
DCA = deoxycholic acid; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End of Study; ET = Early Termination; FGF19 = fibroblast growth factor 19; 
FUP = Follow-up; HBV = hepatitis B virus; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LCA = lithocholic acid; 
LFC = liver fat content; LSM = liver stiffness measurement; MRI-PDFF = magnetic resonance imaging proton density fat fraction; PD = pharmacodynamic; 
PK = pharmacokinetic; RNA = ribonucleic acid; VCTE = vibration-controlled transient elastography; WHR = waist to hip ratio; WHtR = waist to height ratio.
 
 


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Serum Chemistry Panel  
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Amylase  
Potassium 
Aspartate aminotransferase (AST) 
Sodium 
Blood urea nitrogen 
Total bilirubin [1] 
Calcium 
Total protein 
Creatine kinase (CK) 
Uric acid 
Creatinine 
 
CK-muscle/brain 
 
Estimation of glomerular filtration rate by the 
Modification of Diet in Renal Disease 
formula 
 
1. 
If >upper limit of normal, add conjugated (direct) bilirubin.
 
Additional Chemistry Parameters 
Alpha 2 macroglobulin 
Ferritin 
Autotaxin 
Phosphate 
Cardiac troponin I 
 
 
Efficacy Parameters  
ALT 
Adiponectin 
AST 
Cytokeratin-18 
AST/ALT ratio 
Interleukin 6 
Iron-corrected T1 
Fibronectin 
High sensitivity C-reactive protein 
Procollagen type III N-terminal peptide 
Tumor necrosis factor alpha 
Pro-C3 
Chitinase-3-like protein 1 (also known as 
YKL-40) 
Tissue inhibitor of metalloproteinases-1 (and 
derived enhanced liver fibrosis score) 
Hyaluronic acid 
 
 
Pharmacodynamic Parameters 
7αhydroxy-4-cholesten-3-one 
Fibroblast growth factor 19 
Total bile acids 
Chenodeoxycholic acid [1] 
Deoxycholic acid [1] 
Lithocholic acid [1] 
1. 
Plasma levels of total, primary, and secondary bile acids may be assessed as appropriate.
 


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Lipid and Metabolic Profile 
Branched-chain amino acid concentrations [1] 
Hemoglobin A1c 
 
Homeostatic model assessment for insulin resistance (morning fasting glucose and insulin) 
Lipoprotein insulin resistance index by nuclear magnetic resonance based on serum 
cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, 
triglycerides, apolipoprotein B, small dense-LDL, and lipoprotein(a) 
Lipoprotein particle size 
 
Small LDL particle number  
 
Small very low-density lipoprotein (VLDL) particle number  
 
VLDL size 
 
1. 
Liver function test.  
 
Endocrinology 
Human chorionic gonadotropin (hCG) [1] 
Free triiodothyronine 
Thyroid-stimulating hormone 
Follicle-stimulating hormone (FSH) [2] 
Free thyroxine  
 
1. 
Serum hCG pregnancy test at screening and at study exit (whether at the End of Study or Early Termination Visit). Only 
urine hCG tests will be performed at all other study visits. If the urine hCG test is positive, pregnancy will be confirmed by a 
serum hCG test. 
2. 
FSH level will be measured at screening to confirm postmenopausal state in women 55 years of age. 
 
Coagulation 
Activated partial thromboplastin time 
Fibrinogen 
International normalized ratio 
Prothrombin time 
 
Hematology 
Basophils [1] 
Eosinophils [1] 
Erythrocytes [2] 
Hematocrit [2] 
Hemoglobin [2] 
Leukocytes [2] 
Lymphocytes [1] 
Monocytes [1] 
Neutrophils [1] 
Platelets 
Red blood cell count 
Thrombocytes [1] 
White blood cell count and differential [3] 
 
1. 
Partial automated differentiation.  
2. 
Blood quantitatively.  
3. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 


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Urinalysis [1]  
Bilirubin 
Nitrite 
Blood [2] 
pH 
Glucose 
Protein 
Hemoglobin 
Specific gravity 
Ketones 
Urobilinogen 
Leukocytes 
 
1. 
Dipstick urine qualitatively. Further analysis of urine sediment or urine microscopy will be performed when there are 
any abnormalities on any of the following 3 dipstick results: leukocyte esterase, blood, or nitrite, and if judged 
clinically significant by the Investigator. 
2. 
Microscopy is performed only as needed based on positive dipstick test results.
 
Serology 
Hepatitis B virus  
 
Hepatitis C virus (and polymerase chain reaction ribonucleic acid for positive antibody 
samples) 
Human immunodeficiency virus  
 
 


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APPENDIX C: 5-D PRURITUS SCALE 
 


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APPENDIX D: PRURITUS VISUAL ANALOG SCALE 
 
 


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APPENDIX E: CLINICAL SAFETY MONITORING PLAN 
Throughout the study, all treatment-emergent adverse events, clinical assessments, and clinical 
laboratory parameters will be closely monitored against the criteria for drug-induced liver injury 
and muscle toxicity as detailed in this Clinical Safety Monitoring Plan.  
 
 


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DRUG-INDUCED LIVER INJURY MONITORING 
Drug-induced liver injury monitoring in patients with normal liver transaminases and bilirubin at 
baseline should be performed throughout the study according to the procedures summarized in the 
below diagram and text. 
 
AESI = adverse event of special interest; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DSMC = Data 
Safety Monitoring Committee; INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal. 
 


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1. Patients with normal liver transaminases and bilirubin at baseline. 
 If patients with normal baseline liver indices develop elevations of aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) >2  upper limit of normal (ULN) or total bilirubin 
(TBL) >1.5  ULN values during the study, repeat testing should be performed within 
48 hours.  
 If there are persistent elevations (ALT or AST >2  ULN or TBL >1.5  ULN) upon 
repeat testing, close observation (testing and physical examination 2 to 3 times per 
week) should be implemented. The Investigator will assess and record these events on 
an adverse event of special interest (AESI) form and send it to the ENYO safety 
designee via fax or email within 24 hours. 
 Study drug should be discontinued, and the patient should be followed until resolution of signs 
or symptoms, in the following situations:  
 ALT or AST >8  ULN. 
 ALT or AST >5  ULN for more than 2 weeks. 
 ALT or AST >3  ULN and (TBL >2  ULN or international normalized ratio [INR] 
>1.5). 
 ALT or AST >3  ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
For any patients who present with a constellation of syndromes indicative of liver disease as per 
the Investigator’s overall assessment (ie, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia [>5%]), perform liver function tests to determine if 
liver disease is worsening. 
Reinitiation of study drug may be considered after consultation with the Medical Monitor. 
In Part B, the Data Safety Monitoring Committee (DSMC) will be promptly notified for further 
review if any patients experience ALT, AST, or bilirubin elevations 2  above baseline values. 
2. Patients with elevations in liver transaminases or bilirubin at baseline. 
Drug-induced liver injury monitoring in patients with elevations in liver transaminases or bilirubin 
at baseline should be performed throughout the study according to the procedures summarized 
below. 
 If patients with abnormal baseline liver indices develop elevations of AST or ALT 
>2  baseline average or TBL >1.5  baseline average values during the study, repeat testing 
should be performed within 48 hours.  
 If there are persistent elevations (ALT or AST >2  baseline average or 
TBL >1.5  baseline average values) upon repeat testing, then close observation 
(testing and physical examination 2 to 3 times per week) should be implemented and 
discontinuation of study drug should be considered. The Investigator will assess and 
record these events on an AESI form and send to the ENYO safety designee via fax or 
email within 24 hours. 


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 Discontinue the study drug if any of the following occur:  
 Baseline average measurements were <2  ULN and ALT or AST increases to 
>5  baseline measurements. 
 Baseline average measurements were 2  ULN (but <5  ULN as per eligibility 
requirements) and ALT or AST increases to >3  baseline measurements. 
 Baseline average measurements were 5  ULN and ALT or AST increases to 
>2  baseline measurements. 
 ALT or AST increase >2  baseline average measurements AND the increase is 
accompanied by a concomitant increase in TBL to >2  baseline average measurements 
or the INR concomitantly increases by >0.2.  
For any patients who present with a constellation of syndromes indicative of liver disease as per 
the Investigator’s overall assessment (ie, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia [>5%]), perform liver function tests to determine if 
liver disease is worsening. 
Reinitiation of study drug may be considered after consultation with the Medical Monitor. 
In Part B, the DSMC will be promptly notified for further review if any patients experience ALT, 
AST, or bilirubin elevations 2  above baseline values. 
3. For all patients (with normal or elevated AST, ALT, and TBL at baseline), persistent elevations 
upon repeated testing should prompt close observation for suspected drug-induced liver injury. 
Close observation includes the following:  
 Repeating liver enzyme (ALT, AST, and alkaline phosphatase) and serum bilirubin tests 2 or 
3 times weekly.  
 The frequency of repeat testing can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the patient is asymptomatic. 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
 Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets. 
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy due to cardiovascular causes; and 
biliary tract disease. 
 Obtaining a history of exposure to environmental chemical agents. 
 Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct bilirubin). 
 Considering gastroenterology or hepatology consultations. 


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MUSCLE TOXICITY MONITORING 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; INR = international normalized ratio; 
TBL = total bilirubin; ULN = upper limit of normal. 
If a patient presents with muscular symptoms (ie, myalgia, weakness, dark urine) or creatine kinase 
(CK) elevation >3  ULN, the following actions should be taken: 
 Confirm CK elevation immediately. 
 If CK elevation is confirmed to be >3  ULN, perform/assess the following: 
 Electrocardiogram. 
 CK-muscle/brain. 
 Troponin I. 
 Serum creatinine. 
 Calcium and potassium. 
 ALT/AST, TBL, and direct bilirubin. 


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 Myoglobin (serum/urine). 
 Interview for recent intensive muscular effort, trauma, convulsion, electrical injury, 
injury or stress to skeletal muscle, intramuscular injections, recent surgery, 
concomitant medications, or consumption of alcohol, morphine, or cocaine. 
 Search for alternative causes to cardiac or muscular toxicity, ie, stroke, pulmonary 
infarction, dermatomyositis, polymyositis, convulsions, hypothyroidism, delirium 
tremens, or muscular dystrophies. 
 If cardiac origin and rhabdomyolysis is ruled out and CK <5  ULN, monitor CK every week 
until levels return to normal. 
 If cardiac origin, rhabdomyolysis, or CK 5  ULN, discontinue the study drug and monitor 
weekly; consider referral/hospitalization. 
For patients who experience a statin-related serious adverse event, collect pharmacokinetic blood 
samples for statin plasma concentration. 
Causality of muscular adverse events will be adjudicated by the Sponsor or designee using the 
Statin-Associated Muscle Symptom Clinical Index.1 
 
1 Rosenson RS, Miller K, Bayliss M, et al. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): 
revision for clinical use, content validation, and inter-rater reliability. Cardiovasc Drugs Ther. 2017;31(2):179-186. 
DOI: 10.1007/s10557-017-6723-4. 


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APPENDIX F: ALCOHOL USE DISORDERS IDENTIFICATION 
TEST-CONCISE 
The Alcohol Use Disorders Identification Test-Concise (AUDIT-C) has 3 questions and is scored 
on a scale of 0 to 12. Read the questions as written and circle the letter that corresponds to the 
answer. Each AUDIT-C question has 5 answer choices valued from 0 to 4 points. In men, a score 
of 4 or more is considered positive, optimal for identifying hazardous drinking or active alcohol 
use disorders. In women, a score of 3 or more is considered positive. Generally the higher the 
score, the more likely it is that a person’s drinking is affecting his or her safety.  
 
See answer module on the next page.  


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Answer Module  
Question 1: How often do you have a drink containing alcohol?  
 
Question 2: How many standard drinks containing alcohol do you have on a typical day?  
 
Question 3: How often do you have six or more drinks on one occasion?  
 
 


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APPENDIX G: THE ALCOHOL USE DISORDERS IDENTIFICATION 
TEST: INTERVIEW VERSION 
Read questions as written. Read answers carefully. Begin the AUDIT by saying “Now I am going 
to ask you some questions about your use of alcoholic beverages during this past year.” Explain 
what is meant by “alcoholic beverages” by using local examples of beer, wine, vodka, etc. Code 
answers in terms of “standard drinks.” Place the correct answer number in the box at the right. 
Total scores of 8 are recommended as indicators of hazardous and harmful alcohol use.  
 


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APPENDIX H: WORLD ALLERGY ORGANIZATION GRADING 
SYSTEM  
Table 9. 
World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction 
Grading System 
 
  


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Table 9. 
World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction 
Grading System (Continued) 
 


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APPENDIX I: CENTRAL LABORATORY REFERENCE RANGES 


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SAP_001.pdf: