chronic Hepatitis B

Primary Objective: • To determine the safety and tolerance of EYP001a administered in combination with peg-IFN alone or with ETV and peg-IFN over 16 weeks. • To determine effect of EYP001a administered in combination with peg-IFN alone or with ETV and peg-IFN, on hepatitis B surface antigen (HBsAg) plasma levels. Secondary Objectives: • To determine response of hepatitis B virus (HBV) replication markers (HBV-deoxyribonucleic acid [DNA], HBsAg, hepatitis B envelope antigen [HBeAg]) and early viral response markers HBV pregenomic/precore ribonucleic acid (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of the 16-week EYP001a treatment and of the Week 40 maintenance period. • To establish the HBV virologic failure rate (breakthrough)1 during the 24 weeks maintenance period after stopping EYP001a but with ongoing ETV therapy . • To determine the plasma concentration of EYP001a and pharmacodynamic (PD) markers (plasma C4 [7α-hydroxy-4-cholesten-3-one], fibroblast growth factor 19 [FGF19], bile acids [BAs])

EYP001a

EYP001a

Tablet

200

Main evaluation indicators
The safety and tolerability evaluated according to the following items:
o Frequency of stopping rules events
o Treatment-emergent adverse events (TEAEs) (including serious adverse events [SAEs])
o All-cause mortality
o Clinical laboratory tests
o Pruritus assessment
o Vital signs (blood pressure [BP], heart rate, respiratory rate and temperature)
o Concomitant medications
o Physical examinations
o 12-lead electrocardiogram (ECG)

The role of EYP001a evaluated according to the following items:
The amount of HBsAg decrease from day 1 to week 16 of the treatment period (Δ log10)

1. Has given voluntary written informed consent before performance of any study related procedure.
2. Must be 18 to 65 years of age, both inclusive. (Taiwan only recruit 20 to 65 years of age inclusive)
3. Are treatment naive or without HBV treatment for at least 60 days or 5 times the elimination half-life, whichever is longer.
4. Patient has CHB:
a. HBV DNA ≥ 20,000 IU/mL for HBeAg positive and > 2’000 for HBeAg negative and
b. HBsAg ≥ 2.5 log10 IU/mL.
5. Has liver imaging to screen for hepatocellular carcinoma or concomitant pancreaticobiliary disease either in the prior 6 months or at screening.
6. Has liver tests during the Screening period defined as follows:
a. Two baseline values (i.e. two measurements: one can be from medical history if not older than 12 months and one during Screening period) with both measurements of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2 × upper limit of normal (ULN)
b. Normal levels of alkaline phosphatase (ALP) ≤ 1.5 × ULN
c. Patient should have total bilirubin (TBL) ≤ 22.2 μmol/L, which corresponds to ≤ 1.3 mg/dL
d. Has conjugated (direct) bilirubin of ≤ 0.3 mg/dL
e. Has normal gamma-glutamyl transferase (GGT) or clinically non-relevant levels of GGT (≤ 2.0 ULN)
f. International normalized ratio (INR) ≤ 1.2 × ULN (normal range is 0.8 to 1.2)
g. Platelet co unt ≥ 100 G/L
h. Has albumin ≥ 3.5 g/dL.
7. Patient is not of childbearing potential 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.
8. Women of childbearing potential (WOCBP) and male patients with WOCBP partners must agree to use a dual method of contraception as defined in the study protocol or practice complete abstinence from sexual intercourse if this is the patient’s usual and preferred lifestyle throughout the duration of the study and for 90 days after stopping study drug. Patients who are using hormonal contraceptives should be instructed to use an additional contraceptive measure during the study.
Male patients must also refrain from donating sperm from the date of dosing until 90 days after the last dose of the IP.
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.

1. Is an employee of a clinical research organization, vendor, or Sponsor involved with this study.
2. Has known hepatocellular carcinoma or pancreaticobiliary disease.
3. Neutropenia (defined by two confirmed values during Screening period of < 1500/μL).
4. Has Gilbert syndrome.
5. Shows evidence of worsening liver tests, defined as either a confirmed (2 assessments at least 3 days apart) increase > 2 ULN ALT or AST or an increase of > 1.5 × baseline value of TBL or associated with clinical signs or symptoms of liver impairment.
6. Has known or suspected non-CHB liver disease, including, but not limited to, Hepatitis D virus coinfection, alcoholic liver disease, non-alcoholic steatohepatitis (NASH) diagnosed with liver biopsy, autoimmune disease, human immunodeficiency virus, active hepatitis C virus (HCV ), Wilson’s disease, hemochromatosis, hepatocellular carcinoma (normal alpha-fetoprotein [AFP] at screening required) or suspected or known other liver cancer, primary biliary cholangitis, primary sclerosing cholangitis, druginduced liver injury (DILI), bile duct obstruction.
7. History of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of oesophageal varices.
8. Probable or possible F4 stage with a vibration controlled transient elastography (VCTE) > 11.7 kPa leads to exclusion .
9. 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.
10. Is pregnant or breastfeeding.
11. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
12. Has a known pre-existing 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.
13. Has known dyslipidaemia and a higher cardio-vascular risk from worsening lipid parameters because of history of clinically significant cardiovascular or cerebrovascular disease during 12 months prior to study entry.
14. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular disease within 12 months 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.
15. Has participated in any drug study with administration of an investigational drug in the past 30 days, or 5 halflives, whichever is longer, prior to the first study drug administration in the current study.
16. Has had major surgery within 30 days prior to the first study drug administration in the current study.
17. 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
b. Immediate allergic signs (e.g., rhinoconjunctivitis, respiratory) with 2 or more episodes (at whatever time in medical history) due to an identified drugs or food (seasonal rhinoconjunctivitis is not an exclusion)
c. Has ongoing urticaria episodes (attributed to whatever allergen) or has other active (current) immediate type reaction allergies (e.g., allergic rhinoconjunctivitis, allergic asthma, or latex allergy).
d. Has had a moderate or severe allergic reaction (Grade 2 per the World Allergy Organization reference table, i.e., isolated non-drug induced urticaria of Grade 1 is not relevant)
e. Has any allergic condition that might require an emergency epinephrine injection (similar to the EpiPen® Auto-Injector).
18. Is using any of the following disallowed medications within 30 days or 5 half-lives prior to screening whichever is longer, or planned use later during study participation are: vitamin K antagonists such as warfarin, anticancer drug(s) (except anti-hormonal which are allowed), immunomodulator(s), or immunosuppressant(s) or any drug with known liver toxicity for > 2 weeks duration in the year prior to screening (e.g., amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, estrogens at doses greater than those used for hormone replacement, anabolic steroids, or valproic acid or other known hepatotoxins at the Investigator’s discretion), ursodeoxycholic acid, or obeticholic acid. Agents (including over-the-counter weight loss preparations) or medications known to significantly impact body weight (e.g., sibutramine, phenetamine, and orlistat).
19. Statins other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatine or lovastatin.
20. Has planned major visceral or orthopaedic surgery during the study period.
21. Has uncontrolled type 1 diabetes mellitus or type 2 diabetes mellitus (T2DM) with glycated haemoglobin (HbA1c) > 9.5%.
22. Has any of the following exclusionary laboratory results at screening:
a. ALT > 2 × ULN, AST > 2 × ULN
b. INR > 1.2 × ULN, (normal range is 0.8 to 1.2)
c. Platelet count < 100 G/L
d. Estimated glomerular filtration rate < 60 mL/min/1.73m2 (the Modification of Diet in Renal Disease formula)
e. 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.
23. Has history of clinically significant gastrointestinal disease, especially peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, bariatric surgery, renal, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease 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.