A Study of the Oral Farnesoid X Receptor Modulator EYP001a to Assess Its Safety and Anti-viral Effect in Chronic Hepatitis B Patients in Combination With Pegylated Interferon alpha2a Alone and With Entecavir

Study Overview
=================
Brief Summary
-----------------
This is a multi centre, two parallel arm, randomized, open-label, Phase 2a experimental study of oral Farnesoid X Receptor (FXR) modulator EYP001a to assess its safety and anti-viral effect when administered to non-treated (treatment naive or off treatment) chronic Hepatitis B (CHB) patients in combination with entecavir (ETV) and pegylated interferon alpha2a (peg-IFN). An experimental treatment period of 16 weeks will be followed by a 24 week maintenance period with ETV standard of care (SoC).

Detailed Description
-----------------
In total 30 eligible patients will be enrolled and randomized at approximately 7 study sites. Patients will be randomized prior to study drug (EYP001a, ETV and peg-IFN) administration on Day 1 in the ratio of 1:1 into 2 treatment arms: Arm 1: EYP001a QD + ETV 0.5 mg QD + peg-IFN dosed per body surface area (180 µg, 135 µg or 90 µg) QW (± 3 days) (15 patients) Arm 2: EYP001a QD + peg-IFN dosed per body surface area (180 µg, 135 µg or 90 µg) QW (± 3 days) (15 patients) Patients enrolled in the study will be assessed as outpatients. Patient screening will occur no more than 37 days prior to the Day 1 visit. Eligible patients will undergo further assessments on Day 1 to qualify for study drug administration on Day 1. The visits during the study are planned as below: Screening visit: 5 weeks (37 days) 16 weeks treatment period 24 weeks maintenance period. During maintenance period patients are kept on ETV until the end of the trial at Week 40.

Official Title
-----------------
A Phase 2a Open-label Study of the Oral Farnesoid X Receptor (FXR) Modulator EYP001a to Assess Its Safety and Anti-viral Effect in Chronic Hepatitis B (CHB) Patients in Combination With Pegylated Interferon alpha2a (Peg-IFN) Alone and With Entecavir (ETV)

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: EYP001a
* Drug: Entecavir
* Drug: Pegylated interferon alpha2a


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has given voluntary written informed consent before performance of any study related procedure. Are treatment naive or without HBV treatment for at least 60 days or 5 times the elimination half-life, whichever is longer. Patient has CHB: HBV DNA ≥ 20,000 IU/mL for HBeAg positive and ≥2'000 for HBeAg negative and HBsAg ≥ 2.5 log10 IU/mL. Has liver imaging to screen for hepatocellular carcinoma or concomitant pancreaticobiliary disease either in the prior 6 months or at screening. 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. Exclusion Criteria: Is an employee of a clinical research organization, vendor, or Sponsor involved with this study. Has known hepatocellular carcinoma or pancreaticobiliary disease. Neutropenia (defined by two confirmed values during Screening period of < 1500/μL). Has Gilbert syndrome. 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. Has known or suspected non-CHB liver disease History of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of oesophageal varices. Probable or possible F4 stage with a vibration controlled transient elastography (VCTE) > 11.7 kPa leads to exclusion Has known history of alcohol abuse or daily heavy alcohol consumption Has any of the following exclusionary laboratory results at screening: ALT > 2 × ULN, AST > 2 × ULN INR > 1.2 × ULN, (normal range is 0.8 to 1.2) Platelet count < 100 G/L Estimated glomerular filtration rate < 50 mL/min/1.73m2 (the Modification of Diet in Renal Disease formula) Thyroid-stimulating hormone > 1.5 × ULN or abnormal free triiodothyronine or free thyroxine.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>EYP001a Dose A QD + ETV 0.5 mg QD + peg-IFN dosed per body surface area (180 µg, 135 µg or 90 µg) QW | Drug: EYP001a<br>* Oral tablets<br>Drug: Entecavir<br>* Oral tablets<br>Drug: Pegylated interferon alpha2a<br>* Subcutaneous<br>|
| Experimental: Arm 2<br>EYP001a Dose A QD + peg-IFN dosed per body surface area (180 µg, 135 µg or 90 µg) QW | Drug: EYP001a<br>* Oral tablets<br>Drug: Pegylated interferon alpha2a<br>* Subcutaneous<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent adverse events | Number of Treatment-emergent adverse events including serious adverse events | 16 weeks | 
| Measurement of HBsAg decline | Measurement of HBsAg decline (Δ log10) from Day 1 to Week 16 of treatment period | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of HBsAg decline | Measurement of HBsAg decline (Δ log10) | 40 weeks | 
| Measurement of HBV-DNA decline | Measurement of HBV-DNA decline (Δ log10) | 40 weeks | 
| Measurement of HBV-pgRNA decline | Measurement of HBV-pgRNA decline (Δ log10) | 40 weeks | 
| Measurement of HBcrAg decline | Measurement of HBcrAg decline (Δ log10) | 40 weeks | 
| Concentration of EYP001a - Pharmacokinetic | Assessment of fasted plasma concentrations of EYP001a or any active metabolites using a validated liquid chromatography-mass spectrometry | 20 weeks | 
| Concentration of C4 - Pharmacodynamic biomarker | Assessment of concentrations of plasma C4 (7α hydroxy 4 cholesten 3 one) | 40 weeks | 
| Concentration of FGF19 - Pharmacodynamic biomarker | Assessment of concentrations of plasma FGF19 over time (Fibroblast Growth Factor 19) | 40 weeks | 
| Concentration of Bile Acids - Pharmacodynamic biomarker | Assessment of concentrations over time of plasma Bile Acids (chenodeoxycholic acid, deoxycholic acid, lithocholic acid) | 40 weeks |