Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of EYP001a in Healthy Volunteers and Nonalcoholic Steatohepatitis Patients

A Phase 1b, Open-label Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FXR Agonist/Modulator EYP001a in Healthy Volunteers and Nonalcoholic Steatohepatitis Patients

This is a single centre, open label, randomized, 3 treatment arms, with and without food dosing, Phase 1b pharmacology study to assess the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Farnesoid X Receptor (FXR) agonist/modulator EYP001a in healthy volunteers and Nonalcoholic Steatohepatitis (NASH) patients.

Study Overview

• Status: Completed
• Conditions: Healthy; NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: EYP001a

Detailed Description

In total 16 participants (4 healthy volunteers and 12 NASH patients) will be enrolled and randomly assigned to one of the 3 treatment arms:

• Treatment Arm 1: Dose A once daily morning dose (n=4 NASH patients, n=4 healthy volunteers)
• Treatment Arm 2: Dose B once daily morning dose (n=4 NASH patients)
• Treatment Arm 3: Dose C twice daily - first morning dose and second dose 3 hours post first dose (n=4 NASH patients).

Subsequently, all the enrolled participants (both healthy volunteers and NASH patients) will be randomly assigned to one of the 2 parallel study Groups:

• Group A (n=8, 2 healthy volunteers and 6 NASH patients): This group will include 2 NASH patients from Treatment Arms 1, 2 and 3 and 2 healthy volunteers from Treatment Arm 1. Participants in Group A will be dosed in a fasted state on Days 2, 3, 4 and 5 followed by dosing in fed state on Days 6, 7, 8 and 9.
• Group B (n=8, 2 healthy volunteers and 6 NASH patients): This group will include 2 NASH patients from Treatment Arms 1, 2 and 3 and 2 healthy volunteers from Treatment Arm 1. Participants in Group B will be dosed in a fed state on Days 2, 3, 4 and 5 followed by dosing in fasted state on Days 6, 7, 8 and 9.

The maximum total engagement duration for eligible participants in this study is up to 76 days: 60 days screening, 1-day admission visit and 8 days dosing period (in-patient in clinical trial unit) and 7 days follow-up.

The participants who are eligible for enrolment will be admitted to the Clinical Trial Unit on Day 1. The participants will receive EYP001a at the study site by trained personnel per the schedule of dosing for the study from Day 2 to Day 9 in fed/fasted state depending upon the study group. Participants will be discharged on the morning (8:00 AM) of Day 10 after collection of last PK and PD blood samples. Participants will return to the Clinical Trial Unit on Day 16 for the follow-up visit.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia
      • ENYO Pharma clinical site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Have given voluntary written informed consent;
2. Male/female participants aged 18 years to 75 years with a Body Mass Index (BMI) ≥ 25 kg/m² and ≤ 45 kg/m² at screening.

3. A female participant is eligible to participate in this study if:

   1. She is of non-childbearing potential (defined as females with a documented tubal ligation, bilateral oophorectomy or hysterectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone level within the laboratory's reference range for postmenopausal females). A post-menopausal female receiving hormone replacement therapy (HRT) other than hormone replacement patches who is willing to discontinue hormone therapy 28 days before study drug dosing and agrees to remain off hormone replacement therapy for the duration of the study may be eligible for study participation. A post-menopausal female using Hormone Replacement patches who is willing to discontinue the patch 48 hours before Check in on Day -1 and until the completion of her End of Study visit is eligible for study participation.
   2. She is of childbearing potential and is non-pregnant or non-lactating and willing to use adequate contraception from screening until 3 months after the End of Study visit. Adequate contraception is defined as a progesterone only intra uterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence in accordance with the lifestyle of the participant is acceptable.
   3. She is of childbearing potential and is non-pregnant or non-lactating and taking the combined oral contraceptive pill and willing to discontinue the combined oral contraceptive pill 7 days prior to check in on Day -1 and until the completion of her End of Study visit and use adequate contraception from the day of cessation. Adequate contraception is defined as a diaphragm or cervical cap together with a condom. Also, total abstinence in accordance with the lifestyle of the participant is acceptable.
4. Have Alanine Aminotransferase (ALT) >1.5 upper limit of normal (ULN) during screening period.
5. Fibroscan® Vibration-Controlled Transient Elastography (VTCE) liver stiffness (liver stiffness measure (LSM) for >8.5 kPa) and steatosis (Controlled Attenuation Parameter (CAP) ≥250 decibels per meter (dB/m)).
6. Normal liver function at screening for alkaline phosphatase (ALP), Total Bilirubin (TBL), conjugated Bilirubin, platelets, International normalized ratio (INR).

Nota Bene: Criteria 4 and 5 do not apply to healthy volunteers.

Exclusion Criteria:

1. Employee of a contract research organization (CRO) participating in this study or the Sponsor.
2. Patients with known non-NASH chronic liver disease (alcohol, autoimmune, Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), active hepatitis C virus (HCV)).
3. Female with childbearing potential if no dual safe anti-contraception method can be provided.
4. Renal impairment (participants with an estimated glomerular filtration rate (eGFR) computed from the Modification of Diet in Renal Disease (MDRD) formula of < 60ml/min/1.73m² are excluded). Note: participants with mild renal impairment (eGFR >60 ml/min and ≤90 ml/min) are eligible.
5. Has clinically relevant immunosuppression from, but not limited to immunodeficiency conditions such as common variable hypogammaglobulinemia.
6. Has any known pre-existing medical or psychiatric condition that could interfere with the participant's ability to provide informed consent or participate in study conduct, or that may confound study findings.
7. Has a history of clinically significant gastrointestinal (GI) disease, especially peptic ulcerations, GI bleeding, ulcerative colitis, Crohn's disease or Inflammatory Bowel Syndrome, renal, hepatic, 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 participant or impact the validity of the study results.
8. Has participated in any drug study within 60 days prior to the first drug administration in the current study.
9. Has had major surgery within 30 days prior to the first drug administration.
10. Concomitant use of not listed drugs after discussion with Sponsor not admitted.
11. Has a history of relevant drug and/or food allergies

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: EYP001a Dose A; Dose A once daily morning dose	Drug: EYP001a; Oral tablets
Experimental: 2: EYP001a Dose B; Dose B once daily morning dose	Drug: EYP001a; Oral tablets
Experimental: 3: EYP001a Dose C; Dose C twice daily - first dose morning dose and second dose 3 hours post first dose	Drug: EYP001a; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum plasma concentration (Cmax) of EYP001a	Day 2 through day 9
Time to reach maximum concentration (Tmax) after EYP001a administration	Day 2 through day 9
Area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUC0-10h and AUClast) of EYP001a	Day 2 through day 9
Area under the concentration-time curve (AUC) and Maximum plasma concentration (Cmax) ratios	Day 2 through day 9
Type and frequencies of Adverse events	Day 1 through day 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bile acid precursor : C4 (7αhydroxy-4-cholesten-3-one)	pg/mL (picogram per milliliter). These will be measured in plasma samples using a validated method	Day 2 through day 9
Bile acid precursor : Fibroblast growth factor 19 (FGF19)	mg/mL (milligram per milliliter). These will be measured in plasma samples using a validated method	Day 2 through day 9
Total Bile acids (secondary and primary)	These will be measured in plasma samples using a validated method	Day 1 through day 9

Collaborators and Investigators

• Sponsor: Enyo Pharma

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2019
• Primary Completion (Actual): May 25, 2020
• Study Completion (Actual): May 25, 2020

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 5, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): September 25, 2020
• Last Update Submitted That Met QC Criteria: September 24, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: EYP001-107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No