A Randomized, Double-blind Study to Assess the Safety and Efficacy of EDP-305 in Subjects With Liver-biopsy Proven NASH

A Phase 2b Randomized, Double-Blind, Placebo-controlled, Multicenter Study Evaluating Safety and Efficacy of EDP-305 in Subjects With Liver Biopsy Proven Non-alcoholic Steatohepatitis (NASH) (ARGON-2)

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

Study Overview

• Status: Terminated
• Conditions: Non-Alcoholic Steatohepatitis
• Intervention / Treatment: Drug: Placebo; Drug: EDP-305 1.5 mg; Drug: EDP-305 2 mg

Detailed Description

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

This Phase 2b study aimed to evaluate the safety and efficacy of two doses of EDP-305 compared to placebo for the treatment of NASH in subjects with liver biopsy proven NASH. As suggested in the FDA guidance, this late stage Phase 2 study explored the effect of EDP-305/placebo treatment on histological endpoints. The patient population selected for inclusion in the study was designed to represent the target population for treatment. Specifically, in patients with liver disease, there is a significant overlap of NASH and various metabolic conditions including obesity and T2DM. In order to be reflective of the NASH population, these patients were not excluded from participation in this study.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Enanta Pharmaceuticals, Inc; Phone Number: 617 607 0705; Email: nadda@enanta.com

Study Locations

• Argentina
  • Caba
    • Buenos Aires, Caba, Argentina, C1056AB
      • CINME
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
• Germany
  • Hessen
    • Frankfurt am Main, Hessen, Germany, 60590
      • Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz KoeR
• Puerto Rico
  • San Juan, Puerto Rico, 00909
    • Latin Clinical Trial Center
• United Kingdom
  • Middlesex, United Kingdom, HA6 2RN
    • MeDiNova North London Quality Research Site
  • Berkshire
    • Wokingham, Berkshire, United Kingdom, RG40 1XS
      • MeDiNova West London Quality Research Site
  • Essex
    • Romford, Essex, United Kingdom, RM1 3PJ
      • MeDiNova East London Quality Research Site
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • King's College Hospital - King's College Hospital NHS Foundation Trust
  • Kent
    • Sidcup, Kent, United Kingdom, DA14 6LT
      • MeDiNova South London Quality Research Site
  • Northamptonshire
    • Corby, Northamptonshire, United Kingdom, NN18 9EZ
      • MeDiNova Northampton Dedicated research site
  • Warwickshire
    • Kenilworth, Warwickshire, United Kingdom, CV81JD
      • MeDiNova Warwickshire Quality Research Site
  • Yorkshire
    • Shipley, Yorkshire, United Kingdom, BD18 3SA
      • Medinova Yorkshire Quality Research Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Arizona Liver Health
    • Glendale, Arizona, United States, 85306
      • The Institute of Liver Health
    • Phoenix, Arizona, United States, 85013
      • Dignity Health DBA St. Joseph's Hospital and Medical Center
    • Tucson, Arizona, United States, 85710
      • Del Sol Research Management LLC
  • California
    • Bakersfield, California, United States, 93309
      • Rajeev Krishan, MD, Inc
    • Chula Vista, California, United States, 91911
      • eStudy Site
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • Fullerton, California, United States, 92835
      • St. Jude Hospital Yorba Linda dba St. Joseph Heritage Healthcare
    • Garden Grove, California, United States, 92844
      • National Institute of Clinical Research, Inc
    • La Mesa, California, United States, 91942
      • eStudySite - La Mesa
    • Lancaster, California, United States, 93534
      • Om Research LLC
    • Los Angeles, California, United States, 90033
      • Keck Medical Center of USC
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Clemente, California, United States, 92673
      • Southern California Gastrointestinal and Liver Centers
    • San Diego, California, United States, 92114
      • Precision Research Institute, LLC
    • Torrance, California, United States, 90502
      • Paradigm Clinical Research Institute
  • Florida
    • Doral, Florida, United States, 33166
      • Universal Axon Clinical Research
    • Fleming Island, Florida, United States, 32003
      • Fleming Island Center for Clinical Research
    • Homestead, Florida, United States, 33030
      • Universal Axon- Homestead, LLC
    • Inverness, Florida, United States, 34452
      • Nature Coast Clinical Research
    • Jacksonville, Florida, United States, 32205
      • Westside Center for Clinical Research
    • Jacksonville, Florida, United States, 32256
      • ENCORE Borland Groover Clinical Research
    • Jacksonville, Florida, United States, 32226
      • Jacksonville Center for Endoscopy - Southside ; Borland Groover Clinic
    • Lakeland, Florida, United States, 33803
      • Meridien Research
    • Maitland, Florida, United States, 32751
      • Meridien Research
    • Miami, Florida, United States, 33173
      • Well Pharma Medical Research, Corp.
    • Miami, Florida, United States, 33186
      • Med Research Of Florida, LLC
    • Miami, Florida, United States, 33134
      • Research Associates of South Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine-Don Soffer Clinical Research Center
    • Miami Lakes, Florida, United States, 33014
      • San Marcus Research Clinic, Inc.
    • Ocala, Florida, United States, 34471
      • Ocala GI Research
    • Palmetto Bay, Florida, United States, 33157
      • IMIC, Inc.
    • Saint Petersburg, Florida, United States, 33709
      • Meridien Research
    • Tampa, Florida, United States, 33614
      • Guardian Angel Research
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • AGILE Clinical Research Trials, LLC
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612-3852
      • Rush University Medical Center - University Cardiovascular Surgeons
  • Indiana
    • South Bend, Indiana, United States, 46635
      • Digestive Research Alliance of Michiana
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital & Clinics
  • Louisiana
    • New Orleans, Louisiana, United States, 70115-6969
      • Ochsner Health System
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Catonsville, Maryland, United States, 21228
      • Digestive Disease Associates, PA
    • Greenbelt, Maryland, United States, 20770
      • Mid-Atlantic GI Research
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Southern Therapy and Advanced Research LLC GI Associates and Endoscopy Center
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis Univ. School Of Medicine
  • New Jersey
    • Egg Harbor Township, New Jersey, United States, 08234
      • AGA Clinical Research Associates, LLC
  • New York
    • Fresh Meadows, New York, United States, 11366
      • Intercity Gastroenterology
    • New York, New York, United States, 10016
      • New York University Medical Centre
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center School of Medicine and Dentistry
  • North Carolina
    • Concord, North Carolina, United States, 28027
      • Northeast GI Research Division
    • Huntersville, North Carolina, United States, 28078
      • Carolinas HealthCare System Digestive - Huntersville
    • Morehead City, North Carolina, United States, 28557
      • Lucas Research
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Taussig Cancer Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Center for Liver Diseases
  • Tennessee
    • Hermitage, Tennessee, United States, 37076
      • Digestive Health Research, LLC
    • Lebanon, Tennessee, United States, 37090
      • Digestive Health Research
    • Nashville, Tennessee, United States, 37211
      • Quality Medical Research
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute
    • Austin, Texas, United States, 78749
      • Texas Diabetes & Endocrinology
    • DeSoto, Texas, United States, 75115
      • Crescent Health Clinical
    • Garland, Texas, United States, 75044
      • DHAT Research Institute
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, Inc.
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at the Texas Liver Institute
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours St. Mary's Hospital of Richmond, Inc
  • Washington
    • Seattle, Washington, United States, 98105
      • Liver Institute Northwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent documentation signed and dated by the participant.
• Male and female participants, of all ethnic origins, between the ages of 18 and 75 years, inclusive.
• Participants of all ethnic origins had to have a Body Mass Index (BMI) > 25 kg/m2 and ≤ 45 except Asian participants who qualified for the study with BMI > 23 kg/m2.
• Histological evidence of definite NASH based on NASH Clinical Research Network (CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. The biopsy may be obtained either 1) during the Screening window or 2) within 26 weeks prior to the Screening visit.
• NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2).
• Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System.
• Participants had to have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. [Note: participants previously infected by chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) for at least 3 years were allowed.]
• A woman of childbearing potential who was sexually active with a male had to agree to use two effective methods of contraception from the date of Screening until 30 days after the last dose of study drug.
• A male participant who had not had a vasectomy and was sexually active with a woman of childbearing potential had to agree to use effective contraception from the date of Screening to 90 days after the last dose of study drug.
• Participant had to be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol.

Exclusion Criteria:

• Laboratory Screening results as indicated below:

  • Total white blood cells (WBC) <3000 cells/mm3
  • Absolute neutrophil count (ANC) <1500 cells/mm3
  • Platelet count <140,000/mm3
  • International Normalized Ratio, INR >1.2 (unless due to use of anticoagulants)
  • Estimated glomerular filtration rate (eGFR) < 60 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation
  • AST ≥5× ULN
  • ALT ≥5× ULN
  • ALP ≥2× ULN
  • Total bilirubin > 1.5 times ULN during Screening. [Note: Patients with Gilbert's syndrome were allowed following review by the Medical Monitor if they had a known history of Gilbert's syndrome with a normal direct bilirubin value and normal reticulocyte count.]
• Pregnant or nursing females.
• MELD: Model for End-stage Liver Disease score >12.
• Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC).
• History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute biliary obstruction) unless the participant had a cholecytectomy (more than 3 months prior to screening).
• History of liver transplant, or current placement on a liver transplant list.
• Hepatorenal syndrome (type I or II).
• Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of Screening and/or histological presence of liver cirrhosis.
• Prior or planned ileal resection, or prior or planned bariatric surgery. [Note: Participants who had undergone gastric surgeries that did not affect drug absorption (e.g., gastric band or gastric sleeve procedures) were allowed if they were stable for at least 1 year prior to Screening. Gastrectomy or Roux-en-Y bypass was allowed if stable for at least 3 years prior to Screening.]
• Participants with clinically or otherwise documented cardiovascular or cerebrovascular disease including clinically significant anomalies of rhythm or pattern of ECG, that in the judgement of the Principal Investigator (PI) could affect the safety of the participant or their ability to comply with the study requirements.
• HbA1c ≥ 9.5% within 60 days prior to Day 1.
• Use of a new antidiabetic regimen in the months prior to Screening including metformin, glucagon-like peptide (GLP) 1 agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated receptor (PPAR)γ agonists (e.g., pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, participants were to be on a stable dose of antidiabetic drugs: (1) for at least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to Screening with the intention to keep the regimen stable during the study.
• Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to Screening.
• Use of a new fibrate regimen from 12 weeks prior to Screening.
• Participants with contraindications to MRI imaging, or not being able to have the MRI performed.
• Participant had received any investigational agent (including investigational vaccine) or biological product within 30 days or 5 times the half-life (whichever was longer) prior to the planned first dose of study drug.
• Use of an experimental or approved treatment for NASH within 26 weeks of Screening.
• Prior use of OCA within 26 weeks of Screening and/or concurrent treatment with OCA (or any other FXR agonists).
• Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in duration within 1 year prior to Screening with the intention to continue during the study (chronic use of inhaled, topical, ophthalmological, nasal corticosteroids was allowed)
• Use of any prohibited concomitant medications, including systemic CYP3A4 inhibitors and inducers, within 14 days prior to the first dose of study drug and for the duration of the study.
• Clinically significant history of drug sensitivity or drug allergy, as determined by the PI.
• Current or history of significant alcohol consumption defined as: >14 standard drinks per week and/or ≥4 standard drinks per occasion for males and >7 standard drinks per week and/or ≥3 standard drinks per occasion for females.
• History of substance (including alcohol) abuse and in the judgement of the PI, the participant was not suitable for participation in the study.
• Any other condition(s) that would compromise the safety of the participant or compromise the quality of the clinical study, as judged by the PI.
• Use of medication for weight loss or appetite reduction (e.g., orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-prescription supplements) at Screening.
• History of malignancy of any organ system (other than localized and considered cured cutaneous basal or squamous cell carcinoma, or in situ cervical cancer), treated or untreated, within 5 years of Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EDP-305 1.5 mg; Once a day orally for 72 weeks	Drug: EDP-305 1.5 mg; Tablet; Other Names: EDP-305
Experimental: EDP-305 2 mg; Once a day orally for 72 weeks	Drug: EDP-305 2 mg; Tablet; Other Names: EDP-305
Placebo Comparator: Placebo; Once a day orally for 72 weeks	Drug: Placebo; Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Who Achieve ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis and/or Resolution of Steatohepatitis and no Worsening of Liver Fibrosis as Determined by Liver Biopsy	Proportion of participants who achieve ≥1 stage improvement in fibrosis without worsening of steatohepatitis and/or resolution of steatohepatitis and no worsening of liver fibrosis as determined by liver biopsy.	Week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 5D-itch Scale From Baseline	5D-itch scale, change from baseline at Week 12. Change from baseline for 5D-itch scale was analyzed using a restricted maximum likelihood-based mixed model repeated measures (MMRM) technique. The model included treatment, visit, treatment-by-visit interaction as fixed effects along with baseline NAS score and baseline score for 5D-itch scale as covariate. A multidimensional 5D-itch scale developed by Elman (Elman et al., 2010) indicated sum of 0-2 = score of 1, sum of 3-5 = score of 2, sum of 6-10 = score of 3, sum of 11-13 = score of 4, and sum of 14-16 = score of 5. The total 5D score was obtained by summing up the five domain scores and ranges between 5 (no pruritus) and 25 (most severe pruritus).	Baseline, Week 12
Proportion of Participants With Improvement of Fibrosis by at Least 1 Stage and/or Resolution of NASH Without Worsening of Either as Determined by Liver Biopsy	Description of endpoint is Proportion of participants with improvement of fibrosis by at least 1 stage and/or resolution of NASH without worsening of either as determined by liver biopsy.	Week 72
Proportion of Participants With no Worsening of Fibrosis Combined With no Worsening of NASH as Determined by Liver Biopsy	Proportion of participants with no worsening of fibrosis combined with no worsening of NASH as determined by liver biopsy.	Week 72
Proportion of Participants With Resolution of Fibrosis as Determined by Liver Biopsy	Proportion of participants with resolution of fibrosis as determined by liver biopsy at Week 72.	Week 72
Proportion of Participants With Improvement in Each Histologic Feature of NASH by at Least 1 Point as Determined by Liver Biopsy	Proportion of participants with improvement in each histologic feature of NASH by at least 1 point as determined by liver biopsy at Week 72.	Week 72
Proportion of Participants With Improvement of Fibrosis by ≥ 2 Stages by Liver Biopsy	Proportion of participants with improvement of fibrosis by ≥ 2 stages by liver biopsy.	Week 72
Proportion of Participants With Improvement in NAS by at Least 2 Points With no Worsening of Fibrosis as Determined by Liver Biopsy	Proportion of participants with improvement in NAS by at least 2 points with no worsening of fibrosis as determined by liver biopsy at Week 72.	Week 72
Proportion of Participants With Improvement of Fibrosis and Resolution of NASH as a Composite Endpoint as Defined by Both Endpoints Being Met in the Same Participant	Proportion of participants with improvement of fibrosis and resolution of NASH as a composite endpoint as defined by both endpoints being met in the same participant at week 72.	Baseline, Week 72
Proportion of Participants With Resolution of NASH and no Worsening of Liver Fibrosis	Proportion of participants with resolution of NASH and no worsening of liver fibrosis at Week 72.	Week 72
Proportion of Participants With Histological Progression to Cirrhosis as Determined by Liver Biopsy	Proportion of participants with histological progression to cirrhosis as determined by liver biopsy at Week 72.	Week 72
Participants With TEAEs Leading to Discontinuation	Treatment emergent adverse events (TEAEs) were defined as AEs occurring or worsening on or after the first dose of study drug until the last dose of study drug. TEAEs were regarded as leading to discontinuation if they led to discontinuation of the study drug.	Day 1 to Week 72
Percentage Change of Fat in the Liver From Baseline	Percentage change of fat in the liver as assessed by magnetic resonance imaging proton density fat fraction (MRI PDFF) from Baseline to Week 12.	Baseline, Week 12
Change in Liver Stiffness From Baseline	Change in liver stiffness by magnetic resonance elastography (MRE) in kilopascal (kPa) from Baseline at Week 12.	Baseline, Week 12
Change in Triglycerides From Baseline	Change in Triglycerides from Baseline at Week 12.	Baseline, Week 12
Change in Adiponectin From Baseline	Change in adiponectin from Baseline at Week 12.	Baseline, Week 12
Plasma Concentration of EDP-305	Plasma concentration at second post dose (2-4 hours post dose) at Week 12.	2-4 hours post dose at Week 12
Change in VAS (Visual Analog Score) From Baseline	Change in VAS from Baseline at Week 12. Change from baseline was analyzed using a restricted maximum likelihood-based MMRM technique. Two separate scales were used to assess pruritus. An itch VAS was used to record the intensity of the pruritus by Furue (Furue et al., 2013). Scale referred to no pruritus (0 point) and the end of the scale to the most severe pruritus (10 points). If the VAS score was greater than zero (i.e. itch), a multidimensional 5D-itch scale developed by Elman (Elman et al., 2010) indicated sum of 0-2 = score of 1, sum of 3-5 = score of 2, sum of 6-10 = score of 3, sum of 11-13 = score of 4, and sum of 14-16 = score of 5. It was used to assess five different dimensions of pruritus within the last two weeks. The five dimensions assessed were duration, degree, direction, disability, and distribution. The total 5D itch score was obtained by summing up the five domain scores and ranges between 5 (no pruritus) and 25 (most severe pruritus).	Baseline, Week 12
Change in Total Cholesterol From Baseline	Change in Total Cholesterol from Baseline to Week 12 versus placebo.	Baseline, Week 12
Change in HDL From Baseline	Change in HDL from Baseline at week 12.	Baseline, Week 12
Change in LDL From Baseline	Change in LDL From Baseline to Week 12.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: Enanta Pharmaceuticals, Inc
• Investigators: Study Director: Enanta Pharmaceuticals, Inc, Enanta Pharmaceuticals, Inc

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2020
• Primary Completion (Actual): October 4, 2021
• Study Completion (Actual): November 30, 2021

Study Registration Dates

• First Submitted: May 4, 2020
• First Submitted That Met QC Criteria: May 4, 2020
• First Posted (Actual): May 7, 2020

Study Record Updates

• Last Update Posted (Actual): May 19, 2023
• Last Update Submitted That Met QC Criteria: April 25, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Fatty Liver, non-alcoholic fatty liver disease, NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: EDP 305-102; 2019-003876-38 (EudraCT Number)

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