A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis

A Phase 2 Dose Ranging, Randomized, Double Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis (PBC) With or Without an Inadequate Response to Ursodeoxycholic Acid (UDCA)

A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of EDP-305 in subjects with primary biliary cholangitis

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cholangitis
• Intervention / Treatment: Drug: EDP-305 1 mg; Drug: EDP-305 2.5 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Linear Clinical Research
• Austria
  • Carinthia
    • Klagenfurt am Wörthersee, Carinthia, Austria, 9020
      • Klinikum Klagenfurt am Wörthersee
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Medizinische Universität Innsbruck
  • Upper Austria
    • Wels, Upper Austria, Austria, 4600
      • Klinikum Wels-Grieskirchen
• Belgium
  • Liege
    • Liège, Liege, Belgium, 4000
      • CHU de Liège, Cardiology Dept.
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Ziekenhuis Oost-Limburg
  • Oost-vlaanderen
    • Gent, Oost-vlaanderen, Belgium, 9000
      • Universitair Ziekenhuis Gent
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre University Hospital
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Center
• France
  • Alsace
    • Strasbourg cedex, Alsace, France, 67091
      • Nouvel Hôpital Civil
  • Aquitaine
    • Pessac, Aquitaine, France, 33600
      • Hôpital Haut-Lévêque
  • Ile-de-france
    • Paris Cedex 12, Ile-de-france, France, 75012
      • Hôpital Saint-Antoine
    • Villejuif Cedex, Ile-de-france, France, 94800
      • Hopital Paul Brousse
  • Languedoc-roussillon
    • Montpellier cedex 5, Languedoc-roussillon, France, 34295
      • Hopital Saint-Eloi
  • NORD Pas-de-calais
    • Lille, NORD Pas-de-calais, France, 59037
      • Centre Hospitalier Régional Universitaire de Lille
  • Picardie
    • Amiens Cedex 1, Picardie, France, 80054
      • Centre Hospitalier Universitaire Amines-Picardie Hôpital Sud
  • Rhone-alpes
    • Lyon Cedex 04, Rhone-alpes, France, 69317
      • Hôpital de La Croix Rousse
• Germany
  • Berlin, Germany, 13353
    • Charité Universitätsmedizin Berlin
  • Bayern
    • Würzburg, Bayern, Germany, 97080
      • Universitatsklinikum Wurzburg
  • Hessen
    • Frankfurt am Main, Hessen, Germany, 60590
      • Universitätsklinikum Frankfurt
  • Nordrhein-westfalen
    • Bonn, Nordrhein-westfalen, Germany, 53127
      • Universitätsklinikum Bonn
    • Essen, Nordrhein-westfalen, Germany, 45122
      • Universitaetsklinikum Essen
  • Rheinland-pfalz
    • Mainz, Rheinland-pfalz, Germany, 55131
      • Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitätsklinikum Leipzig
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1081 HV
      • Vrije Universiteit Medisch Centrum
  • Zuid-holland
    • Leiden, Zuid-holland, Netherlands, 2333 ZA
      • Leiden Universitair Medisch Centrum
• Spain
  • Barcelona, Spain, 08029
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
  • Valladolid, Spain, 47010
    • Universidad de Valladolid - Hospital Universitario Río Hortega
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain, 20014
      • Hospital Universitario Donostia
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario Virgen de la Arrixaca
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B15 2TT
      • University Hospitals Birmingham NHS Foundation Trust
    • Cambridge, England, United Kingdom, CB2 0QQ
      • Cambridge University Hospitals NHS Foundation Trust
    • Leeds, England, United Kingdom, LS9 7TF
      • The Leeds Teaching Hospitals Nhs Trust
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital NHS Foundation Trust
    • Norwich, England, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospitals Nhs Foundation Trust
    • Nottingham, England, United Kingdom, NG7 2UH
      • Queen's Medical Centre - Nottingham
    • Portsmouth, England, United Kingdom, PO6 3LY
      • Portsmouth Hospitals NHS Trust
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH16 4SA
      • NHS Lothian
• United States
  • Alabama
    • Dothan, Alabama, United States, 36305
      • Digestive Health Specialists Of The Southeast
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Diagnostic Center
    • Little Rock, Arkansas, United States, 76012
      • Texas Clinical Research Institute
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Pasadena, California, United States, 91105
      • Pasadena Liver Center
    • Pasadena, California, United States, 91105
      • California Liver Research Institue
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology - Swedish Medical Center Office
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • Florida
    • Clearwater, Florida, United States, 33756-3839
      • Gastroenterology Consultants of Clearwater
    • Inverness, Florida, United States, 34452
      • Nature Coast Clinical Research
    • Miami, Florida, United States, 33136
      • University of Miami Leonard M. Miller School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30312
      • Consultative Gastroenterology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Louisiana
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center-McAuley Plaza
    • Catonsville, Maryland, United States, 21228
      • Digestive Disease Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48377
      • Henry Ford Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68124
      • CHI Health
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Bronx, New York, United States, 10461-1925
      • Montefiore Medical Center - Bronx
    • Manhasset, New York, United States, 11030
      • Northwell Health
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • Concorde Medical Group
    • New York, New York, United States, 10016
      • Mount Sinai Beth Isreal
    • New York, New York, United States, 10024
      • Weill Cornell Medical College
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Center for Liver Disease
  • Texas
    • Dallas, Texas, United States, 75203
      • The Liver Institute at Methodist Dallas Medical Center
    • Dallas, Texas, United States, 76104
      • Liver Consultants of Texas
    • Houston, Texas, United States, 77030
      • Baylor Saint Luke's Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at The Texas Liver Institute
  • Virginia
    • Richmond, Virginia, United States, 23602
      • Liver Institute of Virginia-Bremo
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish First Hill Campus
    • Seattle, Washington, United States, 98195-6460
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• An informed consent document signed and dated by the subject.
• Male and female subjects of any ethnic origin between the ages of 18 and 75 years, inclusive

• Male or female with a diagnosis of PBC by at least two of the following criteria:

  • History of ALP above ULN for at least six months
  • Positive Anti-Mitochondrial Antibodies (AMA) titers (>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies)
• For subjects with no documented liver biopsy performed within 2 years, subjects must undergo a transient elastography (Fibroscan) showing liver stiffness < 14.0 kPA
• Must be on a stable dose of UDCA12-20 mg/kg/day for at least 6 months prior to Screening or intolerant of UDCA in the opinion of the Investigator (no UDCA for at least 12 weeks prior to Screening)
• Alkaline Phosphatase (ALP) ≥ 1.67 × ULN and/or total bilirubin >ULN but < 2×ULN (<2.4 mg/dL)
• Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA negative and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. Note: subjects previously infected by chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) for at least 3 years will be allowed.
• Female subjects of childbearing potential must agree to use two effective methods of contraception from the date of Screening until 90 days after the last dose of EDP-305.
• All male participants who have not had a vasectomy must use effective contraception from Day -1 to 90 days after their last dose of study drug.
• Male subjects must agree to refrain from sperm donation from the date of Screening until 90 days after their last dose of study drug
• Screening body mass index (BMI) of ≥18 kg/m2
• Subject must be willing and able to adhere to the assessments, visit schedule, prohibitions and restrictions, as described in this protocol

Exclusion Criteria:

• Laboratory Screening Results:

  • AST >5 x ULN
  • ALT >5 x ULN
  • Patients with Gilbert's syndrome will not be allowed due to interpretability of bilirubin levels
  • Total white blood cells (WBC) <3000 cells/mm3
  • Absolute neutrophil count (ANC) <1500 cells/mm3
  • Platelet count <140,000/mm3
  • Prothrombin time (international normalized ratio, INR) >1.2
  • Serum creatinine >2 mg/dL or creatinine clearance <60 mL/min (based on Cockroft-Gault Method)
• Suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the judgment of the Investigator at Screening
• Use of immunosuppressants known to have an effect on the liver of patients with PBC (eg, colchicine, methotrexate, azathioprine, or systemic steroids) in the three months preceding screening
• Current use of fibrates, including fenofibrates. Note: Subjects who discontinued fibrates for at least 3 months before Screening can participate
• Use of an experimental treatment for PBC within the past 6 months
• Co-existing liver or biliary diseases, such as primary sclerosing cholangitis, choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis, cholangiocarcinoma diagnosed or suspected liver cancers
• Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma
• Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 μmol/L)
• Prior variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class A, B and C, esophageal varices, or refractory ascites within the previous 6 months of Screening (defined as date informed consent signed)
• Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease)
• Use of a new statin regimen from Screening and throughout study duration. NOTE: Subjects on a stable dose of statins for at least 3 months prior to Screening are allowed. No dose modification during the study will be allowed.
• Use of immunosuppressants (eg, systemic corticosteroids) for more than 2 consecutive weeks in duration within 1 year prior to 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 mg; Subjects will take 2 tablets once a day orally for 12 weeks	Drug: EDP-305 1 mg; Two tablets daily for 12 weeks
Experimental: EDP-305 2.5 mg; Subjects will take 2 tablets once a day orally for 12 weeks	Drug: EDP-305 2.5 mg; Two tablets daily for 12 weeks
Placebo Comparator: Placebo; Subjects will take two tablets once a day orally for 12 weeks	Drug: Placebo; Two tablets daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With At Least a 20% Reduction in Alkaline Phosphatase (ALP) or Normalization of ALP at Week 12 Compared to Baseline	Percent change was calculated as [(ALP at Week 12 - ALP at Baseline)/ALP at Baseline] *100. The participant was considered to have successfully achieved a 20% reduction in ALP if the result was ≤-20. The participant was considered to have successfully achieved ALP normalization if ALP was abnormal at Baseline and normal at Week 12.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	An adverse event (AE) was defined as any event, side effect, or untoward medical occurrence in a subject enrolled in a clinical trial whether or not it is considered to have a causal relationship to the study drug. A TEAE was an AE that first occurred or began previous to and worsened on or after the first dose date and before the last dose date +7 days.	Up to approximately Week 12
Percentage of Participants With a Treatment-Emergent Serious Adverse Event (SAE) During On-Treatment Period	A SAE is any untoward medical occurrence at any dose that results in death, is a life-threatening event, requires inpatient hospitalization or prolonged hospitalization of an existing hospitalization, results in permanent or prolonged disability or incapacity, is a congenital anomaly or birth defect in the offspring of a study subjects, or is a medically important event.	Up to approximately Week 12
Percentage of Participants Who Stopped Study Treatment Due to a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	An adverse event (AE) was defined as any event, side effect, or untoward medical occurrence in a subject enrolled in a clinical trial whether or not it is considered to have a causal relationship to the study drug. A TEAE was an AE that first occurred or began previous to and worsened on or after the first dose date and before the last dose date +7 days.	Up to approximately Week 12
Change From Baseline to Week 12 in Total, Conjugated and Unconjugated Bilirubin	The data presented below was measured using least square mean change from baseline.	Baseline and Week 12
Change From Baseline to Week 12 in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT)		Baseline and Week 12
Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Enhanced Liver Fibrosis (ELF) Panel and N-terminal Type III Collagen Propeptide (PRO C3)	The ELF panel included hyaluronic acid (HA), procollagen III amino terminal peptide (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP 1). This endpoint also presents PRO C3 results.	Baseline and Week 12
Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: AST to Platelet Ratio Index (APRI) Score	APRI was calculated as ([AST level/AST upper limit of normal]/[Platelet count 1^09/L])×100. AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess liver fibrosis in participants with chronic liver disease. Scores range from 0 to ≥ 2.0, with scores < 0.5 predictive of no liver fibrosis; scores >1.5 significant fibrosis; and scores > 2.0 indicative of cirrhosis. A negative change from baseline indicates a decrease in fibrosis.	Baseline and Week 12
Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Fibrosis-4 (FIB-4) Score	Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score that is calculated using formula: FIB-4 = (Age [years] x AST [U/L]) / (platelets [10^9/L] x (square root of ALT [U/L])). A FIB-4 index of < 1.45 indicates no or moderate fibrosis and an index of > 3.25 indicates extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.	Baseline and Week 12
Change From Baseline to Week 12 in Fibrinogen and C Reactive Protein (CRP) Levels		Baseline and Week 12
Change From Baseline to Week 12 in Interleukin (IL) and Tumor Necrosis Factor (TNF) Levels	For IL, both IL6 and IL1β variants were analysed. For TNF, both TNF α and TNF β (also known as lymphotoxin alpha) variants were analyzed.	Baseline and Week 12
Change From Baseline to Week 12 in Haptoglobin and Alpha2 Macroglobulin Levels		Baseline and Week 12
Change From Baseline to Week 12 in Triglycerides (TG), Total Cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C)		Baseline and Week 12
Change From Baseline to Week 12 in Domain and Total Scores on the 5D-Itch Scale	The 5D-Itch scale is a multidimensional questionnaire completed by participants to quantify the magnitude of pruritus, assessed considering the past 2 weeks. Scale range is 1 to 5 covering five dimensions: duration (1=Less than 6 hrs/day to 5=All day), degree (1=Not present to 5=Unbearable), direction (1=Completely resolved to 5=Getting worse), disability (for Sleep rated as 1=Never affects sleep to 5=Delays falling asleep and frequently wakes me up at night; for Leisure/Social, Housework/Errands and Work/School rated as 1=Never affects activity to 5=Always affects activity), and distribution (assess if itching is present in 16 body locations, scored as 1=present at 0-2 locations to 5=present at 14-16 locations). Total scores (including highest disability score obtained from any of the daily activities) ranged between 5 and 25 where higher scores indicated more severe itching. Negative change scores indicate improvement from the baseline score.	Baseline and Week 12
Change From Baseline to Week 12 in Visual Analog Score (VAS) for Itching	An itch VAS (0-100mm) was used to record the intensity of the event. Participants drew a line on a scale corresponding to the maximum intensity of itch. Lines drawn towards the right of the line indicated greater itching and higher scores indicated more severe itching. Negative change from baseline indicates decrease in itching.	Baseline to Week 12
Change From Baseline to Week 12 in Domain Scores on the Primary Biliary Cholangitis-40 (PBC-40) Quality of Life (QoL) Assessment	The PBC-40 is a survey measuring health related quality of life in participants with PBC. The 40 questions from the PBC-40 questionnaire are scored from 1-5, with 5 representing the highest impact and 1 the lowest impact of PBC on the quality of life. Six domains were computed from the 40 questions: symptoms (score range 7-35), itch (0-15), fatigue (11-55), cognition (6-30), social (8-50) and emotional (1-15). Higher scores indicate worse quality of life and negative change scores indicate improvement from the baseline score.	Baseline and Week 12
Maximum Plasma Concentration (Cmax) of EDP-305 and Its Metabolites	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Time to Maximum Plasma Concentration (Tmax) of EDP-305 and Its Metabolites	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of EDP-305 and Its Metabolites	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Percentage Change From Baseline to Week 12 in Fibroblast Growth Factor 19 (FGF19), 7α-OH-4-cholesten-3-one (C4) and Bile Acid (BA) Concentrations	FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum.	Baseline and Week 12
Percentage Change From Baseline to Week 12 in AUC0-8 and AUC2-8 of Fibroblast Growth Factor 19 (FGF19), 7α-OH-4-cholesten-3-one (C4) and Bile Acid (BA)	AUC0-8 is area under the biomarker concentration-time curve from time zero to 8 hours. AUC2-8 is area under the biomarker concentration-time curve from 2 hours to 8 hours. FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose

Collaborators and Investigators

• Sponsor: Enanta Pharmaceuticals, Inc
• Collaborators: Pharmaceutical Research Associates; Triangle Biostatistics

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2017
• Primary Completion (Actual): December 19, 2019
• Study Completion (Actual): January 16, 2020

Study Registration Dates

• First Submitted: December 23, 2017
• First Submitted That Met QC Criteria: January 3, 2018
• First Posted (Actual): January 9, 2018

Study Record Updates

• Last Update Posted (Actual): May 18, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: PBC; Primary Biliary Cholangitis (PBC)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary
• Other Study ID Numbers: EDP 305-201

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