A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Non-Alcoholic Steatohepatitis

Study Overview
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Brief Summary
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A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of EDP-305 in subjects with Non-Alcoholic Steatohepatitis

Official Title
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A Phase 2 Dose Ranging, Randomized, Double Blind, and Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Non-Alcoholic Steatohepatitis (NASH)

Conditions
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Non-Alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: EDP-305 Dose 1
* Drug: EDP-305 Dose 2
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An informed consent document must be 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 presence of NASH by: Histologic evidence on a historical liver biopsy within 24 months of Screening consistent with NASH with fibrosis (no cirrhosis), and elevated ALT at Screening AND Screening MRI PDFF with >8 % steatosis OR Phenotypic diagnosis of NASH based on elevated ALT and diagnosis of T2DM or pre-diabetes AND Screening MRI PDFF with >8 % steatosis Body mass index (BMI) >25 kg/m2; for Asian-Americans, BMI >23 kg/m2 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. Subject must be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol Exclusion Criteria: Laboratory Screening Results: Total bilirubin > ULN (normal range 0.2-1.2 mg/dL) Total white blood cells (WBC) <3,000 cells/mm3 Absolute neutrophil count (ANC) <1,500 cells/mm3 Platelet count <140,000/mm3 Prothrombin time (international normalized ratio, INR) > 1.2 Creatine kinase above the upper limit of normal (ULN) except when in relation with intense exercise Serum creatinine >2 mg/dL or creatinine clearance <60 ml/min (based on Cockroft Gault method) Known history of alpha-1-antitrypsin deficiency Use of an experimental treatment for NASH within the past 6 months Use of immunosuppressant (eg, corticosteroids) for more than 2 weeks in duration within 1 year prior to Screening and during the course of the study Use of experimental or unapproved drugs within a year of Screening Any other condition(s) (including cardiovascular diseases) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Principal Investigator (PI) Pregnant or nursing females Recipients of liver or other organ transplantation or anticipated need for orthotropic organ transplantation in one year as determined by a Model for End-Stage Liver Disease (MELD) Score ≥ 15 Clinical suspicion of advanced liver disease or cirrhosis Coexisting liver or biliary diseases, such as primary sclerosing cholangitis (PSC), choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis Suspicion of cancer (eg, liver cancer) with the exception of basal cell carcinoma that has been resected Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2xULN 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) Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to Screening) Subject has received an investigational agent or vaccine within 30 days, or a biological product within 3 months or 5 elimination half-lives (whichever is longer) prior to the planned intake of study drug. NOTE: Flu vaccine will be allowed upon Medical Monitor's approval Use of a new statin regimen from Screening and throughout study duration. NOTE: Subjects on a stable dose of statins for at least three months prior to Screening are allowed. No dose modification during the study will be allowed. Current use of fibrates. Note: Subjects who discontinued fibrates for at least 3 months before Screening can participate Clinically significant history of drug sensitivity or allergy, as determined by the PI Uncontrolled diabetes mellitus (ie, HbA1c ≥9% or higher) 60 days prior to Day 1 Subjects with contraindications to MRI imaging, or not being able to have the MRI performed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EDP-305 Dose 1<br>Subjects will take 2 tablets once a day orally for 12 weeks | Drug: EDP-305 Dose 1<br>* Two tablets daily for 12 weeks<br>|
| Experimental: EDP-305 Dose 2<br>Subjects will take 2 tablets once a day orally for 12 weeks | Drug: EDP-305 Dose 2<br>* Two tablets daily for 12 weeks<br>|
| Placebo Comparator: Placebo<br>Subjects will take 2 tablets once a day orally for 12 weeks | Drug: Placebo<br>* Two tablets daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline (Average) in Alanine Aminotransferase (ALT) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the ALT level. Baseline refers to the average of the screening and the Day 1 values; if either the screening or Day 1 values were missing, the non-missing value was used. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 12 | The liver fat percentage was assessed by MRI-PDFF, which is an established method that enables the quantification of fat content in the liver; the value of liver fat is expressed in percentage and ranges from 0 to 100% with higher values representing higher liver fat level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Aspartate Aminotransferase to Platelet Ratio Index (APRI) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the aspartate aminotransferase (AST) level and platelet count. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. The APRI score (AST to platelet ratio index) is an index comprised of biochemical values and is used to determine the degree of hepatic fibrosis. APRI is calculated from the level of AST measured in a blood test (international units per liter [IU/L]) and platelet count (10^9/L) according to the following formula: APRI = ([AST value in IU/L / upper limit of the normal range of AST] / [platelet count in 10^9/L]) × 100. In general, APRI scores range from 0 to >2.0, where scores <0.5 indicate no significant fibrosis, scores >1.5 indicate significant fibrosis, and scores >2.0 have been shown to be best correlated with the presence of cirrhosis. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Triglycerides (TG) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the TG level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Total Cholesterol at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the total cholesterol level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the HDL-C level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the LDL-C level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Adiponectin at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the adiponectin level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Apolipoproteins A1 (ApoA-1) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the ApoA-1 level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Apolipoproteins B (ApoB) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the ApoB level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Apolipoproteins C3 (ApoC3) at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the ApoC3 level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Fasting Blood Glucose at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the fasting glucose level. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Fasting Insulin at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the fasting insulin (in micro International units per milliliter [μIU/mL]). Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Homeostasis Model Assessment (HOMA) Index for Nondiabetic Participants at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation; from the results of fasting glucose and insulin, an insulin resistance (IR) was estimated for the nondiabetic participants using the HOMA-IR computer algorithm. A higher HOMA-IR indicates a higher degree of insulin resistance. Participants who were not considered as having type 2 diabetes mellitus (T2DM) were identified as nondiabetic. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in HOMA Index for Diabetic Participants at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation; from the results of fasting glucose and insulin, an insulin resistance (IR) was estimated for the nondiabetic participants using the HOMA-IR computer algorithm. A higher HOMA-IR indicates a higher degree of insulin resistance. Participants who were considered as having T2DM were identified as diabetic. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Glycated Hemoglobin (HbA1c) in Participants With T2DM at Week 12 | Blood samples were collected at specific timepoints for the laboratory evaluation to assess the HbA1c. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Maximum Plasma Concentration (Cmax) of EDP-305 on Day 1 and Week 12 | The Cmax is the maximum observed plasma concentration, which was measured for EDP-305 on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the Pharmacokinetic (PK) Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Time to Reach Maximum Plasma Concentration (Tmax) of EDP-305 on Day 1 and at Week 12 | The Tmax was measured for EDP-305 on Day 1 and at Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC[Last]) of EDP-305 on Day 1 and at Week 12 | AUC(last) is defined as the area under the plasma concentration-time curve from time zero to time the last quantifiable concentration, computed using the linear up/log down trapezoidal rule. AUC(last) was computed for EDP-305 on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Cmax of EP-022571 on Day 1 and at Week 12 | The Cmax is the maximum observed plasma concentration, which was measured for EP-022571 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Tmax of EP-022571 on Day 1 and at Week 12 | The Tmax was measured for EP-022571 (a metabolite of EDP-305) on Day 1 and at Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| AUC(Last) of EP-022571 on Day 1 and at Week 12 | AUC(last) is defined as the area under the plasma concentration-time curve from time zero to time the last quantifiable concentration, computed using the linear up/log down trapezoidal rule. AUC(last) was computed for EP-022571 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Cmax of EP-022572 on Day 1 and at Week 12 | The Cmax is the maximum observed plasma concentration, which was measured for EP-022572 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Tmax of EP-022572 on Day 1 and at Week 12 | The Tmax was measured for EP-022572 (a metabolite of EDP-305) on Day 1 and at Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| AUC(Last) of EP-022572 on Day 1 and at Week 12 | AUC(last) is defined as the area under the plasma concentration-time curve from time zero to time the last quantifiable concentration, computed using the linear up/log down trapezoidal rule. AUC(last) was computed for EP-022572 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Cmax of EP-022679 on Day 1 and at Week 12 | The Cmax is the maximum observed plasma concentration, which was measured for EP-022679 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Tmax of EP-022679 on Day 1 and at Week 12 | The Tmax was measured for EP-022679 (a metabolite of EDP-305) on Day 1 and at Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| AUC(Last) of EP-022679 on Day 1 and at Week 12 | AUC(last) is defined as the area under the plasma concentration-time curve from time zero to time the last quantifiable concentration, computed using the linear up/log down trapezoidal rule. AUC(last) was computed for EP-022679 (a metabolite of EDP-305) on Day 1 and Week 12 for the samples collected according to the intensive sampling scheme for the participants in the PK Population. | Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12) | 
| Mean Change From Baseline in Body Weight at Week 12 | Body weight was measured at specific timepoints for the participants. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Waist to Hip (WTH) Ratio at Week 12 | The WTH ratio is calculated as the ratio of waist to hip circumference, which was measured at specific timepoints. Baseline refers to the last non-missing value collected prior to the first dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Baseline and Week 12 | 
| Mean Change From Baseline in Fibroblast Growth Factor 19 (FGF19) by Nominal Timepoint (Intensive Pharmacodynamic [PD] Samples) at Week 12 | Blood samples were collected according to the intensive sampling scheme at specific timepoints to assess the PD marker: FGF19. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12) | 
| Mean Change From Baseline in FGF19 by Bin Timepoint (Sparse PD Samples) at Week 12 | Blood samples were collected according to the sparse sampling scheme at specific timepoints to assess the PD marker: FGF19. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12) | 
| Mean Change From Baseline in 7a-Hydroxy-4-Cholestene-3-One (C4) by Nominal Timepoint (Intensive PD Samples) at Week 12 | Blood samples were collected according to the intensive sampling scheme at specific timepoints to assess the PD marker: C4. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12) | 
| Mean Change From Baseline in C4 by Bin Timepoint (Sparse PD Samples) at Week 12 | Blood samples were collected according to the sparse sampling scheme at specific timepoints to assess the PD marker: C4. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12) | 
| Mean Change From Baseline in Bile Acid (BA) by Nominal Timepoint (Intensive PD Samples) at Week 12 | Blood samples were collected according to the intensive sampling scheme at specific timepoints to assess the PD marker: BA. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12) | 
| Mean Change From Baseline in BA by Bin Timepoint (Sparse PD Samples) at Week 12 | Blood samples were collected according to the sparse sampling scheme at specific timepoints to assess the PD marker: BA. Baseline refers to the last non-missing predose value collected prior to the most recent dose of study treatment. Mean change was defined as the mean value at Week 12 minus the mean value at baseline. | Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, Non-Alcoholic Steatohepatitis (NASH)