Non-alcoholic Steatohepatitis
Conditions
Keywords
EYP001 (vonafexor), Liver Diseases, Non-alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, NASH
Brief summary
The purpose of this study is to assess the effects of EYP001a (Vonafexor) with respect to safety, tolerability, pharmacokinetics and on markers of liver inflammation in patients with NASH
Detailed description
This is a 2-part, randomized, double-blind, multicenter, placebo-controlled study to evaluate the safety and efficacy of Vonafexor in patients with NASH who likely have stage F2 to F3 fibrosis at approximately 50 global clinical sites. Overall, approximately 114 eligible patients will be enrolled: 24 patients in Part A (Safety Run-in Cohort), followed by 90 patients in Part B. In Part A, 24 patients will be randomized on Day 1 to 1 of 4 parallel treatment groups: 100 mg Vonafexor twice daily (BID), 200 mg Vonafexor once daily (QD), 400 mg Vonafexor QD, or placebo BID. In Part B, 90 patients will be randomized on Day 1 to 1 of 3 parallel treatment groups: 100 mg Vonafexor QD, 200 mg Vonafexor QD, or placebo QD.
Interventions
DRUGVonafexor
Oral tablets
OTHERPlacebo
Oral tablets
Sponsors
Enyo Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Triple (Participant, Care Provider, Investigator)
Intervention model description
Parallel assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Suspected diagnosis of NASH, evidenced by elevated alanine aminotransferase (ALT), liver stiffness compatible with F2 or F3 fibrosis and Liver Fat Content (LFC) ≥10% as measured by MRI * Women of childbearing potential and male patients with female partners must agree to use a dual method of contraception
Exclusion criteria
* Evidence of worsening liver injury * Previous diagnosis of other forms of non-NASH liver disease * Use of Vitamin E, glitazones, glucagon-like Peptide-1 receptor agonists, ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening * History of cirrhosis or liver decompensation * Known history of alcohol abuse or daily heavy alcohol consumption * Pregnant or breastfeeding women * Type 1 diabetes mellitus and uncontrolled type 2 diabetes mellitus * Patients with contraindications to MRI imaging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | 12 weeks | 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. |
| Analysis of Change From Baseline in Corrected T1 (CT1) | 12 weeks | — |
| Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | 12 weeks | — |
| Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | 12 weeks | — |
| Analysis of Change From Baseline in Glomerular Filtration rate_Part B | 12 weeks | — |
| Analysis of Change From Baseline in Waist Circumference | 12 weeks | — |
| Analysis of Change From Baseline in Waist to Hip ratio_Part B | 12 weeks | — |
| Analysis of Change From Baseline in Glomerular Filtration rate_Part A | 12 weeks | For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group. |
| Analysis of Change From Baseline in Body Weight | 12 weeks | — |
Countries
Belgium, France, Puerto Rico, United Kingdom, United States
Participant flow
Pre-assignment details
For Part A, data from the 3 vonafexor treatment groups were pooled and summarized. Due to the small number of subjects by treatment group in Part A, and as the Study EYP001 202 Part A Pharmacokinetic (PK) results between groups were found to be nonlinear with similar exposure for the vonafexor 200 mg once daily (QD) and vonafexor 400 mg QD groups, only the pooled vonafexor treatment group were compared with the placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Part A Oral dose twice daily for 12 weeks (84 days)
Placebo: Oral tablets | 7 |
| Vonafexor Pooled Part A Oral dose once or twice a day according to treatment arms for 12 weeks (84 days)
Vonafexor: Oral tablets | 17 |
| Placebo Part B Oral dose once daily for 12 weeks (84 days)
Placebo: Oral tablets | 32 |
| Vonafexor 100 mg QD Part B Oral dose once daily for 12 weeks (84 days)
Vonafexor: Oral tablets | 31 |
| Vonafexor 200 mg QD Part B Oral dose once daily for 12 weeks (84 days)
Vonafexor: Oral tablets | 33 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 9 | 0 | 3 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Stopping rules | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo Part A | Vonafexor Pooled Part A | Total | Placebo Part B | Vonafexor 100 mg QD Part B | Vonafexor 200 mg QD Part B |
|---|---|---|---|---|---|---|
| Age, Continuous Age Part A | 48.7 years STANDARD_DEVIATION 18.4 | 56.1 years STANDARD_DEVIATION 8.9 | 54.0 years STANDARD_DEVIATION 12.4 | — | — | — |
| Age, Continuous Age Part B | — | — | 56.4 years STANDARD_DEVIATION 12 | 57.3 years STANDARD_DEVIATION 10.3 | 58.1 years STANDARD_DEVIATION 13.7 | 54.0 years STANDARD_DEVIATION 11.9 |
| BMI BMI Part A | 39.3 kg/m^2 STANDARD_DEVIATION 10.2 | 38.8 kg/m^2 STANDARD_DEVIATION 9 | 38.9 kg/m^2 STANDARD_DEVIATION 9.1 | — | — | — |
| BMI BMI Part B | — | — | 34.7 kg/m^2 STANDARD_DEVIATION 4.5 | 34.3 kg/m^2 STANDARD_DEVIATION 4.3 | 34.3 kg/m^2 STANDARD_DEVIATION 4.1 | 35.4 kg/m^2 STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 31 Participants | 6 Participants | 8 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 12 Participants | 89 Participants | 26 Participants | 23 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height Height Part A | 169.0 cm STANDARD_DEVIATION 7.4 | 163.2 cm STANDARD_DEVIATION 9.9 | 164.9 cm STANDARD_DEVIATION 9.5 | — | — | — |
| Height Height Part B | — | — | 167.3 cm STANDARD_DEVIATION 9.4 | 168.1 cm STANDARD_DEVIATION 9.8 | 167.1 cm STANDARD_DEVIATION 8.5 | 166.8 cm STANDARD_DEVIATION 10.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 7 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 16 Participants | 109 Participants | 29 Participants | 26 Participants | 31 Participants |
| Sex: Female, Male Female | 2 Participants | 14 Participants | 69 Participants | 18 Participants | 14 Participants | 21 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 51 Participants | 14 Participants | 17 Participants | 12 Participants |
| Waist circumference Waist circumference Part A | 128.9 cm STANDARD_DEVIATION 31.5 | 116.1 cm STANDARD_DEVIATION 16 | 119.8 cm STANDARD_DEVIATION 21.7 | — | — | — |
| Waist circumference Waist circumference Part B | — | — | 112.7 cm STANDARD_DEVIATION 11.3 | 112.6 cm STANDARD_DEVIATION 13 | 111.4 cm STANDARD_DEVIATION 8.6 | 114.1 cm STANDARD_DEVIATION 11.8 |
| Weight Weight Part A | 112.4 kg STANDARD_DEVIATION 32.6 | 103.4 kg STANDARD_DEVIATION 25.4 | 106.0 kg STANDARD_DEVIATION 27.3 | — | — | — |
| Weight Weight Part B | — | — | 97.4 kg STANDARD_DEVIATION 16.9 | 97.5 kg STANDARD_DEVIATION 18.3 | 95.8 kg STANDARD_DEVIATION 14 | 98.8 kg STANDARD_DEVIATION 18.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 32 | 0 / 31 | 0 / 33 |
| other Total, other adverse events | 4 / 7 | 6 / 6 | 4 / 5 | 6 / 6 | 22 / 32 | 25 / 31 | 30 / 33 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 5 | 0 / 6 | 1 / 32 | 1 / 31 | 2 / 33 |
Outcome results
Primary
Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)
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.
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The modified ITT (mITT) Population which was defined as patients from the ITT Population who have valid baseline and Week 12/Early Termination (ET) MRI-PDFF measurements of Liver Fat Content (LFC) has been used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -2.3 Percentage of liver fat change |
| Vonafexor 100 mg QD Part B | Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -6.3 Percentage of liver fat change |
| Vonafexor 200 mg QD Part B | Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -5.4 Percentage of liver fat change |
| Placebo Part A | Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | 3.9 Percentage of liver fat change |
| Vonafexor Pooled Part A | Analysis of Absolute Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -4.7 Percentage of liver fat change |
p-value: 0.0015ANCOVA
p-value: 0.0121ANCOVA
p-value: 0.0371ANCOVA
Secondary
Analysis of Change From Baseline in Alanine Aminotransferase (ALT)
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The ITT Population, defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint but for this endpoint 1 patient in Vonafexor 200 mg QD part B arm was excluded because he experienced a serious transaminase increase due to previously undiagnosed auto-immune hepatitis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | -11.7 U/L |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | -16.3 U/L |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | -7.5 U/L |
| Placebo Part A | Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | -4.1 U/L |
| Vonafexor Pooled Part A | Analysis of Change From Baseline in Alanine Aminotransferase (ALT) | 17.7 U/L |
p-value: 0.09Mixed Models Analysis
p-value: 0.47Mixed Models Analysis
p-value: 0.14Mixed Models Analysis
Secondary
Analysis of Change From Baseline in Body Weight
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The Intent-to-Treat (ITT) Population, which was defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Body Weight | -0.1 kg |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Body Weight | -1.7 kg |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Body Weight | -2.5 kg |
| Placebo Part A | Analysis of Change From Baseline in Body Weight | 1.2 kg |
| Vonafexor Pooled Part A | Analysis of Change From Baseline in Body Weight | -2.2 kg |
p-value: 0.017Mixed Models Analysis
p-value: 0.0006Mixed Models Analysis
p-value: 0.006Mixed Models Analysis
Secondary
Analysis of Change From Baseline in Corrected T1 (CT1)
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The modified ITT (mITT) Population which was defined as patients from the ITT Population who have valid baseline and Week 12/ET MRI-PDFF measurements of LFC has been used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Corrected T1 (CT1) | -9.9 msec |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Corrected T1 (CT1) | -80.2 msec |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Corrected T1 (CT1) | -71.8 msec |
| Placebo Part A | Analysis of Change From Baseline in Corrected T1 (CT1) | 35.0 msec |
| Vonafexor Pooled Part A | Analysis of Change From Baseline in Corrected T1 (CT1) | -58.2 msec |
p-value: 0.001ANCOVA
p-value: 0.002ANCOVA
p-value: 0.018ANCOVA
Secondary
Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT)
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The Intent-to-Treat (ITT) Population, which was defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | -3.9 U/L |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | -40.6 U/L |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | -34.1 U/L |
| Placebo Part A | Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | 3.7 U/L |
| Vonafexor Pooled Part A | Analysis of Change From Baseline in Gamma Glutamyltranspeptidase (GT) | -25.2 U/L |
p-value: <0.0001Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: 0.0002Mixed Models Analysis
Secondary
Analysis of Change From Baseline in Glomerular Filtration rate_Part A
For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.
Time frame: 12 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Glomerular Filtration rate_Part A | -4 mL/min/1.73m^2 | Standard Deviation 18.4 |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Glomerular Filtration rate_Part A | -11.3 mL/min/1.73m^2 | Standard Deviation 12.5 |
Secondary
Analysis of Change From Baseline in Glomerular Filtration rate_Part B
Time frame: 12 weeks
Population: The Intent-to-Treat (ITT) Population, which was defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Glomerular Filtration rate_Part B | -2.7 mL/min/1.73m2 |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Glomerular Filtration rate_Part B | 6.2 mL/min/1.73m2 |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Glomerular Filtration rate_Part B | 3.2 mL/min/1.73m2 |
p-value: 0.003Mixed Models Analysis
p-value: 0.04Mixed Models Analysis
Secondary
Analysis of Change From Baseline in Waist Circumference
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The Intent-to-Treat (ITT) Population, which was defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Waist Circumference | 0.1 cm |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Waist Circumference | -1.2 cm |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Waist Circumference | -2.2 cm |
| Placebo Part A | Analysis of Change From Baseline in Waist Circumference | -1.8 cm |
| Vonafexor Pooled Part A | Analysis of Change From Baseline in Waist Circumference | -2.9 cm |
p-value: 0.16Mixed Models Analysis
p-value: 0.01Mixed Models Analysis
p-value: 0.57Mixed Models Analysis
Secondary
Analysis of Change From Baseline in Waist to Hip ratio_Part B
Time frame: 12 weeks
Population: The Intent-to-Treat (ITT) Population, which was defined as all patients who were randomized and administered at least 1 dose of study drug was used to analyse this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Part B | Analysis of Change From Baseline in Waist to Hip ratio_Part B | 0.014 ratio |
| Vonafexor 100 mg QD Part B | Analysis of Change From Baseline in Waist to Hip ratio_Part B | -0.017 ratio |
| Vonafexor 200 mg QD Part B | Analysis of Change From Baseline in Waist to Hip ratio_Part B | -0.010 ratio |
p-value: 0.0017Mixed Models Analysis
p-value: 0.0093Mixed Models Analysis
Secondary
Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)
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.
Time frame: 12 weeks
Population: For Part A, as per ICH, analysis were performed as defined in the SAP: data from the 3 vonafexor treatment groups were pooled and compared with the placebo group.~The modified ITT (mITT) Population which was defined as patients from the ITT Population who have valid baseline and Week 12/ET MRI-PDFF measurements of LFC has been used to analyse this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Part B | Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -10.5 Percent change |
| Vonafexor 100 mg QD Part B | Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -30.4 Percent change |
| Vonafexor 200 mg QD Part B | Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -25.3 Percent change |
| Placebo Part A | Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | 11.7 Percent change |
| Vonafexor Pooled Part A | Analysis of Percent Change (Relative) From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -25.0 Percent change |
p-value: 0.0017ANCOVA
p-value: 0.018ANCOVA
p-value: 0.13ANCOVA