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Clinical Trial Results:
A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With Nonalcoholic Steatohepatitis

Summary
EudraCT number	2018-003119-22
Trial protocol	BE FR GB
Global end of trial date	06 Jul 2021

Results information
Results version number	v1(current)
This version publication date	15 Dec 2022
First version publication date	15 Dec 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

EYP001-202

ISRCTN number

US NCT number

NCT03812029

WHO universal trial number (UTN)

Sponsor organisation name

Enyo Pharma SA

Sponsor organisation address

60 avenue Rockefeller, Lyon, France, 69008

Public contact

Chief Medical Officer, ENYO Pharma SA, 33 437 700 219, ps@enyopharma.com

Scientific contact

Chief Medical Officer, ENYO Pharma SA, 33 437 700 219, ps@enyopharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Jul 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Jun 2021

Global end of trial reached?

Yes

Global end of trial date

06 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to determine the efficacy and safety profiles of EYP001a versus placebo on liver fat content (LFC) from baseline to Week 12 in patients with NASH.

Protection of trial subjects

The Clinical Study Protocol (CSP), informed consent documents, and any other appropriate study-related documents were reviewed and approved by an IEC/IRB.

Background therapy

Vonafexor is an agonist of the FXR, a key regulator of bile, lipid, and glucose metabolism, currently under clinical investigation as a new therapy for a functional cure of chronic HBV infection. In an experimental rodent model of NASH, vonafexor analogue has been shown to reduce liver steatosis, inflammation, apoptosis, and fibrosis. Moreover, bile acid activation of the FXR improved the histological features of NASH in patients with noncirrhotic NASH. The purpose of this Phase 2a study was to assess the effects of vonafexor compared with placebo on markers of LFC, inflammation, and fibrosis with respect to safety, tolerability, PK, PD, and lipid/metabolic profiles in subjects with a NASH diagnosis compatible with Stage F2 to F3 fibrosis.

Evidence for comparator

Placebo.

Actual start date of recruitment

30 Jan 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Puerto Rico: 3

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

United States: 93

Worldwide total number of subjects

120

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Males, females aged 18y or older provided informed consent and with a suspected diagnosis of NASH with fibrosis (non invasive testing) or a documented biopsy of Stage F2 to F3 liver fibrosis were enrolled in this study. Part A planned to randomize 24 subjects and 24 were randomized. Part B planned to randomize 90 subjects and 96 were randomized.

Screening details

Following sequence of screening procedures were applied to each patient who signs an informed consent form: eligibility based on clinical and biological inclusion and exclusion criteria; eligibility based on FibroScan criteria; confirmation of eligibility based on MRI-PDFF results. Screening was up to 12 weeks prior to Day 1.

Period 1 title

Part A and B (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Carer, Assessor, Subject

Are arms mutually exclusive

Yes

Part A Placebo

Arm description

Part A Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo twice a day

Part A EYP001a pooled

Arm description

Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD

Arm type

Experimental

Investigational medicinal product name

EYP001a

Investigational medicinal product code

EYP001a

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EYP001a once or twice a day according to treatment arms

Part B Placebo

Arm description

Part B Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo once a day

Part B EYP001a 100mg

Arm description

Part B EYP001a 100mg

Arm type

Experimental

Investigational medicinal product name

EYP001a

Investigational medicinal product code

EYP001a

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EYP001a once a day

Part B EYP001a 200mg

Arm description

Part B EYP001a 200mg

Arm type

Experimental

Investigational medicinal product name

EYP001a

Investigational medicinal product code

EYP001a

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EYP001a once a day

Number of subjects in period 1	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Started	7	17	32	31	33
Completed	5	7	32	25	23
Not completed	2	10	0	6	10
Stopping rules	-	1	-	-	-
Consent withdrawn by subject	1	-	-	2	2
Adverse event, non-fatal	-	9	-	3	5
Lost to follow-up	-	-	-	-	3
Protocol deviation	1	-	-	1	-

Baseline characteristics

Top of page

Reporting group title

Part A Placebo

Reporting group description

Part A Placebo

Reporting group title

Part A EYP001a pooled

Reporting group description

Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD

Reporting group title

Part B Placebo

Reporting group description

Part B Placebo

Reporting group title

Part B EYP001a 100mg

Reporting group description

Part B EYP001a 100mg

Reporting group title

Part B EYP001a 200mg

Reporting group description

Part B EYP001a 200mg

Reporting group values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg	Total
Number of subjects	7	17	32	31	33	120
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	48.7 ( 18.4 )	56.1 ( 8.9 )	57.3 ( 10.3 )	58.1 ( 13.7 )	54.0 ( 11.9 )	-
Gender categorical
Units: Subjects
Female	2	14	18	14	21	69
Male	5	3	14	17	12	51
Ethnicity
Units: Subjects
Hispanic or latino	2	5	6	8	10	31
Not Hispanic or latino	5	12	26	23	23	89
Race
Units: Subjects
American Indian or Alaska native	0	0	0	0	1	1
Asian	0	0	0	0	0	0
Black or African American	0	1	3	2	1	7
Native hawaiian or other pacific islander	0	0	0	0	0	0
White	7	16	29	26	31	109
Other	0	0	0	3	0	3
Height
Units: cm
arithmetic mean (standard deviation)	169.0 ( 7.4 )	163.2 ( 9.9 )	168.1 ( 9.8 )	167.1 ( 8.5 )	166.8 ( 10.1 )	-
Weight
Units: kg
arithmetic mean (standard deviation)	112.4 ( 32.6 )	103.4 ( 25.4 )	97.5 ( 18.3 )	95.8 ( 14.0 )	98.8 ( 18.4 )	-
BMI
Units: kg/m2
arithmetic mean (standard deviation)	39.3 ( 10.2 )	38.8 ( 9.0 )	34.3 ( 4.3 )	34.3 ( 4.1 )	35.4 ( 5.1 )	-
Waist circumference
Units: cm
arithmetic mean (standard deviation)	128.9 ( 31.5 )	116.1 ( 16.0 )	112.6 ( 13.0 )	111.4 ( 8.6 )	114.1 ( 11.8 )	-

End points

Top of page

Reporting group title

Part A Placebo

Reporting group description

Part A Placebo

Reporting group title

Part A EYP001a pooled

Reporting group description

Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD

Reporting group title

Part B Placebo

Reporting group description

Part B Placebo

Reporting group title

Part B EYP001a 100mg

Reporting group description

Part B EYP001a 100mg

Reporting group title

Part B EYP001a 200mg

Reporting group description

Part B EYP001a 200mg

Primary: Liver Fat Content

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End point title

Liver Fat Content

End point description

Change from baseline to D84

End point type

Primary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	5	12	32	28	28
Units: percent
least squares mean (confidence interval 95%)	3.9 (-2.5 to 10.4)	-4.7 (-8.5 to -0.9)	-2.3 (-4.0 to -0.6)	-6.3 (-8.1 to -4.5)	-5.4 (-7.2 to -3.6)

Analysis of change from baseline in LFC

Comparison groups

Part B EYP001a 100mg v Part B Placebo v Part B EYP001a 200mg v Part A EYP001a pooled v Part A Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

ANCOVA

Confidence interval

Secondary: glomerular filtration rate part A

Top of page

End point title

glomerular filtration rate part A ^[1]

End point description

Change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Other arms are reported in a separate endpoint.

End point values	Part A Placebo	Part A EYP001a pooled
Number of subjects analysed	7	17
Units: mL/min/1.73m2
geometric mean (standard deviation)	-4 ( 18.4 )	-11.3 ( 12.5 )

No statistical analyses for this end point

Secondary: Analyse of % change from baseline Liver Fat Content

Top of page

End point title

Analyse of % change from baseline Liver Fat Content

End point description

% change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	5	12	32	28	28
Units: percent
least squares mean (confidence interval 95%)	11.7 (-28.5 to 51.9)	-25.0 (-48.4 to -1.5)	-10.5 (-19.0 to -2.0)	-30.4 (-39.4 to -21.3)	-25.3 (-34.3 to -16.2)

Analysis of % change from baseline in LFC

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A EYP001a pooled v Part A Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

ANCOVA

Confidence interval

Secondary: Analyse of change from baseline in CT1

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End point title

Analyse of change from baseline in CT1

End point description

Change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	5	12	32	28	28
Units: msec
least squares mean (confidence interval 95%)	35.0 (-27.0 to 97.0)	-58.2 (-98.7 to -17.8)	-9.9 (-38.5 to 18.7)	-80.2 (-110.6 to -49.8)	-71.8 (-100.4 to -43.2)

Analysis of change from baseline in CT1

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

ANCOVA

Confidence interval

Secondary: ALT

Top of page

End point title

ALT

End point description

Analysis change from baseline to D84 One patient in VONA-200QD arm part B excluded because experienced a serious transaminase increase due to previously undiagnosed auto-immune hepatitis.

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	7	17	32	31	32
Units: U/L
least squares mean (confidence interval 95%)	-4.1 (-27.5 to 19.3)	17.7 (1.9 to 33.5)	-11.7 (-18.9 to -4.6)	-16.3 (-24.1 to -8.4)	-7.5 (-15.3 to 0.4)

Analysis of change from baseline in ALT

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Gamma GT

Top of page

End point title

Gamma GT

End point description

Analysis change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	7	17	32	31	33
Units: U/L
least squares mean (confidence interval 95%)	3.7 (-7.8 to 15.2)	-25.2 (-34.2 to -16.3)	-3.9 (-9.9 to 2.2)	-40.6 (-47.1 to -34.0)	-34.1 (-40.6 to -27.7)

Analysis of change from baseline in GGT

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Body weight

Top of page

End point title

Body weight

End point description

Analysis change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	7	17	32	31	33
Units: kg
least squares mean (confidence interval 95%)	1.2 (-1.0 to 3.4)	-2.2 (-3.7 to -0.7)	-0.1 (-1.0 to 0.9)	-1.7 (-2.7 to -0.7)	-2.5 (-3.5 to -1.5)

Analysis of change from baseline in body weight

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Waist circumference

Top of page

End point title

Waist circumference

End point description

Analysis change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

End point values	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	7	17	32	31	33
Units: cm
least squares mean (confidence interval 95%)	-1.8 (-5.0 to 1.4)	-2.9 (-5.0 to -0.7)	0.1 (-1.2 to 1.3)	-1.2 (-2.6 to 0.1)	-2.2 (-3.6 to -0.9)

Analysis change from baseline waist circumference

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Waist to hip ratio part B

Top of page

End point title

Waist to hip ratio part B ^[2]

End point description

Analysis change from baseline to D84

End point type

Secondary

End point timeframe

From baseline to D84

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Other arms are reported in a separate endpoint.

End point values	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	32	31	33
Units: ratio
least squares mean (confidence interval 95%)	0.014 (0.001 to 0.026)	-0.017 (-0.031 to -0.003)	-0.010 (-0.024 to 0.004)

Analysis change from baseline waist hip ratio

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: glomerular filtration rate part B

Top of page

End point title

glomerular filtration rate part B ^[3]

End point description

End point type

Secondary

End point timeframe

Change from baseline to D84

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Other arms are reported in a separate endpoint.

End point values	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Number of subjects analysed	32	31	33
Units: mL/min/1.73m2
least squares mean (confidence interval 95%)	-2.7 (-6.6 to 1.2)	6.2 (1.9 to 10.2)	3.2 (-1.2 to 7.7)

Analysis of change from baseline in eGFR

Comparison groups

Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

ANCOVA

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

After the first dose of study drug until D96

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Part A Placebo

Reporting group description

Part A Placebo - treatment emergent AE

Reporting group title

Part A EYP001a pooled

Reporting group description

Part A EYP001a pooled - treatment emergent AE

Reporting group title

Part B Placebo

Reporting group description

Part B Placebo - treatment emergent AE

Reporting group title

Part B EYP001a 100mg

Reporting group description

Part B EYP001a 100mg - treatment emergent AE

Reporting group title

Part B EYP001a 200mg

Reporting group description

Part B EYP001a 200mg - treatment emergent AE

Serious adverse events	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	1 / 32 (3.13%)	1 / 31 (3.23%)	2 / 33 (6.06%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Transaminases increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	1 / 32 (3.13%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A Placebo	Part A EYP001a pooled	Part B Placebo	Part B EYP001a 100mg	Part B EYP001a 200mg
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 7 (57.14%)	16 / 17 (94.12%)	22 / 32 (68.75%)	25 / 31 (80.65%)	30 / 33 (90.91%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	2 / 32 (6.25%)	1 / 31 (3.23%)	1 / 33 (3.03%)
occurrences all number	0	0	2	1	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 7 (14.29%)	1 / 17 (5.88%)	1 / 32 (3.13%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	1	0	0
Adverse drug reaction
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	2
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	3
Investigations
Low density lipoprotein increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)
occurrences all number	0	1	0	1	0
Transaminases increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	1	0	0	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	2 / 32 (6.25%)	1 / 31 (3.23%)	0 / 33 (0.00%)
occurrences all number	0	0	2	1	0
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	1 / 7 (14.29%)	1 / 17 (5.88%)	1 / 32 (3.13%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	1	0	0
Electric shock
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Foot fracture
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Post-traumatic pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Limb injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	3 / 33 (9.09%)
occurrences all number	0	0	0	0	3
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	2 / 31 (6.45%)	0 / 33 (0.00%)
occurrences all number	0	0	0	2	0
Nervous system disorders
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	1
Headache
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	4 / 32 (12.50%)	3 / 31 (9.68%)	2 / 33 (6.06%)
occurrences all number	0	0	6	4	2
Eye disorders
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 7 (0.00%)	2 / 17 (11.76%)	2 / 32 (6.25%)	0 / 31 (0.00%)	5 / 33 (15.15%)
occurrences all number	0	2	2	0	5
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	2 / 17 (11.76%)	0 / 32 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	2	0	0	2
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	2
Abdominal rigidity
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	1
Constipation
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	1 / 31 (3.23%)	1 / 33 (3.03%)
occurrences all number	1	0	0	1	1
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	1 / 31 (3.23%)	4 / 33 (12.12%)
occurrences all number	0	1	0	1	5
Toothache
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	3 / 32 (9.38%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	3	0	0
Hepatobiliary disorders
Hepatic cyst
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 7 (0.00%)	16 / 17 (94.12%)	4 / 32 (12.50%)	19 / 31 (61.29%)	22 / 33 (66.67%)
occurrences all number	0	22	4	29	36
Hyperhidrosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)
occurrences all number	0	1	0	1	0
Rash macular
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Rash pruritic
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Skin lesion
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	2
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Renal cyst
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Gastroenteritis viral
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 17 (5.88%)	2 / 32 (6.25%)	1 / 31 (3.23%)	1 / 33 (3.03%)
occurrences all number	0	1	2	1	1
COVID-19
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	2 / 31 (6.45%)	1 / 33 (3.03%)
occurrences all number	0	0	0	2	2
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 7 (14.29%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	1 / 32 (3.13%)	2 / 31 (6.45%)	1 / 33 (3.03%)
occurrences all number	0	0	1	2	1
Hypercholesterolaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	0 / 31 (0.00%)	3 / 33 (9.09%)
occurrences all number	0	0	0	0	4
Hyperlipidaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 17 (0.00%)	0 / 32 (0.00%)	2 / 31 (6.45%)	0 / 33 (0.00%)
occurrences all number	0	0	0	2	0

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Were there any global substantial amendments to the protocol? Yes

14 Nov 2018

Consolidated and signed version of the draft sent to FDA

11 Jan 2019

Eligibility criteria restricted (reduced allowable variability in baseline ALT and AST). Version incorporating outcome of discussions with FDA during the IND review period.

28 May 2019

Eligibility criteria expanded (increased allowable variability in baseline ALT, AST, ALP, and total bilirubin). Increased Screening Period (increased from 60 days to 12 weeks). Centra lab reference ranges for ALT, AST, and ALP updated. Following correspondence on May 3, 2019 from ENYO to FDA regarding the high SF rate, and FDA’s advice letter dated May 9, 2019 in which FDA provided recommended protocol modifications to improve the SF rate.

24 Mar 2020

Following DSMC-review of the unblinded Part A data and unscheduled interim analysis of Part A data (presented in Section 10), the following changes to study conduct were implemented: Eligibility criteria restricted: − Subjects with a BMI >45 kg/m2 were excluded. − eGFR exclusion criteria decreased from <60 mL/min/1.73 m2 to <50 mL/min/1.73 m2. Changes to study design: − Reduction in the number of subjects to be enrolled in Part B (reduced from 136 to 90 subjects). − Removal of the vonafexor 400 mg QD treatment group from Part B. − Dosing strategy for vonafexor a 200 mg QD in Part B updated to a step-up strategy (100 mg QD for the first 2 weeks of treatment, followed by an uptitration to 200 mg QD) to address the pruritus-related tolerance issues observed in the unblinded Part A data. − The Clinical Safety Monitoring Plan updated to ensure, in Part B, the DSMC were promptly notified for further review if any subjects experience ALT, AST, or bilirubin elevations 2×baseline values. − Removal of inhouse 24-hour PK monitoring.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With Nonalcoholic Steatohepatitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Liver Fat Content

Primary: Liver Fat Content

Secondary: glomerular filtration rate part A

Secondary: glomerular filtration rate part A

Secondary: Analyse of % change from baseline Liver Fat Content

Secondary: Analyse of % change from baseline Liver Fat Content

Secondary: Analyse of change from baseline in CT1

Secondary: Analyse of change from baseline in CT1

Secondary: ALT

Secondary: ALT

Secondary: Gamma GT

Secondary: Gamma GT

Secondary: Body weight

Secondary: Body weight

Secondary: Waist circumference

Secondary: Waist circumference

Secondary: Waist to hip ratio part B

Secondary: Waist to hip ratio part B

Secondary: glomerular filtration rate part B

Secondary: glomerular filtration rate part B

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With Nonalcoholic Steatohepatitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Liver Fat Content

Primary: Liver Fat Content

Secondary: glomerular filtration rate part A

Secondary: glomerular filtration rate part A

Secondary: Analyse of % change from baseline Liver Fat Content

Secondary: Analyse of % change from baseline Liver Fat Content

Secondary: Analyse of change from baseline in CT1

Secondary: Analyse of change from baseline in CT1

Secondary: ALT

Secondary: ALT

Secondary: Gamma GT

Secondary: Gamma GT

Secondary: Body weight

Secondary: Body weight

Secondary: Waist circumference

Secondary: Waist circumference

Secondary: Waist to hip ratio part B

Secondary: Waist to hip ratio part B

Secondary: glomerular filtration rate part B

Secondary: glomerular filtration rate part B

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With Nonalcoholic Steatohepatitis