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Clinical Trial Results:
A Phase 2a, randomized, double-blind, placebo-controlled study of oral FXR modulator EYP001a combined with nucleos(t)ide analogues (NA) in virologically suppressed chronic hepatitis B patients to improve functional cure rates

Summary
EudraCT number	2019-001629-28
Trial protocol	PL
Global end of trial date	25 Nov 2021

Results information
Results version number	v1(current)
This version publication date	07 Sep 2022
First version publication date	07 Sep 2022
Other versions

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

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Trial information

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Sponsor protocol code

EYP001-201

ISRCTN number

US NCT number

NCT04465916

WHO universal trial number (UTN)

Other trial identifiers

IND number: 142570

Sponsor organisation name

Enyo Pharma SA

Sponsor organisation address

60 avenue Rockefeller, Lyon, France, 69008

Public contact

Chief Medical Officer, ENYO Pharma SA, +33 4 3770 0219, ps@enyopharma.com

Scientific contact

Chief Medical Officer, ENYO Pharma SA, +33 4 3770 0219, 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

25 Nov 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Jun 2021

Global end of trial reached?

Yes

Global end of trial date

25 Nov 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

To determine the effect of EYP001a on top of NA (SOC therapy) on HBsAg plasma levels

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

ENYO Pharma is developing EYP001a, a selective, synthetic, non-bile salt, carboxylic acid agonist, or modulator, of the farnesoid X receptor (FXR), for the treatment of chronic hepatitis B (CHB) virus infections. Chronic liver diseases are major public health problems. Current worldwide estimations show that 844 million people have chronic liver diseases, with a mortality rate of 2 million deaths per year. Patients with chronic hepatitis B virus infection have increased rates of liver-related mortality due to the development of complications, including fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, there is an urgent need for improved treatment options for chronic liver diseases.

Evidence for comparator

Placebo

Actual start date of recruitment

12 May 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Hong Kong: 2

Country: Number of subjects enrolled

Korea, Republic of: 19

Worldwide total number of subjects

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

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Recruitment details

The study was open to chronic HBV carriers with no recent (3 months) history of any clinically significant conditions, which, in the opinion of the investigator, would jeopardize the safety of the patient or impact the validity of the study results. Study planned to randomized 49 patients and 26 were finally randomized.

Screening details

Screening procedures were applied to each patient who signs an informed consent form: eligibility based inclusion and exclusion criteria. Patient screening occured no more than 90 days prior to the Day 1 visit. Eligible patients undergone further assessments on Day 1 to qualify for study drug .

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Placebo and NA

Arm description

Placebo + NA

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

Investigational medicinal product name

Nucleos(t)ide analogue

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NA treatment (ETV or TDF) provided in combination with placebo as a SOC per the dosing guidelines presented in the country-specific label(s). Entecavir (ETV) 0.5 mg daily (or per country specific label) or Tenofovir Disoproxil Fumarate (TDF) 300 mg daily which is equivalent to 245 mg of tenofovir disoproxil given per country specific label). Patients continued to receive NA treatment during the follow-up phase as well.

EYP001a and NA

Arm description

EYP001a 200mg + NA

Arm type

Experimental

Investigational medicinal product name

EYP001a

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200 mg of EYP001a once a day

Investigational medicinal product name

Nucleos(t)ide analogue

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NA treatment (ETV or TDF) provided in combination with EYP001a as a SOC per the dosing guidelines presented in the country-specific label(s). Entecavir (ETV) 0.5 mg daily (or per country specific label) or Tenofovir Disoproxil Fumarate (TDF) 300 mg daily which is equivalent to 245 mg of tenofovir disoproxil given per country specific label). Patients continued to receive NA treatment during the follow-up phase as well.

Number of subjects in period 1	Placebo and NA	EYP001a and NA
Started	7	19
Completed	6	19
Not completed	1	0
Consent withdrawn by subject	1	-

Baseline characteristics

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Reporting group title

Placebo and NA

Reporting group description

Placebo + NA

Reporting group title

EYP001a and NA

Reporting group description

EYP001a 200mg + NA

Reporting group values	Placebo and NA	EYP001a and NA	Total
Number of subjects	7	19	26
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	46.29 ± 8.46	45.16 ± 8.32	-
Gender categorical
Units: Subjects
Female	1	5	6
Male	6	14	20
Race
Units: Subjects
Asian	5	19	24
Black or african american	1	0	1
White	1	0	1
Ethnicity
Units: Subjects
Not hispanic or latino	6	16	22
Unknown	1	3	4
Weight
Units: kg
arithmetic mean (standard deviation)	82.857 ± 21.084	68.821 ± 11.293	-
Height
Units: cm
arithmetic mean (standard deviation)	172.529 ± 11.342	168.763 ± 9.333	-

End points

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Reporting group title

Placebo and NA

Reporting group description

Placebo + NA

Reporting group title

EYP001a and NA

Reporting group description

EYP001a 200mg + NA

Primary: HBsAg decline

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End point title

HBsAg decline

End point description

End point type

Primary

End point timeframe

From baseline to week 16

End point values	Placebo and NA	EYP001a and NA
Number of subjects analysed	7	19
Units: log10
least squares mean (standard error)	-0.07 ± 0.03	-0.03 ± 0.02

General linear model for repeated measures

Comparison groups

Placebo and NA v EYP001a and NA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Virologic failure rate of HBV DNA

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End point title

Virologic failure rate of HBV DNA

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Placebo and NA	EYP001a and NA
Number of subjects analysed	6	19
Units: patients number
Week 16	0	0
Week 20	0	0
Week 28	0	0
Week 40	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After the first dose of study drug until W40

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo and NA

Reporting group description

Placebo + NA

Reporting group title

EYP001a and NA

Reporting group description

EYP001a 200mg + NA

Serious adverse events	Placebo and NA	EYP001a and NA
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 7 (0.00%)	0 / 19 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

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

Non-serious adverse events	Placebo and NA	EYP001a and NA
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 7 (42.86%)	17 / 19 (89.47%)
Investigations
Serum ferritin decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
White blood cell count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Syncope
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	2
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	2
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Vaccination site discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Abdominal pain lower
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
Chronic gastritis
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	3 / 19 (15.79%)
occurrences all number	0	4
Faeces discoloured
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Hiatus hernia
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
Nausea
subjects affected / exposed	0 / 7 (0.00%)	2 / 19 (10.53%)
occurrences all number	0	2
Oesophagitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 19 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Emphysema
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	2
Throat irritation
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	1 / 7 (14.29%)	15 / 19 (78.95%)
occurrences all number	1	19
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	2 / 19 (10.53%)
occurrences all number	0	3
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

03 Jul 2019

• Shortening treatment period from 24 weeks to 16 weeks and increased frequency of safety monitoring to every 2 weeks during treatment period. • Expand DSMC safety overview and incorporate futility rules whereby the DSMC would stop the study after the DSMC review meeting when 50% of subjects reach Week 12 if there is no evidence of vonafexor benefit. • Study stopping rules expanded and DSMC oversight increased.

17 Jul 2019

• Treatment stopping rules modified such that treatment will be suspended for SAEs considered also as “possibly related” to study drug.

09 Aug 2019

• Discontinuation criteria in event of drug-induced liver injury updated to comply with inclusion criteria of ALT or AST ≤ 2 × upper limit of normal (ULN)

22 Jan 2020

• The daily oral vonafexor dose to be administered for 16 weeks was reduced from 400 mg QD (two 200 mg tablets) to 200 mg QD (one 200 mg tablet). • Timepoint Week 40 of maintenance was added to secondary endpoints HBV-pgRNA decline (Δ log10) and HBcrAg decline (Δ log10).

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
26 Feb 2021	The DSMC review meeting was held to review preliminary results of 26 out of 49 planned subjects randomized. No effect on virology markers was observed when vonafexor was administered on top of NAs in the studied population. Based on outcomes of this meeting, ENYO Pharma decided that new randomizations were to be stopped. Despite vonafexor being well tolerated, the lack of an impact on virology markers shifts the risk benefit ratio for subjects to be randomized, and it was not considered in their interest to start treatment. Already randomized subjects were however maintained in the study with no changes to be followed up to Week 40 per protocol to gather long-term safety data in CHB aviremic subjects.	-

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, placebo-controlled study of oral FXR modulator EYP001a combined with nucleos(t)ide analogues (NA) in virologically suppressed chronic hepatitis B patients to improve functional cure rates

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: HBsAg decline

Primary: HBsAg decline

Secondary: Virologic failure rate of HBV DNA

Secondary: Virologic failure rate of HBV DNA

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 2a, randomized, double-blind, placebo-controlled study of oral FXR modulator EYP001a combined with nucleos(t)ide analogues (NA) in virologically suppressed chronic hepatitis B patients to improve functional cure rates

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: HBsAg decline

Primary: HBsAg decline

Secondary: Virologic failure rate of HBV DNA

Secondary: Virologic failure rate of HBV DNA

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, placebo-controlled study of oral FXR modulator EYP001a combined with nucleos(t)ide analogues (NA) in virologically suppressed chronic hepatitis B patients to improve functional cure rates