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Clinical Trial Results:
An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).

Summary
EudraCT number	2016-002996-91
Trial protocol	DE GB
Global end of trial date	08 Jul 2019

Results information
Results version number	v1(current)
This version publication date	04 Jan 2021
First version publication date	04 Jan 2021
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

CB8025-21629

ISRCTN number

US NCT number

NCT02955602

WHO universal trial number (UTN)

Sponsor organisation name

CymaBay Therapeutics, Inc.

Sponsor organisation address

7575 Gateway Blvd, Suite 110, Newark, United States, 94560

Public contact

Mary Standen, CymaBay Therapeutics, Inc., 001 5102938800, mstanden@cymabay.com

Scientific contact

Alexandra (Sasha) Steinberg, CymaBay Therapeutics, Inc., 001 5102938800, asteinberg@cymabay.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

30 Jul 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the safety and efficacy of seladelpar 2 mg, 5 mg and 10 mg over 8 weeks of treatment in subjects of primary biliary cholangitis (PBC) as measured by the mean percent change from baseline in serum alkaline phosphatase (ALP) levels. After completion of the 8-week initial treatment period, subjects entered a 44-week open-label extension period for a total of up to 52 weeks of treatment. During the extension period subjects took seladelpar orally once daily for up to 52 weeks. The 2 mg group was started in order to define the lower dose range for efficacy after review of initial treatment period results for the 5 mg and the 10 mg groups.

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki and its revisions and the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). The study was also in compliance with the applicable local regulatory requirements and laws of each country in which the study was conducted, as well as with any applicable guidelines.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Nov 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

United States: 82

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

Germany: 11

Worldwide total number of subjects

119

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 conducted at 33 sites in the Canada, Germany, United Kingdom, and United States between 28 November 2016 and 08 July 2019.

Screening details

A total of 192 subjects were screened of which 121 subjects randomized (2 subjects were not treated) into study and 71 were screen failures. Subjects were randomized to the 5 and 10 mg treatment groups for entry to the 8-week initial treatment period study, while those in the 2 mg treatment group entered after being sequentially assigned their dose

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Seladelpar 2 mg

Arm description

Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg.

Arm type

Experimental

Investigational medicinal product name

Seladelpar

Investigational medicinal product code

Other name

MBX-8025

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Seladelpar capsules taken once a day (QD) orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration up to 10 mg for efficacy reasons could be made after 12 weeks of treatment.

Seladelpar 5 mg

Arm description

Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

Seladelpar

Investigational medicinal product code

Other name

MBX-8025

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment to up to 10 mg.

Seladelpar 10 mg

Arm description

Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.

Arm type

Experimental

Investigational medicinal product name

Seladelpar

Investigational medicinal product code

Other name

MBX-8025

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period

Number of subjects in period 1	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Started	11	53	55
Completed	10	46	49
Not completed	1	7	6
Consent withdrawn by subject	1	3	2
Adverse event, non-fatal	-	3	-
Study entry with violation of protocol	-	-	3
Confirmed Paget's Disease	-	1	-
Lost to follow-up	-	-	1

Baseline characteristics

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Reporting group title

Seladelpar 2 mg

Reporting group description

Reporting group title

Seladelpar 5 mg

Reporting group description

Reporting group title

Seladelpar 10 mg

Reporting group description

Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.

Reporting group values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg	Total
Number of subjects	11	53	55	119
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	8	41	41	90
From 65-84 years	3	12	14	29
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	55.2 ( 9.6 )	57.5 ( 8.1 )	57.4 ( 9.7 )	-
Gender categorical
Units: Subjects
Female	11	51	50	112
Male	0	2	5	7
Race
Units: Subjects
White	10	50	49	109
Black or African-American	0	1	3	4
Asian	0	2	1	3
American Indian or Alaska native	0	0	1	1
Native Hawaiian or other Pacific Islander	0	0	0	0
Other	1	0	0	1
Multiple	0	0	1	1

End points

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Reporting group title

Seladelpar 2 mg

Reporting group description

Reporting group title

Seladelpar 5 mg

Reporting group description

Reporting group title

Seladelpar 10 mg

Reporting group description

Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.

Primary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)

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End point title

Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)

End point description

Relative change from baseline is in serum ALP levels at Week 8 (endpoint). The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Primary

End point timeframe

Week 8 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percent Change
arithmetic mean (standard deviation)
Percent change (n= 11, 47, 51)	-26.06 ( 9.15 )	-33.38 ( 17.81 )	-41.42 ( 13.05 )

Statistical Analysis 1, 5 mg vs 2 mg

Statistical analysis description

The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 8 weeks of treatment

Comparison groups

Seladelpar 2 mg v Seladelpar 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.2242

Method

ANCOVA

Confidence interval

Statistical Analysis 2, 2 mg vs 10 mg

Statistical analysis description

Comparison groups

Seladelpar 2 mg v Seladelpar 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0021

Method

ANCOVA

Confidence interval

Statistical Analysis 3, 5 mg vs 10 mg

Statistical analysis description

The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg and 10 mg treatment groups after 8 weeks of treatment.

Comparison groups

Seladelpar 5 mg v Seladelpar 10 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0024

Method

ANCOVA

Confidence interval

Secondary: Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)

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End point title

Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)

End point description

Absolute change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Absolute Change
arithmetic mean (standard deviation)
Absolute Change at Week 12 (n= 11, 46, 49)	-68.318 ( 63.276 )	-135.902 ( 150.954 )	-127.867 ( 60.284 )
Absolute Change at Week 52 (n= 10, 42, 48)	-101.150 ( 107.956 )	-158.310 ( 143.668 )	-133.760 ( 76.151 )

No statistical analyses for this end point

Secondary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)

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End point title

Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)

End point description

Mean percent change in ALP from baseline to Weeks 12 and 52 (Endpoint) The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percent Change
arithmetic mean (standard deviation)
Percent Change at Week 12 (n= 11, 47, 51)	-22.56 ( 13.92 )	-34.49 ( 20.62 )	-43.20 ( 12.39 )
Percent Change at Week 52 (n= 11, 45, 49)	-32.72 ( 22.48 )	-40.09 ( 24.23 )	-44.19 ( 15.52 )

Statistical Analysis 1, 5 mg vs 2 mg (12 weeks)

Statistical analysis description

The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 12 weeks of treatment.

Comparison groups

Seladelpar 2 mg v Seladelpar 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0493

Method

ANCOVA

Confidence interval

Statistical Analysis 2, 2 mg vs 10 mg (12 weeks)

Statistical analysis description

Comparison groups

Seladelpar 10 mg v Seladelpar 2 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0003

Method

ANCOVA

Confidence interval

Statistical Analysis 3, 5 mg vs 10 mg (12 weeks)

Statistical analysis description

The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 12 weeks of treatment.

Comparison groups

Seladelpar 5 mg v Seladelpar 10 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0053

Method

ANCOVA

Confidence interval

Statistical Analysis 4, 2 mg vs 5 mg (52 weeks)

Statistical analysis description

Comparison groups

Seladelpar 2 mg v Seladelpar 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.3466

Method

ANCOVA

Confidence interval

Statistical Analysis 5, 2 mg vs 10 mg (52 weeks)

Statistical analysis description

The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg vs 10 mg treatment groups after 52 weeks of treatment.

Comparison groups

Seladelpar 2 mg v Seladelpar 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0949

Method

ANCOVA

Confidence interval

Statistical Analysis 6, 5 mg vs 10 mg (52 weeks)

Statistical analysis description

The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 52 weeks of treatment.

Comparison groups

Seladelpar 5 mg v Seladelpar 10 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.251

Method

ANCOVA

Confidence interval

Secondary: Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint

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End point title

Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint

End point description

Reporting was done for percentage of subjects with response defined by Composite Risk Scores (ALP Less than [<] 1.67 x ULN at endpoint, Total BIL within normal limits at endpoint, and ≥15% ALP reduction from baseline to Endpoint). The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. The mITT analysis was performed in a manner similar to primary endpoint. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

12 Weeks and 52 Weeks

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Week 12 (n= 11, 47, 51)	45.5	48.9	66.7
Week 52 (n= 11, 45, 49)	63.6	53.3	67.3

No statistical analyses for this end point

Secondary: Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)

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End point title

Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)

End point description

Percentage of subjects with response based on Paris I risk score was defined as ALP less than or equal to (≤) 3x ULN and aspartate aminotransferase (AST) less than or equal to (≤) 2 x ULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

At Weeks 12, 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Week 12 (n=9, 35, 37)	81.8	76.1	75.5
Week 52 (n=9, 34, 38)	90	81.0	79.2

No statistical analyses for this end point

Secondary: Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)

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End point title

Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)

End point description

Percentage of subjects with response based on Paris II risk score was defined as ALP≤1.5xULN and AST≤1.5xULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

At Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Week 12 (n=4, 17, 29)	36.4	37.0	59.2
Week 52 (n=5, 23, 29)	50.0	54.8	60.4

No statistical analyses for this end point

Secondary: Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)

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End point title

Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)

End point description

Percentage of subjects with response based on Toronto I risk score defined as ALP ≤ 1.67 x ULN. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

At Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Week 12 (n=7, 24, 40)	63.6	51.1	78.4
Week 52 (n=7, 26, 35)	63.6	57.8	71.4

No statistical analyses for this end point

Secondary: Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)

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End point title

Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)

End point description

Percentage of subjects with response based on Barcelona risk scores was defined as Normalization of ALP or a Decrease of ALP ≥ 40%. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. . n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

At Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Week 12 (n=1, 20, 32)	9.1	42.6	62.7
Week 52 (n=5, 30, 32)	45.5	66.7	65.3

No statistical analyses for this end point

Secondary: Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)

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End point title

Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)

End point description

Percentage of subjects with response based on Rotterdam risk scores was defined in terms of populations of early stage (normal Total Bilirubin and normal Albumin), moderately advanced stage (either abnormal Albumin or abnormal Total Bilirubin), and advanced stages (both abnormal Albumin and abnormal Total Bilirubin). The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

At Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Percentage of subjects
number (not applicable)
Early Stage (12 Weeks, n=11, 36, 42)	100	82.6	81.6
Early Stage (52 weeks, n=10, 36, 42)	100	85.7	87.5
Moderately Advanced Stage (12 weeks, n=0, 7, 9)	0	15.2	18.4
Moderately Advanced Stage (52 weeks, n=0, 3, 5)	0	7.1	18.4
Advanced Stage (12 weeks, n=0, 1, 0)	0	2.2	0
Advanced Stage (52 weeks, n=0, 3, 1)	0	7.1	2.1

No statistical analyses for this end point

Secondary: Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)

End point description

Change from baseline in TB levels at endpoint is being reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: mg/dL
arithmetic mean (standard deviation)
Week 12 (n= 11, 46, 49)	-0.010 ( 0.121 )	-0.055 ( 0.161 )	-0.067 ( 0.199 )
Week 52 (n= 10, 42, 48)	0.002 ( 0.152 )	-0.028 ( 0.263 )	-0.068 ( 0.190 )

No statistical analyses for this end point

Secondary: Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)

End point description

Change from baseline in AST levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12, 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: U/L
arithmetic mean (standard deviation)
Week 12 (n= 11, 46, 49)	-2.50 ( 16.72 )	-1.13 ( 24.28 )	-3.35 ( 10.55 )
Week 52 (n= 10, 42, 48)	-7.05 ( 10.50 )	-6.18 ( 13.98 )	-6.14 ( 9.18 )

No statistical analyses for this end point

Secondary: Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)

End point description

Change from baseline in ALT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: U/L
arithmetic mean (standard deviation)
Week 12 (n= 11, 46, 49)	-5.59 ( 16.07 )	-10.48 ( 21.41 )	-10.87 ( 20.25 )
Week 52 (n= 10, 42, 48)	-14.30 ( 25.12 )	-17.29 ( 17.46 )	-15.32 ( 13.89 )

No statistical analyses for this end point

Secondary: Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)

End point description

Change from baseline in GGT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: U/L
arithmetic mean (standard deviation)
Week 12 (n= 11, 46, 49)	-43.68 ( 56.87 )	-75.35 ( 87.57 )	-80.82 ( 109.06 )
Week 52 (n= 10, 42, 48)	-78.60 ( 81.59 )	-91.37 ( 102.23 )	-88.08 ( 122.14 )

No statistical analyses for this end point

Secondary: Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)

End point description

The prognostic model for estimating disease severity and survival was utilized for subjects by assessing the Model for End-stage Liver Disease (MELD) score. To calculate the MELD score, samples for creatinine, bilirubin, international normalized ratio (INR), and sodium values were taken as specified in assessment schedule. The MELD scores were calculated as per following formulae: MELD(i) score = 10×(0.957×ln[creatinine, mg/dL]+0.378×ln[bilirubin, mg/dL]+1.120×ln[INR] + 0.643). If MELD(i) is less than or equal to 11 then MELD score = MELD(i). If MELD(i) is greater than 11 then MELD score = MELD(i) + (1.32 *(137 - (Na)) – (0.033*MELD(i)*(137 – Na)) The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Units on a scale
arithmetic mean (standard deviation)
Week 12 (n= 11, 46, 48)	-0.3 ( 1.6 )	0.1 ( 1.2 )	0.1 ( 1.0 )
Week 52 (n= 10, 42, 48)	-0.7 ( 1.6 )	0.3 ( 1.1 )	0.2 ( 1.2 )

No statistical analyses for this end point

Secondary: Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)

End point description

The Global PBC Study Group (GLOBE) score was assessed using the validated tool to accurately stratify patients into high- and low- risk for liver transplantation or death at 12 months of ursodeoxycholic acid (UDCA) treatment. Samples for bilirubin, ALP, albumin, and platelet count determination were used as per specifications to calculate the GLOBE score. Formula used : (0.044378×age+0.93982×ln[total bilirubin/ULN]+[0.335648×ln(alkaline phosphatase/ULN)]-2.266708×albumin /LLN-0.002581×platelet count per 109/L)+1.216865. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	53	55
Units: Units on a scale
arithmetic mean (standard deviation)
Week 12 (n= 10, 43, 46)	-0.079 ( 0.260 )	-0.292 ( 0.304 )	-0.346 ( 0.269 )
Week 52 (n= 9, 37, 43)	-0.180 ( 0.217 )	-0.271 ( 0.354 )	-0.404 ( 0.298 )

No statistical analyses for this end point

Secondary: Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)

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End point title

Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)

End point description

The UK-PBC Risk Score at endpoint is defined by the mean percentage risk that a PBC patient treated with ursodeoxycholic acid (UDCA) would develop liver failure requiring liver transplantation in 5, 10 and 15 years from diagnosis. Formula used for UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(AP12 x ULN-1.722136304) - 0.0422873*(((TA12 xULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-1.17673001)-0.4161954*(Platelet x LLN-1.873564875)). Where, Baseline survivor function = 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years respectively. AP12, TA12 and BIL12 refers to the AP, transaminases (ALT, AST), and total bilirubin assessments, respectively. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for timepoint

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Units on a scale
arithmetic mean (standard deviation)
5 years (week 12, n= 11, 44, 48)	1.3929 ( 0.6976 )	2.2553 ( 2.5145 )	1.8124 ( 1.7267 )
5 years (week 52, n= 10, 40, 47)	1.3145 ( 0.7704 )	2.3485 ( 3.4325 )	1.7244 ( 1.6121 )
10 years (week 12, n= 11, 44, 48)	4.5705 ( 2.2479 )	7.1229 ( 7.4904 )	5.8293 ( 5.3605 )
10 years (week 52, n= 10, 40, 47)	4.3128 ( 2.4649 )	7.2322 ( 9.5794 )	5.5607 ( 5.0092 )
15 years (week 12, n= 11, 44, 48)	8.3008 ( 3.9932 )	12.4002 ( 12.1785 )	10.3469 ( 9.1269 )
15 years (week 52, n= 10, 40, 47)	7.8325 ( 4.3413 )	12.3028 ( 14.5701 )	9.9008 ( 8.5396 )

No statistical analyses for this end point

Secondary: Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)

End point description

VAS is the commonly used graphic tool for self-reporting of pruritus intensity in patients. VAS is a simple to use, validated, reliable and widely applicable too that does not determine the impact of pruritus to quality of life. It comprises of a 100-mm horizontal line labelled as “no symptom” on left end and “worst imaginable symptom” on right end. Based on the intensity of the itch patient is instructed to draw a vertical line on the horizontal scale having a range [VAS values (unit: mm) ranging from 0 to 100, where 0 represents “no itching” and 100 “worst possible itching”]. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Units on a scale
arithmetic mean (standard deviation)
Week 12 (n= 11, 45, 49)	-3.7 ( 6.4 )	-5.5 ( 25.0 )	-12.3 ( 22.3 )
Week 52 (n= 10, 42, 48)	-3.3 ( 11.7 )	-9.6 ( 22.5 )	-16.5 ( 23.0 )

No statistical analyses for this end point

Secondary: Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)

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End point title

Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)

End point description

The PBC-40 QoL questionnaire is a disease-specific health-related tool developed for measuring the psychometric profile in PBC patients. It has 10 domains and a 43 questions relevant to PBC, including Cognitive, Social, Emotional Function, Fatigue, Itch, and Other Symptoms. Questions in domains: 1) digestion and diet (questions 1-3); 2) experiences (questions 4-7); 3) itching (questions 8-10); 4) fatigue (questions 11-18); 5) effort and planning (questions 19-21); 6) memory and concentration (questions 22-27); 7) affects to you as person (questions 28-33); 8) affects to your social life (questions 34-37); 9) overall impact on your life (questions 38-40); 10) general health and well-being (questions A-C). Within a domain, items are scored from 1 to 5 and the individual item scores are summed to give a total domain score. High scores represent high impact and low scores low impact of PBC on QoL. mITT, included population; n, number of subjects evaluable at respective timepoint

End point type

Secondary

End point timeframe

Weeks 12 and 52 (Endpoint)

End point values	Seladelpar 2 mg	Seladelpar 5 mg	Seladelpar 10 mg
Number of subjects analysed	11	49	52
Units: Units on a scale
arithmetic mean (standard deviation)
General Symptoms	1.9 ( 2.7 )	-0.7 ( 5.1 )	-0.5 ( 3.6 )
Itch	-0.4 ( 2.0 )	-0.5 ( 3.4 )	-0.8 ( 3.1 )
Fatigue	-1.5 ( 6.1 )	-2.1 ( 10.4 )	-3.0 ( 5.2 )
Cognitive Function	-0.9 ( 2.4 )	-0.6 ( 5.7 )	-0.7 ( 2.8 )
Social	0.8 ( 2.8 )	-0.5 ( 7.9 )	-1.0 ( 6.3 )
Emotional	-0.9 ( 1.6 )	-1.0 ( 2.6 )	-0.8 ( 2.1 )
General Symptoms, Week 12 (n= 11, 45, 49)	1.9 ( 2.7 )	-0.7 ( 5.1 )	-0.5 ( 3.6 )
General Symptoms, Week 52 (n= 10, 42, 48)	0.3 ( 2.4 )	-1.4 ( 4.4 )	-0.1 ( 4.4 )
Itch, Week 12 (n= 11, 45, 49)	-0.4 ( 2.0 )	-0.5 ( 3.4 )	-0.8 ( 3.1 )
Itch, Week 52 (n= 10, 42, 48)	0.4 ( 2.7 )	-1.3 ( 3.2 )	-1.4 ( 3.7 )
Fatigue, Week 12 (n= 11, 45, 49)	-1.5 ( 6.1 )	-2.1 ( 10.4 )	-3.0 ( 5.2 )
Fatigue, Week 52 (n= 10, 42, 48)	-1.2 ( 7.8 )	-3.0 ( 8.5 )	-3.4 ( 6.3 )
Cognitive Function, Week 12 (n= 11, 45, 49)	-0.9 ( 2.4 )	-0.6 ( 5.7 )	-0.7 ( 2.8 )
Cognitive Function, Week 52 (n= 10, 42, 48)	-0.7 ( 7.6 )	-1.4 ( 5.3 )	-0.6 ( 2.5 )
Social, Week 12 (n= 11, 44, 49)	0.8 ( 2.8 )	-0.5 ( 7.9 )	-1.0 ( 6.3 )
Social, Week 52 (n= 10, 42, 48)	-3.3 ( 5.2 )	-1.6 ( 7.2 )	-1.6 ( 6.2 )
Emotional, Week 12 (n= 11, 44, 48)	-0.9 ( 1.6 )	-1.0 ( 2.6 )	-0.8 ( 2.1 )
Emotional, Week 52 (n= 10, 42, 47)	-2.1 ( 2.3 )	-1.3 ( 2.7 )	0.9 ( 2.1 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to week 56

Adverse event reporting additional description

Adverse events

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Seladelpar 2 mg

Reporting group description

Subjects received seladelpar 2 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons. The 2 mg group was started after safety and efficacy review of the 5 mg and the 10 mg groups was completed.

Reporting group title

Seladelpar 10 mg

Reporting group description

Subjects were randomized to receive seladelpar 10 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons.

Reporting group title

Seladelpar 5 mg

Reporting group description

Subjects were randomized to receive seladelpar 5 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons.

Serious adverse events	Seladelpar 2 mg	Seladelpar 10 mg	Seladelpar 5 mg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 11 (9.09%)	5 / 55 (9.09%)	8 / 53 (15.09%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 55 (0.00%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 11 (0.00%)	1 / 55 (1.82%)	0 / 53 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 55 (0.00%)	1 / 53 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Seladelpar 2 mg	Seladelpar 10 mg	Seladelpar 5 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 11 (100.00%)	47 / 55 (85.45%)	45 / 53 (84.91%)
Injury, poisoning and procedural complications
Diarrhoea
subjects affected / exposed	4 / 11 (36.36%)	9 / 55 (16.36%)	7 / 53 (13.21%)
occurrences all number	4	9	7
Nausea
subjects affected / exposed	4 / 11 (36.36%)	6 / 55 (10.91%)	9 / 53 (16.98%)
occurrences all number	8	6	11
Abdominal pain upper
subjects affected / exposed	3 / 11 (27.27%)	5 / 55 (9.09%)	7 / 53 (13.21%)
occurrences all number	3	5	8
Vomiting
subjects affected / exposed	3 / 11 (27.27%)	5 / 55 (9.09%)	4 / 53 (7.55%)
occurrences all number	3	5	6
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 11 (9.09%)	5 / 55 (9.09%)	5 / 53 (9.43%)
occurrences all number	1	5	7
Abdominal distension
subjects affected / exposed	2 / 11 (18.18%)	4 / 55 (7.27%)	4 / 53 (7.55%)
occurrences all number	2	4	4
Abdominal pain
subjects affected / exposed	3 / 11 (27.27%)	3 / 55 (5.45%)	3 / 53 (5.66%)
occurrences all number	3	3	3
Dry mouth
subjects affected / exposed	2 / 11 (18.18%)	4 / 55 (7.27%)	2 / 53 (3.77%)
occurrences all number	2	4	2
Dyspepsia
subjects affected / exposed	3 / 11 (27.27%)	1 / 55 (1.82%)	2 / 53 (3.77%)
occurrences all number	3	1	4
Urinary tract infection
subjects affected / exposed	1 / 11 (9.09%)	8 / 55 (14.55%)	8 / 53 (15.09%)
occurrences all number	2	12	11
Nasopharyngitis
subjects affected / exposed	4 / 11 (36.36%)	6 / 55 (10.91%)	5 / 53 (9.43%)
occurrences all number	5	9	7
Upper respiratory tract infection
subjects affected / exposed	1 / 11 (9.09%)	3 / 55 (5.45%)	5 / 53 (9.43%)
occurrences all number	1	3	6
Influenza
subjects affected / exposed	0 / 11 (0.00%)	2 / 55 (3.64%)	5 / 53 (9.43%)
occurrences all number	0	2	5
Bronchitis
subjects affected / exposed	0 / 11 (0.00%)	3 / 55 (5.45%)	3 / 53 (5.66%)
occurrences all number	0	3	3
Pruritus
subjects affected / exposed	6 / 11 (54.55%)	12 / 55 (21.82%)	11 / 53 (20.75%)
occurrences all number	9	12	13
Arthralgia
subjects affected / exposed	1 / 11 (9.09%)	7 / 55 (12.73%)	6 / 53 (11.32%)
occurrences all number	1	8	6
Back pain
subjects affected / exposed	3 / 11 (27.27%)	3 / 55 (5.45%)	5 / 53 (9.43%)
occurrences all number	3	3	5
Myalgia
subjects affected / exposed	0 / 11 (0.00%)	2 / 55 (3.64%)	5 / 53 (9.43%)
occurrences all number	0	2	6
Muscle spasms
subjects affected / exposed	1 / 11 (9.09%)	2 / 55 (3.64%)	3 / 53 (5.66%)
occurrences all number	1	2	6
Musculoskeletal pain
subjects affected / exposed	1 / 11 (9.09%)	4 / 55 (7.27%)	1 / 53 (1.89%)
occurrences all number	1	5	1
Fatigue
subjects affected / exposed	3 / 11 (27.27%)	6 / 55 (10.91%)	9 / 53 (16.98%)
occurrences all number	3	6	10
Headache
subjects affected / exposed	2 / 11 (18.18%)	3 / 55 (5.45%)	6 / 53 (11.32%)
occurrences all number	5	3	9
Dizziness
subjects affected / exposed	2 / 11 (18.18%)	3 / 55 (5.45%)	5 / 53 (9.43%)
occurrences all number	2	3	5
Cough
subjects affected / exposed	2 / 11 (18.18%)	3 / 55 (5.45%)	4 / 53 (7.55%)
occurrences all number	2	3	4
Oropharyngeal pain
subjects affected / exposed	2 / 11 (18.18%)	4 / 55 (7.27%)	1 / 53 (1.89%)
occurrences all number	2	4	2
Dry eye
subjects affected / exposed	2 / 11 (18.18%)	4 / 55 (7.27%)	1 / 53 (1.89%)
occurrences all number	2	4	1

More information

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Were there any global substantial amendments to the protocol? Yes

24 Feb 2017

•Enrollment in the 5 and 10 mg dose groups was changed from ~12 to ~18 subjects each. Subjects in the 2 mg (n ~ 6) and 20 mg (n ~ 12) dose groups were to be registered in the study. •Because of the level of activity observed in the 5 and 10 mg dose groups at Interim Analysis 1, the 2 mg dose group was added and the next highest dose was decreased from 25 mg to 20 mg to limit exposure to seladelpar. •Dose titration options for the extension period were changed from 5, 10, and 25 mg to 1, 2, 5, 10, 15, and 20 mg. •microRNA-122 was added as a biomarker of liver disease.

25 Apr 2017

•After Interim Analysis 2, the extension period was changed from 18 to 44 weeks, and the treatment period was extended from 26 to 52 weeks. The total study duration (8 weeks’ initial treatment + extension period + 4 weeks’ follow-up) was extended from 30 to 56 weeks. •An exclusion criterion was added: total bilirubin > ULN and albumin < LLN with the exception of subjects with Gilbert’s syndrome. Subjects with Gilbert’s syndrome were to be excluded if direct bilirubin was >ULN. •During the extension period, dose up-titration to above 10 mg could not be performed until interim analysis results were available and the 20 mg dose group was initiated. •Barcelona PBC response criteria were added to outcome measures. •Prohibited systemic steroids were specified as long term (>2 weeks). •Review of medical history was to include history of liver related symptoms. •Physical examinations were to include evaluation of liver related symptoms. •A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period. •Prothrombin time was removed from laboratory evaluations. •Subjects who withdrew from the study could be replaced.

17 Jul 2017

•During the extension period, dose up-titration to above 10 mg was prohibited until interim analysis results were available. •The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment. •The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each. The size of the 20 mg dose group remained ~12 subjects. •The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6 to up to 12 receiving 5 mg, from ~6 to up to 12 receiving 10 mg, and from ~6 to up to 12 receiving 20 mg. •Prohibited systemic steroids were specified as long term (>2 weeks). •Review of medical history was to include history of liver related symptoms. •Physical examinations were to include evaluation of liver related symptoms. •A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period.

20 Jul 2017

•The 20 mg dose was removed. •Dose up-titration to 15 mg could take place only within 26 weeks of treatment. Beyond 26 weeks the highest dose was to be 10 mg. •The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment. •The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each. •The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6 to up to 12 receiving 5 mg, and from ~6 to up to 12 receiving 10 mg.

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: An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)

Primary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)

Secondary: Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)

Secondary: Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)

Secondary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint

Secondary: Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint

Secondary: Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)

Secondary: Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)

Secondary: Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)

Secondary: Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).