A Phase 2, Double-Blind, Randomized, Parallel-Group Study Evaluating the Efficacy, Safety, and Tolerability of Obeticholic Acid, Administered in Combination with Bezafibrate, in Subjects with Primary Biliary Cholangitis Who Had an Inadequate Response or Who Were Unable to Tolerate Ursodeoxycholic Acid

Primary biliary cholangitis is a chronic liver disease resulting from
progressive destruction of the bile ducts in the liver called the intrahepatic
bile ducts. When the ducts are destroyed, bile builds up in the liver
contributing to inflammation and scarring (fibrosis).
The current first line treatment for PBC is Ursodeoxycholic Acid (UDCA).
However, it has shown that PBC may progress despite using this treatment.
In this study an alternative treatment will be investigated, namely OCA
combined with Beza. OCA is a modified version of a natural compound made in the
liver called bile acid, which helps with digestion and has effects on liver
function. Beza helps the liver process triglycerides and may add additional
benefit to OCA in the treatment of PBC to improve liver function.

This study has been transitioned to CTIS with ID 2024-513762-18-00 check the CTIS register for the current data.

The primary objective is to assess the effects of the combination of OCA and
BZF on alkaline phosphatase
(ALP) in comparison to BZF alone in subjects with primary biliary cholangitis
(PBC)

To assess the effects of the combination of OCA and BZF in comparison to BZF
alone in subjects with PBC on
the following:
• Biochemical disease markers, including ALP, GGT, ALT, AST, total and
conjugated bilirubin, and a lipid panel.
• Disease-specific symptoms as assessed by health-related quality of life
questionnaires (PBC-40, pruritus visual analog scale [VAS], EQ-5D-5L, and SF-36)
• Biomarkers of bile acid synthesis and homeostasis, including 7α-
hydroxy-4-cholesten-3-one (C4) and bile acids
• Safety and tolerability

This Phase 2, proof-of-concept, randomized, double-blind, parallel-group study
will evaluate the efficacy, safety, and tolerability of OCA (5 mg and 10 mg)
administered in combination with 2 different BZF doses (200 mg and 400 mg) or
BZF alone (at two doses, 200 mg and 400 mg) in up to 72 subjects with PBC over
at least 12 weeks.

Protocol Version 2 and 3 overview of differences: Protocol version 2 had a
3-arm design (Group 1, OCA 5 mg to 10 mg; Group 2, OCA 5 mg to 10 mg + BZF 200
mgimmediate release [IR]; Group 3, OCA 5 mg to 10 mg + BZF 400 mg sustained
release [SR], whereas Protocol Version 3 onwards has a 4-arm design: Group 1
(Treatment A: BZF 200 mg IR); Group 2
(Treatment B: BZF 400 mg SR); Group 3 (Treatment C: OCA 5 mg to 10 mg + BZF 200
mg IR); and Group 4 (Treatment D: OCA 5 mg to 10 mg + BZF 400 mg SR). Subjects
enrolled under Protocol Version 2 will remain on the initial study
arm/treatment regimen (one of 3 treatment arms) throughout the double-blind
(DB), DB-follow-up and LTSE periods while completing the visits and assessments
described under Protocol Version 4. Upon completion of visit 10 of the DB
Follow-up period, subjects enrolled under the current protocol approved at the
site, will transition to the LTSE period.

Screening Period (2 weeks and up to 8 weeks):
Subjects will be screened for a period of 2 to 8 weeks before being randomized
into the study to allow for the collection of repeat serum chemistry samples
(there will be 2 screening visits at least 2 weeks apart) for verification of
inclusion/exclusion criteria and to establish baseline (including Day 1).

Double-Blind Treatment Period (12 weeks):
Subjects who meet the entry requirements will be randomized in a 1:1:1:1 ratio
on Day 1 to receive either Treatment A (BZF 200 mg IR once daily [QD]),
Treatment B (BZF 400 mg SR tablet QD), Treatment C (OCA 5 mg*10 mg QD + BZF 200
mg IR QD), or Treatment D (OCA
5 mg*10 mg QD + BZF 400 mg SR QD).

Subjects who are randomized to combination groups will receive OCA 5 mg QD from
Day 1 to the day before the Week 4 Visit, followed by OCA 10 mg QD from the
Week 4 Visit through the end of the study. To preserve the study blind,
appearance-matched placebo tablets for OCA and/or BZF will be administered to
subjects in each treatment group from Day 1 to Week 12 as shown in the study
design diagrams for the double-blind (DB) and LTSE treatment periods. Subjects
will be instructed to begin dosing on Day 1 and to take investigational product
at approximately the same time each day (morning dosing for the entire study is
preferred to align with all study visits). Subjects must be instructed to
swallow the tablets whole; investigational product must not be chewed, divided,
or crushed and must be taken with food and water (ad libitum) throughout the
study. At study visits, all doses of investigational product (and of UDCA, for
subjects on UDCA) will be administered at the clinic. Subjects are instructed
to take investigational product with a meal onsite after all procedures have
been completed, following a fast of at least 8 hours before dosing. A low-fat
meal or meal replacement drink will be given with investigational product
administration at visits with serial PK collections.
Subjects will be maintained on the DB dose and will transition to the DB
Follow-Up Period on the same dose. All subjects will be held in the DB
Follow-Up Period until the last subject completes Week 12 of the DB Period.

Please refer to Appendix A for a description of treatment arms and study design
for subjects who were randomized under Protocol Version 2.

Treatment A:
OCA 5 mg*10 mg QD:
- 1 OCA 5 mg tablet (Weeks 0 to 4)
- 1 OCA 10 mg tablet (Week 4 to end of DB treatment)
- 1 placebo BZF 200 mg IR tablet
- 1 placebo BZF 400 mg SR tablet

Treatment B:
OCA 5 mg*10 mg QD + BZF 200 mg IR QD:
- 1 OCA 5 mg tablet (Weeks 0 to 4)
- 1 OCA 10 mg tablet (Week 4 to end of DB treatment)
- 1 BZF 200 mg IR tablet
- 1 placebo BZF 400 mg SR tablet

Treatment C:
OCA 5 mg*10 mg QD + BZF 400 mg SR QD:
- 1 OCA 5 mg tablet (Weeks 0 to 4)
- 1 OCA 10 mg tablet (Week 4 to end of DB treatment)
- 1 placebo BZF 200 mg IR tablet
- 1 BZF 400 mg SR tablet

BZF = bezafibrate; DB = double-blind; IR = immediate release; OCA = obeticholic
acid; QD = once daily; SR = sustained
release

Please refer to table 1 and 2 in section 7.1.2 of the protocol (schedule of
assessments) for more information.

The patient participation in this study will take approximately 2 years. During
this period, the patient will visit the hospital about 13 times and the patient
will be called about 3 times by the study team. A visit will take approximately
4-8 hours, this is depending on the tests and procedures that take place during
a study visit. For some visits, the patient must fast 8 hours prior to the
study visit. During this period, the patient is only allowed to drink water.

The following tests and procedures will take place during these visits:
- Physical examination is performed and questions are asked about the medical
history.
- ECG is done.
- Fibro Scan (TE).
- Weight, height, hips and waist circumference, blood pressure temperature and
heart rate are measured.
- Blood and urine samples are taken.
- The research doctor will also perform a pregnancy test on female subjects of
child-bearing age.
- The subject is asked to fill in a number of questionnaires regarding the
quality of life: PBC-40, EQ-5D-5L, SF-36

Possible side effects that are already known are described in the
Investigator's Brochure and the patient informed consent form.