Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being
undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical
outcomes in 428 subjects with PBC. The study will include a screening period of up to 8
weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to
treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the
majority of subjects; dose and frequency will be modified for subjects with cirrhosis and
classified as Child-Pugh B or C. Randomization will be stratified by standard treatment with
UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits
approximately every 3 months. At the 3 month visit or any study visit thereafter, if study
treatment is tolerated, participants' dose should be titrated per protocol in a blinded
manner eg for participants who are non-cirrhotic or classified as Child-Pugh A and randomized
to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to
receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these
participants who are non-cirrhotic or classified as Child-Pugh A, but should be increased to
10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will
be assessed by monitoring adverse events and vital signs, and blood and urine testing. The
study is event driven and total duration will be determined by the time required to accrue
approximately 127 primary endpoint events, estimated to be approximately 10 years. Subjects
are expected to have a minimum follow-up time of approximately 6 years.

Inclusion Criteria:

1. Definite or probable PBC diagnosis (consistent with American Association for the Study
of Liver Diseases [AASLD] and the European Association for the Study of the Liver
[EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence
of ≥2 of the following 3 diagnostic factors:

- History of elevated Alkaline phosphatase levels for at least 6 months prior to
Day 0

- Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low
titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or
antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid
dehydrogenase complex])

- Liver biopsy consistent with PBC

2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN

3. Age ≥18 years

4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA
for at least 12 months with a stable dose for ≥3 months prior to Day 0

5. Contraception: Female subjects of childbearing potential must use ≥1 effective method
of contraception during the trial and until 30 days following the last dose of
investigational product. Effective methods of contraception are considered to be:

- Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection; or

- Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with
spermicide; or

- Intrauterine device (IUD); or

- Vasectomy (partner); or

- Abstinence, if in line with the preferred and usual lifestyle of the subject

6. Must provide written informed consent and agree to comply with the study protocol

Exclusion Criteria:

1. History or presence of other concomitant liver diseases including:

- Hepatitis C virus infection

- Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis
B surface antigen and hepatitis B e antigen negative) may be included in this
study after consultation with the medical monitor

- Primary sclerosing cholangitis (PSC)

- Alcoholic liver disease

- Definite autoimmune liver disease or overlap hepatitis

- Nonalcoholic steatohepatitis (NASH)

- Gilbert's Syndrome

2. Presence of clinical complications of PBC or clinically significant hepatic
decompensation, including:

- History of liver transplant, current placement on a liver transplant list, or
current Model of End Stage Liver Disease (MELD) score >12. Subjects who are
placed on a transplant list despite a relatively early disease stage (for example
per regional guidelines) may be eligible as long as they do not meet any of the
other exclusion criteria

- Cirrhosis with complications, including history (within the past 12 months) or
presence of:

- Variceal bleed

- Uncontrolled ascites

- Encephalopathy

- Spontaneous bacterial peritonitis

- Known or suspected HCC

- Prior transjugular intrahepatic portosystemic shunt procedure

- Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine
>2 mg/dL (178 μmol/L)

3. Mean total bilirubin >5x ULN

4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable)
or ileal resection or plan to undergo either of these procedures

5. Other medical conditions that may diminish life expectancy, including known cancers
(except carcinomas in situ or other stable, relatively benign conditions such as
chronic lymphocytic leukemia)

6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy
test (confirmed by a positive serum pregnancy test), or lactating

7. Known history of human immunodeficiency virus infection

8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or
fractures within 3 months prior to Day 0)

9. Other clinically significant medical conditions that are not well controlled or for
which medication needs are anticipated to change during the study

10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0

11. Participation in another investigational product, biologic, or medical device study
within 30 days prior to Screening. Participation in a previous study of OCA is allowed
with 3 months washout prior to enrollment in this study

12. Mental instability or incompetence, such that the validity of informed consent or
ability to be compliant with the study is uncertain

13. History of known or suspected clinically significant hypersensitivity to OCA or any of
its components

14. UDCA naïve (unless contraindicated)