Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis

Inclusion Criteria:

1. Definite or probable PBC diagnosis (consistent with American Association for the Study
of Liver Disease [AASLD] and European Association for 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

- Positive antimitochondrial antibodies (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. At least 1 of the following qualifying biochemistry values:

- ALP ≥ 1.67x upper limit of normal (ULN)

- Total bilirubin > ULN but < 2x ULN

3. Age ≥ 18 years

4. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months)
prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0.

5. Contraception: Female patients must be postmenopausal, surgically sterile, or if
premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of
contraception during the trial and for 30 days after the end of treatment (EOT) visit.
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)

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

Exclusion Criteria:

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

- Hepatitis C virus (HCV) infection; patients with active hepatitis B (HBV)
infection will be excluded, however, patients who have seroconverted (Hbs Ag and
Hbe Ag negative) may be included 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 (due to interpretability of bilirubin levels)

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

- History of liver transplantation, current placement on a liver transplant list or
current Model for End Stage Liver Disease (MELD) score ≥ 15

- Portal hypertension with complications, including: known gastric or large
esophageal varices, poorly controlled or diuretic resistant ascites, history of
variceal bleeds or related therapeutic or prophylactic interventions (e.g., beta
blockers, insertion of variceal bands or transjugular intrahepatic portosystemic
shunt [TIPS]), or hepatic encephalopathy

- Cirrhosis with complications, including history or presence of: spontaneous
bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN

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

3. Patients with severe pruritus or those requiring systemic treatment for pruritus
(e.g., with bile acid sequestrants [BAS] or rifampicin) within 2 months of Day 0 will
be excluded

4. Administration of the following medications is prohibited as specified below:

- Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose
to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate,
mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide
and other systemic corticosteroids; potentially hepatotoxic drugs (including
α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)

- Prohibited 12 months prior to Day 0 and throughout the trial (i.e., to last dose
to last dose and/or EOT): antibodies or immunotherapy directed against
interleukins or other cytokines or chemokines

5. Patients who have previously participated in a clinical trial of OCA will not be
allowed to participate

6. History or presence of clinically concerning cardiac arrhythmias likely to affect
survival during the trial, or prolongation of Screening (pretreatment) QT or QTc
interval of > 500 milliseconds (msec)

7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a
positive serum pregnancy test), or lactating

8. Known history of human immunodeficiency virus (HIV) infection

9. Presence of any other disease or condition that is interfering with the absorption,
distribution, metabolism, or excretion of drugs including bile salt metabolism in the
intestine. Patients with inflammatory bowel disease or who have undergone gastric
bypass procedures will be excluded (gastric lap band is acceptable).

10. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease)
or which may diminish life expectancy to < 2 years, including known cancers (except
carcinomas in situ or other stable, relatively benign conditions such as chronic
lymphatic leukemia)

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

12. Anticipated changes to current concomitant medications during the course of the trial

13. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol per
week (i.e., the equivalent of 14 4-ounce (125 mL) glasses of wine or 14 12 ounce
cans/bottles of beer), or other substance abuse within 1 year prior to Day 0

14. Participation in another investigational drug, biologic, or medical device trial
within 30 days prior to Screening

15. History of noncompliance with medical regimens, or patients who are considered to be
potentially unreliable

16. Blood or plasma donation within 30 days prior to Day 0

17. Mental instability or incompetence, such that the validity of informed consent or
compliance with the trial is uncertain