A Phase 3, Double Blind, Placebo Controlled Trial and Long Term Safety Extension of Obeticholic Acid in Patients with Primary Biliary Cirrhosis

Relevance/Medical Need:
The only approved drug therapy for PBC is the bile acid UDCA marketed under
many names including, Ursodiol, URSO®, Actigall®, URSO 250® and URSO Forte*).
There is a significant proportion of patients who experience an incomplete
response to UDCA treatment with continued PBC disease progression. There is no
alternative medical treatment currently available to slow disease progression
in such non-responsive patients. With no other available treatment options,
there is a need for additional effective and safe therapies for the treatment
of PBC. This study is designed to determine the safety and the efficacy of OCA
as a potential treatment for PBC. OCA has orphan drug designation for the
treatment of PBC.

Justification of Dose Selection:
The safety and tolerability of OCA has been established in healthy subjects,
and in 2 different patient populations, including PBC patients, at doses up to
50 mg once daily. In patients with PBC it has been demonstrated that OCA can
significantly reduce alkaline phosphatase (ALP) levels in patients at doses of
10, 25 and 50 mg, but with an increase in the incidence and severity of
pruritus at the higher dose levels. This phase 3 trial has been designed to
assess the efficacy, safety and tolerability of lower doses (5 mg and 10 mg) of
OCA in patients with PBC so as to provide pivotal data to support a marketing
authorization application for OCA in this indication.

Under Protocol Version 3 and prior versions all patients entering the LTSE will
start at the 5 mg dose which may be increased (titrated) up to 25 mg daily
(doses higher than 25 mg daily may be allowed up to 50 mg but will require
sponsor approval). The 5 mg starting dose was chosen in order to maintain the
blind of the DB phase and assess the continued response and tolerability of
patients taking 10 mg during the DB phase. Data for the 25 mg dose from the
747-202 phase 2 trial has shown a benefit in patients who were able to tolerate
this dose.

The DB phase of this Phase 3 PBC trial (747-301) evaluated the safety and
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 months based
on efficacy and tolerability) and 10 mg; both treatment groups exhibited
clinically meaningful improvements in liver biochemistry and both doses were
safe and generally well-tolerated. Starting patients on 5 mg OCA and titrating
to 10 mg based on the clinical response appears to be an appropriate dosing
strategy in patients with PBC and is the planned dose regimen for OCA in the
treatment of PBC at the time of marketing approval. Hence, effective with
Protocol Version 4, patients who are tolerating 5 mg OCA daily and whose
bilirubin and/or ALP are > ULN should be titrated to a maximum of 10 mg daily.
Patients who were titrated above 10 mg prior to Protocol Version 4 may remain
on their current dose or the dose may be decreased as clinically indicated.

However, effective with Protocol Version 5, all patients will be titrated to a
maximum of 10 mg daily. If a patient is receiving a dose that is greater than
10 mg daily OCA, they should be down-titrated to a maximum daily dose of 10 mg
OCA. The exact dose and/or dosing frequency will depend on several factors
including the patient*s Child-Pugh score, tolerability and clinical response.

Justification for Placebo:
The placebo arm is included to maintain the study blind and scientific validity
of the study. However, patients will also continue their pre-study,
standard-of-care dose of UDCA for PBC throughout the study with the exception
of patients who cannot tolerate UDCA(their standard of care does not include
UDCA).

Justification for Duration of Treatment:
Patients will be dosed in the DB phase of this trial for 12 months. In the
earlier phase 2 trials, the majority of the effects (reductions in ALP and
liver enzymes) were seen after 1 month of treatment. A longer trial duration
of 12 months, will allow an evaluation of both efficacy (effectiveness) and
safety over a considerably longer period of time. Patients who complete the DB
phase (including those who receive placebo) will be enrolled in a very long (5
year) open label, safety extension upon completing the DB phase, which will
allow for a continued, thorough evaluation of the long-term safety and efficacy
of the study medication at doses up to 25 mg daily.

The trial will be conducted in compliance with Good Clinical Practice (GCP)
guidelines. Additionally, the protocol and the investigations are adapted for
the PBC patient population and will be approved by responsible research ethics
committee(s) in accordance with current International Committee of
Harmonisation (ICH) guidelines.

*Obeticholic acid is also known as OCA and was previously called INT-747. OCA
is also known as, 6α-ethylchenodeoxycholic acid; 6-ECDCA.

Main Objective:
To assess the effects of OCA in patients with PBC on:
-Serum alkaline phosphatase (ALP) and total
bilirubin, together as a composite endpoint
-Safety
Secondary Objectives:
To assess the effects of OCA in patients with PBC on:
-Hepatocellular injury and liver function, including histology
(inflammatory,
structural [portal, parenchymal] and fibrotic assessments)
-Disease specific symptoms
-Biomarkers and noninvasive assessments of liver fibrosis
-Bile acids
-Other exploratory evaluations

This is a phase 3, double blind (DB), placebo controlled, parallel group trial
followed by a long term safety extension (LTSE) of OCA in patients with PBC.
In the DB phase, approximately 180 patients (60 patients per arm) will be
randomized in a 1:1:1 ratio to 1 of 3 treatment arms: (a) placebo, (b) 10 mg
OCA, or (c) 5 mg titrating to 10 mg OCA. Study medication will be administered
orally, once daily for 12 months.
Under Protocol Version 3 and in prior versions, during the LTSE phase, patients
could receive up to 25 mg of OCA for up to 5 years.
Effective with Protocol Version 4, patients should be titrated to a maximum of
10 mg daily. Patients who were titrated above 10 mg prior to Protocol Version 4
may remain on their current dose or the dose may be decreased as clinically
indicated.

However, effective with Protocol Version 5, all patients will be titrated to a
maximum of 10 mg daily. If a patient is receiving a dose that is greater than
10 mg daily OCA, they should be down-titrated to a maximum daily dose of 10 mg
OCA. The exact dose and/or dosing frequency will depend on several factors
including the patient*s Child-Pugh score tolerability and clinical response.
Patients will continue their standard treatment of ursodeoxycholic acid (UDCA)
throughout trial participation. Those patients who do not tolerate UDCA will
continue receiving the investigational drug only for the duration of the trial
(initial DB phase and 5 years during the LTSE phase).

In the DB phase, first of three group of patients will receive orally placebo
once daily for 12 months, patients in the second group will receive orally 10
mg of OCA once daily for 12 months, and third group will receive orally 5 mg
of OCA titrating to 10 mg once daily for 12 months.
Under Protocol Version 3 and in prior versions, during the LTSE phase, patients
may receive up to 25 mg of OCA for up to 5 years.Effective with Protocol
Version 4, patients should be titrated to a maximum of 10 mg daily. Patients
who were titrated above 10 mg prior to Protocol Version 4 may remain on their
current dose or the dose may be decreased as clinically indicated.

However, effective with Protocol Version 5, all patients will be titrated to a
maximum of 10 mg
daily. If a patient is receiving a dose that is greater than 10 mg daily OCA,
they should be down-titrated to a maximum daily dose of
10 mg OCA. The exact dose and/or dosing frequency will depend on several
factors including the patient*s Child-Pugh score
tolerability and clinical response.

New Safety information:
• No patient should be dosing above 10 mg once daily
• All patients should be monitored during treatment for signs and symptoms
related to progression of their PBC disease. Patients who progress to moderate
or severe hepatic impairment (i.e., Child-Pugh A to Child-Pugh B or C) should
have their dose adjusted to align with the approved label dosing. All subjects
with moderate or severe hepatic impairment should be dosing at or below the
maximum allowed dose of 10 mg twice weekly.

Common and very common side effects depend on the type of liver disease you
have and includes itching, irritated or chaffed skin or skin wounds (ie, due to
itching), abdominal bloating and pain, constipation, diarrhea, feeling tired,
headache nausea, rash, joint pain, bruising, difficulty sleeping, dizziness,
dry eyes, sore throat, swelling of ankles, rapid or irregular heartbeat, fever
and abnormal function of thyroid gland.
As of September 2017, more than 3000 patients have received the study drug
[Ocaliva® (OCA)] in the *post-marketing* setting. Post-marketing means that in
the United States, Canada and Europe, where OCA has been approved for the
treatment of PBC, information on side effects in patients who are not
participating in a clinical study, but who are taking OCA under the care of
their doctor, are now being collected. Although information reported for these
patients is often not as detailed compared to that collected in a clinical
study, there have been recent safety findings reported for patients being
treated with OCA that you should be aware of. Patients with PBC who received
commercially available OCA have reported liver related events, which sometimes
resulted in death. The Sponsor reviewed the data and found that these patients
had moderate to severe liver disease and OCA was prescribed at a dose up to 7
times more than they were supposed to take. It is not known if these side
effects were possibly related to OCA, or to their liver disease. If your
disease gets worse, the dose of study drug may need to be reduced, stopped for
a little while or stopped forever by your study doctor.
In clinical studies, the blood levels of OCA were found to be higher in some
patients who had worse liver function or liver impairment. Liver impairment is
often caused by outside factors, such as disease, or liver injury from other
medical treatments. Patients with moderate or severe liver impairment have
liver cells that do not function properly, which means, the liver may not be
able to carry out normal activities that help the body function. This is
important because in clinical studies of PBC, liver-related side effects have
been shown to happen with higher levels of OCA in the blood. In addition, in
ongoing NASH clinical studies there have been reports of serious liver illness,
including one death in a patient with severe liver disease. The patients who
experienced these events in the NASH clinical studies were taking other
medications that are known to cause liver-related side effects. These patients
also had other ongoing medical conditions and health issues, that may have
contributed to these serious events. The following side effect may occur:
swelling of your stomach-area from a build-up of fluid
yellowing of your skin or the whites of your eyes
black, tarry, or bloody stools
coughing up or vomiting blood, or your vomit looks like *coffee grounds*
mental changes such as confusion, sleepier than usual or harder to wake up,
slurred speech, mood swings, or changes in personality
There may also be worsening in the results of tests that monitor your body*s
ability to prevent bleeding.
Blood fat level changes (such as an increase in cholesterol) are typically
associated with undesirable effects on the heart and blood vessels, such as
narrowing of blood vessels. Use of OCA may lead to such changes in blood fat
levels. However, it is not clear if these changes caused by OCA also lead to
undesirable effects on the heart and blood vessels, such as heart attacks or
strokes.

The course of disease in chronic progressive liver diseases is hard to predict,
and it may be difficult to tell apart liver-related adverse events due to the
worsening of your liver disease from potential liver injury due to other
causes, including ongoing medical treatments. For all patients participating
in clinical studies with OCA, it is important that you understand the signs and
symptoms of possible worsening (progression) of your liver disease. These signs
and symptoms may include the following:
abdominal (belly) pain worsening or new fatigue (tired)
nausea rash
vomiting diarrhea
weight loss fever and chills
weakness loss of appetite
confusion pale-colored stools
swelling of the legs or abdomen markedly reduced urination
yellowing of the skin or the whites of eyes dehydration
urine color change from pale to deep amber [dark]

Pregnancy:
The effects of OCA on pregnancy and the unborn child (fetus) in people are
unknown. In experimental animal studies with OCA lasting up to 2 years, no
effect on pregnancy or animal fetal development has been seen. Nevertheless,
in the absence of data from humans, female patients who are able to become
pregnant must use at least 1 effective method of birth control throughout the
study period and for 30 days after taking the last dose of study drug.

Allergic Reactions
In addition to the risks listed above, there may be unknown, infrequent, and
unforeseeable risks associated with the use of the study drug, including severe
or life-threatening allergic reactions or unexpected interactions with another
medication. Symptoms of an allergic reaction may include rash; flushing;
itching; sneezing or runny nose; abdominal pain; diarrhea; swelling of face,
tongue, or throat; dizziness, lightheadedness, or fainting; trouble breathing;
irregular or racing heart rate; and seizures.
If you have any known allergies, please inform the study doctor or study staff.