Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis

Patients with PSC often have ongoing inflammation and fibrosis (scars) along the length of
their bile ducts, and eventually this involves the liver itself which can lead to cirrhosis
(severe scarring), severe infections (cholangitis), bile duct cancer and death.

Although many patients are treated with UDCA, and experience improvement in their liver
tests and relief of symptoms, no medical treatment to date has been found to produce a
long-term improvement of inflammation and scarring, or to improved survival. For this
reason, there is a great need to identify new medications which are effective for the
treatment of PSC.

Recent work in animals by the research group at Yale University School of Medicine has shown
that the combination of UDCA and ATRA produced a significant improvement in liver scarring
and inflammation in animals with bile duct disease similar to that seen in PSC. This
improvement included a lowering in the levels of bile acids, which are harmful to the liver,
and a lowering of inflammation in the liver tissue of these animals. The benefits seen in
this study were greater in animals receiving the combination of UDCA and ATRA compared to
animals who received either medicine alone.

The medication ATRA is related to vitamin A, and has been used for many years as a topical
medication in the treatment of skin conditions such as acne and psoriasis. It has also been
used for nearly 20 years as an oral medicine in the treatment of a form of blood cancer
(acute promyelocytic leukemia), where it is given for 90 days at a time. ATRA has been shown
to produce a remission from the leukemia and is currently a standard treatment for patients
with that specific condition. ATRA is not used routinely in the care of patients with liver
or bile duct disease.

Based on the benefits observed by treatment with ATRA and UDCA in our animal studies, the
investigators plan to study this combination in patients with PSC and believe that this may
be an effective regimen for patients with this condition. The investigators will check blood
tests of the liver and bile ducts before, during, and after the treatment in order to look
for changes to liver tests which would be due to the medication combination.

Therefore, the goal of this study is to study the changes to liver tests in patients with
PSC who take a combination of UDCA and ATRA for 90 days, comparing levels at the beginning
of the study to those at the end of the study.

Inclusion Criteria:

- Diagnosis of PSC for at least 6 months, made by clinical evaluation in addition to
one of the following: a prior endoscopic retrograde cholangiography (ERC), magnetic
resonance cholangiography (MRC, also termed MRI/MRCP) or liver biopsy.

- Progressing disease or stable disease with persistent elevation in AP despite
treatment with UDCA (15 mg/kg/day) for at least 6 months.

- Measures of progressing disease:

1. Cholangitis within the past 12 months.

2. Presence or progression of biliary abnormalities on MRI/MRC.

3. Elevated liver tests (alkaline phosphatase, bilirubin, AST, ALT).

- Age between 18 and 80.

Exclusion Criteria:

- Pregnancy or planned pregnancy during study period and within 6 months of study
completion.

- Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher cardiac
disease, hyperlipidemia, hypertriglyceridemia, hepatic injury, or adverse event
related to administration of UDCA or ATRA.

- Prior intolerance to UDCA or ATRA (or related oral vitamin A compounds).

- Evidence of decompensated cirrhosis within the past 6 months (i.e. variceal bleeding,
uncontrolled ascites, hepatic encephalopathy, jaundice).

- Estimated need for liver transplantation within 1 year.

- Any evidence of hepatocellular carcinoma, cholangiocarcinoma, or other malignancy.