A phase I, open-label, randomized, 4-way crossover study in subjects with chronic Hepatitis B virus infection to assess pharmacokinetics (fasted/fed), safety, tolerability and pharmacodynamics of single oral doses of Farnesoid X receptor agonist EYP001a.

EYP001a is a new investigational compound that may eventually be used for the
treatment of chronic hepatitis B. Hepatitis B is a worldwide common infection
of the liver caused by a virus.

If it does not heal spontaneously and evolves into chronic hepatitis, there is
no effective treatment. If the infection has not healed spontaneously after 6
months, it is a chronic hepatitis B virus infection. Currently, there is no
treatment to cure chronic hepatitis B virus infection. However, the virus can
be suppressed with drugs currently available.

EYP001a is a 'farnesoid X receptor (FXR) agonist (stimulator). The FXR receptor
is a protein located on the cell nucleus mainly in liver cells. Its function is
being regulated by bile acids. The FXR receptor plays a role in the production
of bile acids and cholesterol, and in various metabolic processes, including
fat and carbohydrate metabolism. For its multiplication, the hepatitis B virus
is dependent on the action of this FXR receptor: when the FXR receptor is
stimulated, the hepatitis B virus will be inhibited. Therefore, the compound
does not act directly on the virus but on a certain function of the host which
the virus depends upon. In the future, the combination of an FXR agonist
(stimulator) with drugs that inhibit the virus directly may possibly cure a
chronic hepatitis B virus infection.

EYP001a is not registered as a drug but has been administered to healthy
volunteers before in a clinical study at PRA. Several FXR agonists are under
development for other, non-viral, liver disease including non-alcoholic fatty
liver disease. However, the use of an FXR agonist as a possible drug for the
treatment of hepatitis B is new. To date, one FXR agonist has been registered:
Ocaliva®.

The purpose of the study is to investigate how quickly and to what extent
EYP001a is absorbed into, distributed in and eliminated from the body (this is
called pharmacokinetics) when EYP001a is administered with and without food. It
will also be investigated how safe EYP001a is and how well EYP001a is
tolerated. In addition, the effect of EYP001a on certain blood markers,
including the virus concentration, will be investigated; this is called
pharmacodynamics. Because bile acids are subject to a distinct variation during
the day, the study compound will be given in the morning and in the evening,
both with and without food.

This study will be performed in a maximum of 14 subjects with a chronic
hepatitis B virus infection.

The screening visit will take place at the AMC, at the UMCG or at PRA. The
follow-up visit will take place at the AMC for subjects who have been screened
at the AMC and at PRA for subjects who have been screened at the UMCG and at
PRA. For all subjects, the study itself will take place at the PRA clinical
research center in Groningen.

The actual study will consist of 2 periods; the volunteer will not leave the
clinical research center between the 2 periods. The volunteer will stay in the
clinical research center for 13 days (12 nights): this will be from the
afternoon of Day -1 (1 day before first administration of the study compound;
also called admission) to the morning of Day 12. Period 1 will start at
admission on Day -1 and will end just before the first dose on Day 8 in Period
2. Period 2 will start just before the first dose on Day 8 in Period 2 and will
end at discharge from the clinical research center on Day 12.

Each dose of 300 mg EYP001a will be administered as oral capsules with 240
milliliters of tap water.

The study will consist of 2 periods during each of which the volunteer will be
administered 2 single doses of 300 milligrams (mg) EYP001a. Thus the volunteer
will receive a total of 4 single doses of 300 mg EYP001a each. EYP001a will be
given in the form of oral capsules: 3 capsules with 100 mg EYP001a each will
have to be swallowed per dose.

All potential drugs cause adverse effects; the extent to which this occurs
differs. EYP001a has been investigated in animals. In rats and dogs EPY001a was
well tolerated and few side effects were seen: in dogs, hypersalivation
(excessive production of saliva) and vomiting were observed. No effects were
seen on the nervous system, lung function and heart function. Some slight
changes were seen in blood results that usually quickly returned to normal.

EYP001a has also been administered to healthy men before in a clinical study
that is currently ongoing at PRA. No complaints considered to be related to the
study compound were observed at single doses of 30, 60, 120 and 250 mg EYP001a.
At a single dose of 500 and 800 mg EYP001a, several volunteers reported
short-lasting light nausea or dyspepsia, and at a single dose of 800 mg
EYP001a, 1 volunteer reported diarrhea, these side effects occurred shortly
after dosing.

There is limited information on other FXR agonists that are under development:
it is known that they have generally shown to be safe up to now. However, the
occurrence of pruritus has been reported with the the aforementioned registered
drug Ocaliva®.

Procedures: pain, minor bleeding, bruising, possible infection