A phase I, open-label, randomized, three-way cross-over study comparing bioavailability of two formulations and assessing the food effect on tablet formulation after PXL770 single oral dose in healthy subjects

PXL770 is a new compound that may eventually be used for the treatment of
non-alcoholic fatty liver disease (NAFLD). NAFLD is the accumulation of fat in
the liver which is not caused by excessive alcohol consumption. Some patients
with NAFLD also develop inflammation in the liver, this is called non-alcoholic
steatohepatitis (NASH). The inflammation leads to damage and scar tissue
(fibrosis) in the liver. This can lead to liver cirrhosis, cancer and
eventually liver failure. PXL770 works by activating a protein (AMPK) that
results, among other things, in a decrease in the uptake of fat by the liver,
which can be beneficial for patients that suffer from NASH. PXL770 was first
developed as a capsule formulation. The Sponsor is now developing a tablet
formulation that is intended to be used for further clinical studies.

The purpose of this study is compare a tablet formulation of PXL770 to the
capsule formulation of PXL770. It will be investigated how quickly and to what
extent PXL770 in each formulation is absorbed and eliminated from the body. To
limit the differences between the participants, only Caucasian participants can
participate in this study.

Furthermore, we will assess whether the consumption of a meal just after
administration of the tablet formulation has an effect on the pharmacokinetics
of PXL770.

It will also be investigated how safe the new compound PXL770 is and how well
it is tolerated when it is administered to healthy volunteers.

PXL770 has been administered to humans before. It has also been extensively
tested in the laboratory and on animals. PXL770 will be tested at a fixed dose
of 250 milligrams (mg).

The actual study will consist of 3 periods. In each period the volunteer will
stay in the research center for 5 days (4 nights).

During the participation in the study, the volunteer will follow the scheme
below:

Screening * Period 1 * Period 2 * Period 3 * Follow-up

In each period, Day 1 is the day of administration of the study compound. In
each period, the volunteer is expected at the research center at 14:00 h in the
afternoon prior to the day of each administration of the study compound (Day
1). The volunteer will leave the research center on Day 4 of each period.

The volunteer will receive 250 mg PXL770, 3 times over the course of 3 periods.
PXL770 will be administered twice as a tablet formulation and once as a capsule
formulation. Each administration will be given with 240 milliliters (mL) of
(tap) water. The study compound must not be chewed prior to swallowing. Which
treatment the volunteer will receive in each period will be determined by
drawing lots. The volunteer will be assigned to one of the following 6
sequences:

Sequence Period 1 Period 2 Period 3
1 Capsule Tablet Tablet (with a meal)
2 Tablet (with a meal) Capsule Tablet
3 Tablet Tablet (with a meal) Capsule
4 Tablet (with a meal) Tablet Capsule
5 Tablet Capsule Tablet (with a meal)
6 Capsule Tablet (with a meal) Tablet

The volunteer will receive 250 mg PXL770, 3 times over the course of 3 periods.
PXL770 will be administered twice as a tablet formulation and once as a capsule
formulation. Each administration will be given with 240 milliliters (mL) of
(tap) water. The study compound must not be chewed prior to swallowing. Which
treatment the volunteer will receive in each period will be determined by
drawing lots. The volunteer will be assigned to one of the following 6
sequences:

Sequence Period 1 Period 2 Period 3
1 Capsule Tablet Tablet (with a meal)
2 Tablet (with a meal) Capsule Tablet
3 Tablet Tablet (with a meal) Capsule
4 Tablet (with a meal) Tablet Capsule
5 Tablet Capsule Tablet (with a meal)
6 Capsule Tablet (with a meal) Tablet

There will be a period of at least a 8 days between PXL770 administration in
each period, to make sure the study compound has left the body.

The study compound may cause side effects.

PXL770 has been administered to 104 humans before in 3 previous clinical trials
with different doses up to 500 mg during 10 days. Only a limited amount of side
effects of PXL770 in humans have been reported to date. However, PXL770 has
also been studied extensively in the laboratory and in animals.

No serious complaints have been observed, only mild and moderate complaints.
The following complaints were most frequently observed:
- headache, observed in 5 volunteers
- abdominal complaints (abdominal pain, diarrhea), observed in 7 volunteers

The study compound may also have side effects that are still unknown. In
addition to unknown side effects, there is a small chance that an allergic
reaction will occur. This can be caused by the study compound or other
ingredients used to make the formulation.

Possible discomforts due to procedures

Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. On these days, blood will be sampled regularly to
determine the course of the concentration of the study compound in the blood
over time.

In total, we will take about 370 milliliters of blood from the volunteer. This
amount does not cause any problems in adults. To compare: a blood donation
involves 500 mL of blood being taken each time.

To make a heart tracing, electrodes will be pasted at specific locations on
your arms, chest and legs. Prolonged use of these electrodes can cause skin
irritation.

A sample for the coronavirus test will be taken from the back of the nose and
throat using a swab. Taking the sample only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and the
eyes may become watery.