A single-center, open-label study to evaluate the absorption, distribution, metabolism and excretion (ADME) and pharmacokinetics of ZPL389 following a single oral dose of [14C]ZPL389 in healthy male subjects.

ZPL389 is a new compound that may eventually be used for the treatment of
inflammatory diseases such as atopic dermatitis. This is a type of eczema that
begins early in life during infancy and childhood. And often precedes asthma
and allergic disorders. The symptoms of this chronic inflammatory disease are
itching, dry scaly skin, redness, swelling and cracked skin, and sores.
Histamine is a substance in your body that is, among other things, involved in
the immune response, inflammation and allergies. If histamine is released in
the body this can result in the well-known allergy reactions like sneezing,
runny nose and itching, but histamine also plays a role in the itching and
other skin problems in eczema.

ZPL389 is a, so-called, histamine 4 receptor antagonist, which means that
ZPL389 blocks histamine from activating cells with a histamine 4 receptor.
Activation of this receptor can result in inflammatory responses and it is
thought that, by blocking this receptor, the inflammatory response can be
reduced and thus be beneficial in treating chronic inflammatory diseases such
as atopic dermatitis.

The purpose of this study is to investigate how safe the new compound ZPL389 is
and how well it is tolerated when it is administered to healthy volunteers.
ZPL389 has been administered to humans before. It has also been previously
tested in the laboratory and on animals.

It will also be investigated how quickly and to what extent ZPL389 is absorbed
and eliminated from the body (pharmacokinetics). ZPL389 will be labeled with 14
Carbon (14C) and is thus radioactive. In this way ZPL389 can be traced in
blood, urine and feces. In addition, the effects of ZPL389 on the body will be
investigated.

In addition, the effect of genetic information on how volunteers body responds
to ZPL389 will be investigated (pharmacogenetics).

The study will consist of 1 period during which the volunteer will stay in the
research center for 21 days (20 nights). This will be followed by at least 1
and a maximum of 5 overnight visit(s). These visits will take place on Day 26,
33, 40, 54 and 68. End of study visit on Day 68-69 is fixed.

Day 1 is the day of administration of the study compound. The volunteer is
expected at the research center at 14:00 h in the afternoon before the day of
administration of the study compound (on Day -1). You will leave the research
center on Day 20 of the study.

Entry: Day -1
Administration of the study compound: Day 1
Discharge: Day 20
Overnight visits*: Day 26-27, Day 33-34, Day 40-41, Day 54-55
End-of- study visit: Day 68-69
Follow-up phone call (or email): 30 days after the last visit + Day 120

*It is possible that the volunteer does not have to return for (all) the
overnight visits, this depends on the radioactivity levels in urine and feces.

For the (possible) overnight visits the volunteers are expected in the research
center at 11:00 h in the morning of Day 26, 33, 40, 54, and 68 and the
volunteer an leave in the afternoon the next day. The number of overnight
visits will depend on the amount of radioactivity left in urine and feces. The
amount of radioactivity in urine and feces will be measured daily from Day 1
onwards. If, from Day 20 onwards, the radioactivity levels in urine and feces
are below the pre-defined levels for 2 consecutive days, the volunteer will not
have to return for additional overnight visits.

The volunteer should be aware that for the overnight visits the volunteer needs
to collect urine and feces during the 24 hours before the visit and bring these
to the research center. And also during these visits urine and feces will be
collected.

During the end-of-study visit on Day 68-69 volunteers health will be checked
for the last time during which the volunteer will stay 1 night at the research
center. The volunteers are expected in the research center at 11:00 h in the
morning of Day 68, and the volunteer can leave in the afternoon the next day.
This visit will consist of a physical examination including measurement of
blood pressure, heart rate, and body temperature, weight, a heart trace,
several blood and urine tests and questions about their wellbeing.

The volunteer should be aware that for the end-of-study visit urine and feces
should be collected during the 24 hours before the visit and to bring these to
the research center. And also during this visit urine and feces will be
collected.

The volunteer will receive a follow-up phone call or email approximately 30
days after the last visit to the research center. The volunteer will be asked
questions about their wellbeing. The volunteer will also be contacted on Day
120 to check continued compliance with the 120-day condom use requirement

100 mg radioactive labeled ZPL389 will be given as oral capsules with 240
milliliters (mL) of (tap) water.

During the first 4 hours after administration of the study compound the
volunteer is not be allowed to lie down (except when indicated as such by one
of the investigators), as this may influence the uptake of the study compound.

One of the investigators will inspect volunteers hands and mouth after the
study compound intake.

The study compound may cause side effects.

ZPL389 has been administered to man before and has been studied extensively in
the laboratory and in animals.

ZPL389, up to doses of 400 mg, has been investigated in 264 subjects (100
healthy volunteers, 12 subjects with asthma, 65 patients with atopic dermatitis
and 87 patients with psoriasis). ZPL389 was found to be safe and well
tolerated.

The effect of ZPL389 were studies in patients with atopic dermatitis. 65
patients received ZPL389 and 33 patients received placebo. The side effects
were similar between the placebo and the ZPL389 group.
The most common side effects were:
•nasopharyngitis (common cold); this occurred in 12 subjects (18%) in the
ZPL389 group and in 8 subjects (24%) in the placebo group.
•headache; this occurred in 7 subjects (11%) in the ZPL389 group and in 4
subjects (12%) in the placebo group.

In a study investigating the effects of ZPL389 in psoriasis patients (87
patients receiving ZPL389 and 42 patients receiving placebo) side effects were
similar between the ZPL389 and placebo group.
The most common side effects were:
•nasopharyngitis (common cold); this occurred in 5 subjects (5.7%) in the
ZPL389 group and in 2 subjects (4.8%) in the placebo group.
•headache; this occurred in 5 subjects (5.7%) in the ZPL389 group and in 3
subjects (7.1%) in the placebo group.

The study compound may also have side effects that are still unknown.

Possible discomforts due to procedures
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. In total, we will take about 475 milliliters (mL) 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 (small, plastic patches) will be pasted at
specific locations on the arms and legs. Prolonged use of these electrodes can
cause skin irritation (rash and itching).

Exposure to radiation
This study involves using radioactive markers. The additional amount of
radiation volunteer will be exposed to in this study is 0.93 mSv (milliSievert
[a unit for radioactivity]). To compare: the background radiation in the
Netherlands is ~2.5 mSv per year.

Procedures: pain, minor bleeding, bruising, possible infection