A first-in-human, randomized, double-blind, placebo-controlled, study to evaluate the safety, tolerability, and pharmacokinetics of single ascending oral doses of GLPG4059 in adult, healthy, male subjects.

GLPG4059 is a new compound that may potentially be used for the treatment of
type 2 diabetes. People with type 2 diabetes have too much sugar (glucose) in
their blood and need medication to control their blood sugar level. GLPG4059 is
able to lower blood sugar levels by inhibiting a protein, the so-called
Per-Arnt-Sim Kinase (PASK), which is involved in the regulation of sugar levels
in the body.

This study will be performed in a maximum of 57 healthy male volunteers. The
study will be performed in 2 parts, Part 1 and Part 2. Part 1 will consist of a
maximum of 6 groups of 8 volunteers each. The volunteers can participate in one
of these groups. Part 2 will consist of 1 group of 9 volunteers.

The purpose of this study is to investigate how safe the new compound GLPG4059
is and how well it is tolerated when it is administered to healthy male
volunteers. Also, the concentrations of GLPG4059 in blood and urine will be
measured (pharmacokinetics). In addition, the effect of food on the
pharmacokinetics of GLPG4059 in the body will be investigated (Part 2 only).
Also, the pharmacokinetics of 2 formulations (liquid and tablet) of GLPG4059
will be compared with each other. Furthermore, the effect of GLPG4059 on the
sugar levels in the blood will be investigated (pharmacodynamics).

GLPG4059 has not been administered to humans before. It has been previously
tested in the laboratory and on animals.

GLPG4059 will be given as orally as liquid and tested at various dose levels.
In Part 1, the effects of GLPG4059 will be compared to the effects of a
placebo. Whether the volunteers will receive GLPG4059 or placebo will be
determined by chance.

For Part 1 the actual study will consist of 1 period during each of the
volunteers will stay in the research center for 6 days (5 nights). Day 1 is the
day of administration of the study compound. The volunteers are expected at the
research center at 11:00 hrs in the morning of Day -1. They will leave the
research center on Day 4.

For Part 2 the actual study will consist of 3 periods during each of the
volunteers will stay in the research center for 6 days (5 nights). In each
period, Day 1 is the day of administration of the study compound. In each
period, the volunteers are expected at the research center at 11:00 hrs in the
morning of Day -1. In each treatment period, they will leave the research
center on Day 4 of each period. There will be at least 7 days between
administration of the study compound in each period.

Just before administration of the study compound it will be decided based on
the latest test results whether the volunteer is suitable for participation or
not. One of the tests that will be done to make a final decision on the
eligibility for participation will be a test to detect the presence of the
coronavirus. This test will be done upon entry to the research center and is
mandatory. Until the test results are available, volunteer will be separated
from other volunteers and only have very limited contact with study staff. This
is to avoid virus spread from potentially infected volunteers to other
volunteers or to the study staff. Until the results are available, it is not
certain whether the volunteer is infected or not and can thus potentially
infect others. The test results will be available within one hour. If volunteer
test positive for coronavirus, he cannot participate in the study.

When volunteer enter the research center 2 samples will be collected at the
same time to test if volunteer is a carrier of SARS-CoV-2. This test will be
repeated on the day after dosing (Day 2) and at follow-up. It may be decided
that more tests are needed (eg, if volunteer has COVID-19 symptoms).

Part 1:
Volunteer will receive a single dose of the study compound in the morning of
Day 1 orally as a liquid (between 0.15 and 15 milliliters. The study compound
will be administered via a syringe into the mouth. After administration of the
study compound, volunteer is required to drink 240 mL of water. The study
compound will be administered after volunteer has fasted overnight for at least
10 hours (no eating and drinking except water). Following administration of the
study compound, volunteer will fast for a period of 4 hours until the scheduled
lunch. During fasting volunteer is allowed to drink water, except during 1 hour
before and 1 hour after administration of the study compound (except for the
240 mL water taken with the dose). In each group, 6 volunteers will receive
GLPG4059 and 2 volunteers will receive placebo.

For safety reasons, in each group, initially 2 volunteers will receive the
study compound. One volunteer will receive GLPG4059, and 1 will receive
placebo. After administration, the safety and tolerability of the study
compound in these 2 volunteers will be closely monitored. If there are no
concerns about the safety and tolerability 48 hours after administration, then
the remaining 6 volunteers will receive the study compound (5 will receive
GLPG4059 and 1 will receive placebo).

The lowest planned GLPG4059 dose is 15 mg. The GLPG4059 dose levels after Group
A can be adjusted based on the results of the previous dose level(s). The
maximum dose is expected to be 1000 mg GLPG4059. However, this can be increased
depending on the level of GLPG4059 found in the blood after previous dose
level(s). There are defined limits of the level of GLPG4059 in the blood that
cannot be exceeded. These limits have been defined to ensure volunteer is not
exposed to levels of the study compound that had adverse effects in animals.
The next dose will only be increased if the lower dose level of the previous
group was found to be well tolerated and in case of no objection by the Medical
Research Ethics Committee. Furthermore, the expected GLPG4059 blood
concentrations of the next dose level should not exceed the predefined limits.
The study will be discontinued if, in the opinion of the investigator and/or
the Sponsor, unacceptable adverse effects appear.

Part 2:
The study consists of 3 treatment periods. In each treatment period, they will
receive a single dose of the study compound in the morning of Day 1 orally as a
liquid (1 treatment period) and as a tablet (2 treatment periods). The liquid
formulation will be administered via a syringe (without a needle) into the
mouth. After administration of the liquid formulation, they are required to
drink 240 mL of water. The tablet formulation will be administered with 240 mL
of water.

In 2 of the 3 treatment periods, the study compound (liquid formulation in 1
treatment period and tablet formulation in 1 treatment period) will be
administered after they have fasted overnight for at least 10 hours (no eating
and drinking except water). Following administration of the study compound, you
will fast for a period of 4 hours, until the scheduled lunch. During fasting
you are allowed to drink water, except during 1 hour before and 1 hour after
administration of the study compound (except for the 240 mL water taken with
the dose).

In the other treatment period, the study compound will be administered 30
minutes after the start of a high-fat breakfast with a standard composition.
This breakfast must be started exactly on time and must be finished within 20
minutes. Volunteer will have to consume the entire breakfast. The high-fat
breakfast will be started after volunteer has fasted overnight for at least 10
hours. Following administration of the study compound, volunteer will fast for
a period of 4 hours, until the scheduled lunch. During fasting volunteer is
allowed to drink water, except during 1 hour before and 1 hour after
administration of the study compound (except for the 240 mL water taken with
the dose).

The GLPG4059 dose level to be administered will be the same in the fasted state
and after a breakfast. The dose level of GLPG4059 will be selected based on the
information obtained in Part 1. The dose will be selected such that the
concentrations in the blood will not exceed those observed in Part 1 following
doses that were safe and well tolerated. Before administration of the study
compound volunteer will be informed about what dose level volunteer will
receive. The study will be discontinued if, in the opinion of the
investigators, unacceptable adverse effects appear.

As GLPG4059 will be administered to humans for the first time in this study,
side effects of GLPG4059 in humans have not been reported to date. However,
GLPG4059 has been studied extensively in the laboratory and in animals.

In rats, after multiple administrations of GLPG4059 in doses much higher than
the one given in this study, adverse heart findings (dying of muscle cells of
the heart, bleeding, inflammatory cells in the heart) were observed in 2 out
of 15 female rats. No adverse effects were observed in male rats, which
received the same dose.

Other findings consisted of microscopic changes in the kidneys, large
intestines, thymus, spleen, and bone marrow, correlating with an increased red
blood cell turnover. Additional findings consisted of disturbance of certain
hormones (estrous cycle), increase in liver enzymes and bilirubin, changes in
blood proteins and a reduced calcium concentration. All these findings were
fully reversible after a 2-week treatment-free period.
In dogs, after single dose of GLPG4059, a slight heart rate increase was
observed.

In dogs, after multiple administrations of GLPG4059, adverse heart findings
(dying of muscle cells of the heart, bleeding, inflammatory cells in the heart)
were reported in both male and female dogs. In an additional study in dogs,
effects were seen on the heart rate, blood pressure, and ECGs after multiple
high doses. After the highest dose was administered (300 mg/kg body weight),
the blood pressure first dropped and then increased (this is called
compensatory mechanism) also leading to an increased heart rate. At the same
time there were changes in the ECGs.

Based on experiments, GLPG4059 did not cause any damage to DNA.

With the treatment of GLPG4059 there is a risk on hypoglycemia (low blood sugar
levels); however, this risk in healthy volunteers is considered very low. This
low risk on hypoglycemia is because GLPG4059 seems to work by increasing the
sensitivity of insulin; thus one dose of GLPG4059 is not expected to change
this. Furthermore, healthy volunteers are able to counteract any effect of the
drug on lowering glucose by certain hormones that oppose the action of another
hormone.

The study compound may also have (serious) adverse effects that are still
unknown. In addition to unknown adverse effect, there is a (small) chance that
an allergic reaction will occur. This can be caused by the study compound or
the excipients.

Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising.

To make a heart tracing, electrodes (small, plastic patches) will be placed at
specific locations on the arms, chest and legs. To continuously monitor the
heart rate, electrodes (small, plastic patches) will be pasted at specific
locations on the chest and abdomen and will stay there for about 25 hours in
each period (also during the night).
Prolonged use of these electrodes may cause skin irritation (rash and itching).
The skin irritation usually disappears when the patches are removed.

Blood pressure and heart rate: an inflatable cuff will be placed on the arm and
a machine will measure the blood pressure and heart rate. The volunteer may
experience mild discomfort in your arm while the cuff is inflated.

Monitoring of your blood glucose for safety purpose will be performed in case
of symptoms by use of finger prick.

The high-fat breakfast is a big breakfast consisting of 2 fried eggs, fried
potatoes and bacon. The volunteer must consume this breakfast entirely.
Particularly for light eaters, it can be difficult to consume the entire
breakfast.

Samples for the coronavirus test will be taken from the back of the nose and
throat using swabs. Taking the samples 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, they may experience a stinging sensation and the eyes may
become watery.