An alternating panel, single ascending dose trial to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, relative bioavailability, and food effect of orally administered AS-1763 in healthy subjects

AS-1763 is a new compound that may potentially be used for the treatment of
diseases of the immune system. More specifically for the treatment of immune
system diseases that are caused by a type of immune cell that is called a
B-cell. This includes diseases such as leukemia and other types of cancer
(B-cell lymphoma). B-cells play a central role in the immune system and your
body*s ability to defend itself against pathogens. In certain types of diseases
of the immune system, the B-cells may not be working properly or they may be
overactive. AS-1763 is intended to slow down the B-cell activity and may
therefore potentially be used for the treatment of these diseases. In addition
to B-cell diseases, the study compound is also being developed for the
treatment of inflammatory and autoimmune disorders such as rheumatoid
arthritis.

In this study we will investigate how safe the new compound AS-1763 is and how
well it is tolerated when it is used by healthy participants.

We also investigate how quickly and to what extent AS-1763 is absorbed,
transported, and eliminated from the body.

We will compare AS 1763 as a drink (Group A and B) to AS 1763 as a tablet
(Group C).

In Group A and B, we also look at the effect of AS 1763 on cells in your blood
(this is called pharmacodynamics). We compare the effects of AS 1763 as a drink
with the effects of a placebo. A placebo is a compound without any active
ingredient. Please note that when the term *study compound* is used in this
document, we mean AS 1763, placebo, or both.

In Group C, we also investigate if food has an effect on how the body handles
the AS 1763 tablet.

This is the first study where AS 1763 is given to humans. It has been
extensively tested in the laboratory and on animals. In this study, AS 1763
will be tested at various dose levels.

For the study it is necessary that you stay in the research center for 4
periods (Group A), 3 periods (Group B), or 2 periods (Group C) of 5 days (4
nights).

Day 1 is the day when subjects receive the study compound AS-1763. Subjects
will leave the research center on Day 4 of each period.

Group A and B
Subjects will be given AS-1763 or placebo as a drink. After administration of
the study compound, the vial will be rinsed twice with 20 mL solution, which
subjects will also be required to drink. This will be followed by drinking an
additional amount of water so that in total subject ingested 200 milliliters
(mL).

The study compound will be given after subjects have been fasting for 10 hours.

Whether subjects will receive AS-1763 or placebo will be determined by chance.
Per group, 6 participants will receive AS-1763 and 2 participants will receive
placebo. This study will be done double-blinded. In each period, different
participants will receive placebo.

Group C
The volunteer will be given AS-1763 as a tablet with a maximum of 200
milliliters (mL) of water.

All participants will receive the study compound once with a breakfast and once
without breakfast. The order in which this will occur will be determined by
drawing lots. In each period the volunteer must fast for at least 10 hours
overnight before intake of AS 1763 or before the start of breakfast (as
applicable). In one period, the volunteer will receive a high-fat breakfast
with a standard composition, which must be started exactly on time and must be
finished in 30 minutes or less. The entire breakfast must be consumed.

Participants will be divided in two three groups: Group A, Group B, and Group
C. In total the volunteer will receive the study compound 4 times (Group A), 3
times (Group B) or 2 times (Group C). There will be at least 28 days between
consecutive study compound intakes (between treatment periods) in Group A and B
and at least 7 days between dosings in Group C.

Group A and B:
The table below shows the planned dose levels for each group. The doses after
treatment period 1 can be adjusted. For example because the study compound had
more or less effect than was expected. However, the dose will not be lower than
5 milligram (mg). The dose for the next group will only be increased if the
lower dose of the previous group was found to be well tolerated and in case of
no objection by the Medical Research Ethics Committee. The study will be
discontinued if, in the opinion of the investigators, unacceptable side effects
appear.

The planned dose levels for each group is as follows:

Treatment period* 1A 1B 2A 2B 3A 3B
4A
Group A 5mg 100mg 600mg 1000mg
Group B 25mg 300 mg
800mg

* From treatment period 1B onwards, the dose that subjects will receive will be
based on the results of the previous groups. The dose may therefore be
different from what is mentioned in the table. Subjects will be informed
verbally about the dose that subjects will receive.

Group C
Participants in Group C will receive 100 mg AS 1763 in each period (twice in
total). Please refer to the table below for an overview of the possible
treatments per period.

Group C Period 1 Period 2
Sequence AB 100 mg after fasting 100 mg after food
Sequence BA 100 mg after food 100 mg after fasting

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
canula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment (bruising) of the puncture
site. In some individuals, a blood draw can sometimes cause pallor, nausea,
sweating, low heart rate, or drop in blood pressure with dizziness or fainting.

The total amount of blood collected in the entire study will not exceed 500
milliliters (mL). This amount does not cause any problems in adults. To
compare: a blood donation involves 500 mL of blood being taken each time. If
the investigator thinks it is necessary for the safety of a participant, extra
samples might be taken for possible additional testing. If this happens, the
total amount of blood drawn will be more than the amount indicated above.

Heart tracing
To make a heart tracing, electrodes will be placed on arms, chest and legs. To
monitor heart rate, electrodes will be placed on the chest and abdomen.
Prolonged use of these electrodes can cause skin irritation.

Meals/Fasting
If the volunteer has to fast for a prolonged time during the study, this may
lead to symptoms such as dizziness, headache, stomach upset, or fainting.

For Group C: The high-fat breakfast is a big breakfast containing eg, 2 fried
eggs, fried potatoes and bacon. The volunteer must consume the whole breakfast
in 30 minutes or less. It can be difficult to consume the entire breakfast,
particularly for light eaters.

Coronavirus test
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 subject to gag. When the sample is taken from the back of
the nose, subject may experience a stinging sensation and the eyes may become
watery.