A Phase 1 trial to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AS-0871 and to evaluate the relative bioavailability and the food effect of new oral formulations of AS-0871 in healthy subjects.

AS-0871 is a new compound that may potentially be used for the treatment of
allergic and autoimmune disorders such as hives and rheumatoid arthritis.
AS-0871 inhibits the activity of white blood cells called basophils, which may
be overactive in certain allergic diseases. AS-0871 also has an effect on cells
called B-cells. B-cells are part of the immune system and play a central role
in the volunteers body 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-0871 is intended to slow down the B-cell activity
and may therefore potentially be used for the treatment of these diseases.

In this study we will investigate how safe the new compound AS-0871 is and how
well it is tolerated when it is used by healthy participants.

We will also investigate how quickly and to what extent AS-0871 is absorbed,
transported, and eliminated from the body (this is called pharmacokinetics).

Part 1:
In addition, we will look at the effect of food on how the body handles AS-0871
in capsules. To study this, the study compound will be given once with and once
without food.

Part 1a:
In addition, we will look at the effect of food on how the body handles AS-0871
in tablets. To study this, the study compound will be given once with and once
without food.

Part 2:
In addition, we will look at the effect of AS-0871 in tablets on white blood
cells and we check for any breakdown products (metabolites) of AS-0871.

We will compare the effects of AS-0871 with the effects of a placebo.

AS-0871 has been given to humans before in a previous clinical study. It has
also been extensively tested in the laboratory and on animals. AS-0871 will be
tested at various dose levels in this study.

Part 1:
The study will take approximately 6 weeks from the screening until the
follow-up visit.
For the study, it is necessary that the volunteer stays in the research center
for 2 periods of 5 days (4 nights). This will be followed by a follow-up visit
after the second period.

The volunteer will receive a dose of the study compound once per period, so two
times in total. Each dose will be 300 milligram (mg) AS-0871. Each capsule is
50 mg, so, in total, 6 capsules per dosing.

Part 1a:
The study will take approximately 6 weeks from the screening until the
follow-up visit.
For the study, it is necessary that the volunteer stays in the research center
for 2 periods of 5 days (4 nights). This will be followed by a follow-up visit
after the second period.

The volunteer will receive a dose of the study compound once per period, so two
times in total. Each dose will be 300 milligram (mg) AS-0871. Each tablet is 50
mg, so, in total, 6 tablets per dosing.

Part 2:
The study will take a maximum of 7 weeks weeks from the screening until the
follow-up visit.
For the study, it is necessary that the volunteer stays in the research center
for 18 days (17 nights). Afterwards the volunteer will come back to the
research center for the follow-up visit.

The volunteer will receive a dose of the study compound twice daily for 13
days, with one additional dose on Day 14. This means that the volunteer will
have 27 doses in total. There will be 12 hours between each dosing. The dose
that the volunteer will receive depends on which group he is in. The study
compound will be given as capsules. Each capsule contains 50 milligram AS-0871
or placebo. The number of capsules the volunteer has to take depends on which
group he is in.

The volunteer will be given AS-0871 (Part 2: or placebo) as oral capsules (part
1) or tablets (part 1a and 2) with 240 milliliters (mL) of (tap) water. Intake
of the study compound should occur within 6 minutes. More water (up to 160 mL
for a total of 400 mL) may be used and more time (up to 4 minutes for a total
of 10 minutes) may be given if needed.

Part 1:
Participants will receive the study compound as capsules with a breakfast in
one period and without breakfast in the other period. The order in which this
will occur depends on what group the volunteer is in. 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 within 20 minutes.

Part 1a:
Participants will receive the study compound as tablets with a breakfast in one
period and without breakfast in the other period. The order in which this will
occur depends on what group the volunteer is in. 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 within 20 minutes.

Part 2:
Whether the study compound as tablets will be given after fasting or after food
will be decided based on the results of Part 1 and Part 1a of this study (which
examines the effect of food on the absorption of AS-0871).

Possible side effects:
The study compound may cause side effects.

One study has been completed in which a total of 16 healthy adult male and
female participants received at least 1 single dose of AS-0871. Doses of 5, 25,
100, 300, 600, and 900 mg were tested in this study. Overall, single doses of
AS-0871 up to 900 mg after fasting and at 300 mg after food were well
tolerated. Below you can find an overview of side effects that were considered
to be related to the treatment with AS-0871. They were all of mild intensity
and resolved during the study.
- Headache (7 participants)
- Nausea ( 6 participants)
- Vomiting (3 participants)
- Diarrhea (2 participants)
- Fever (2 participants)
- Fatigue (2 participants)
- Flatulence (1 participant)
- Throat irritation (1 participant)
- Taste disorder (1 participant)
- Malaise (1 participant)
- Feeling hot (1 participant)
- Excessive sweating (1 participant)

No relevant abnormalities were observed in any of the laboratory measurements,
ECGs, vital signs, or physical examinations. In one subject, a transient mild
elevation of liver enzymes was observed at 600 and 900 mg of AS 0871. This was
not considered clinically relevant (not of practical importance).

The occurrence of headache and gastrointestinal disorders have also been
reported for compounds that are similar to AS-0871, like acalabrutinib.

Acalabrutinib is a marketed compound that has a similar mechanism of action as
AS-0871. The safety of acalabrutinib was tested in different doses in 59
healthy volunteers. Of the 59 healthy volunteers, 16 had 1 or more side effect
during the study. In total, 3 side effects were assessed to be related to
acalabrutinib. These were constipation, somnolence, and feeling cold and were
generally mild. No effect of acalabrutinib was observed on laboratory values,
physical examinations, vital signs, or ECG measurements.

Based on experience with other compounds that have a similar mode of action as
AS-0871, we will be paying attention for bleeding or bruising. Results of an
investigation with AS-0871 in dogs have become available in November 2022. In
this dog study, the animals were treated for 13 weeks with different doses of
AS-0871. In one animal, given a relatively high dose level, a small spot of
bleeding was observed in the heart muscle. Compared with the doses planned to
be given in this part of the trial, there are still sufficient safety margins.
For the planned 50 mg dose level (Group B), the safety margin is 8.4-fold, for
the planned 100 mg dose level (Group C), the safety margin is 4.2-fold, and for
the planned 200 mg dose level (Group D), the safety margin is 2.1-fold. The
exact relationship of the finding with the dosing of AS-0871 is not clear yet.
Since the animals were dosed for 13 weeks twice daily, it is expected that the
risk for participants in this trial with 14 days of dosing with AS-0871 is
still very low. In addition, extra safety measures are implemented during your
stay in the research center with telemetry to monitor your heart activity and
clotting measurements to monitor these blood parameters in more detail.

The study compound may also have (serious) 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 that are used to prepare the formulation.

Possible discomforts:
Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula (a tube in a vein in the arm) 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, seating, low heart rate, or drop in blood
pressure with dizziness or fainting.

In total, we will take about part 1: 106 milliliters, part 1a: 130 milliliters,
part 2: 319 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. 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 may be more than the
amount indicated above.

Heart tracing
To make a heart tracing, electrodes (small, plastic patches) will be placed on
the arms, chest and legs of the volunteers. (Part 2: To monitor the volunteers
heart activity over a longer period, electrodes (small, plastic patches) will
be placed on the chest and abdomen). Prolonged use of these electrodes can
cause skin irritation (rash and itching), but the test itself is harmless.

Meals/Fasting
Part 1: The high-fat breakfast is a big breakfast containing eg, 2 fried eggs,
fried potatoes and bacon. The volunteer must consume the whole breakfast within
20 minutes. It can be difficult to consume the entire breakfast, particularly
for light eaters .

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.

Coronavirus test
Samples for the coronavirus test will be taken from the back of nose and throat
of the volunteer 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 volunteers throat may cause the volunteer to gag. When the
sample is taken from the back of the nose of the volunteer, the volunteer may
experience a stinging sensation and the eyes of the volunteers may become
watery.