A phase I, randomized, double-blind, placebo-controlled, single-center study designed to evaluate the safety, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of GDC-6599 and the effect of food on the pharmacokinetics and pharmacodynamics of GDC-6599 in
healthy adult subjects

Asthma is a chronic inflammatory disease in the lungs. Asthma results in
narrowed airways and extra mucus production in the airways. This can trigger
coughing, make breathing difficult and shortness of breath. Asthma prevalence
seems to be increasing worldwide. At the moment there is no cure for asthma,
but current treatment can help control the symptoms. Development of new
therapies targets towards patients which respond poorly to current treatment
methods. Patients with asthma and other respiratory diseases often say cough is
a bothersome symptom and significantly contributes to disease burden. Cough is
called chronic if it persists for longer than 8 weeks. Chronic cough may be a
result of asthma or another lung disease. There may also be no clear reason why
slight irritation causes coughing.
GDC-6599 is a new compound that may potentially be used for the treatment of
asthma and chronic cough. GDC­6599 is a so-called TRPA1 inhibitor and targeting
TRPA1 is expected to reduce airway obstruction and sensitivity. The aim of
GDC-6599 is reducing the (worsening of) symptoms in patients with asthma and
reducing the symptoms in patients with chronic cough.

In this study we will investigate how safe the new compound GDC-6599 is and how
well it is tolerated when it is used by healthy participants.

We also investigate how quickly and to what extent GDC-6599 is absorbed,
transported, and eliminated from the body (this is called pharmacokinetics). In
addition, we look at the effect of GDC-6599 on an itch/pain test (this is
called pharmacodynamics).

GDC-6599 has not been administered to humans before. It has been extensively
tested in the laboratory and on animals. GDC-6599 will be tested at various
dose levels.

We will compare the effects of GDC-6599 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 GDC-6599, placebo, or
both.

For this study we are looking for 92 healthy male or female participants. The
study will consist of 3 parts.

The first part of this study will consist of taking a single dose of GDC-6599
or placebo, where the dose is increased per group. This is called a *single
ascending dose* (SAD) study. The second part of this study will consist of
taking a single dose of GDC-6599 or placebo when fasting, and then 1 or 2 more
times with food. This is called a *food effect* (FE) study. The third part of
this study consists of taking repeat doses of GDC-6599 or placebo for up to 29
days, where the dose is increased per group. We call this a *multiple ascending
dose* (MAD) study.

SAD:
For the study it is necessary that the volunteer stays in the research center
for 1 period of 6 days (5 nights). This will be followed by 3 short visits to
the research center. These short visits will take place on Day 6, Day 8 and Day
15.

Day 1 is the day when the volunteer receives the study compound. The volunteer
is expected at the research center 2 days before administration of the study
compound. The volunteer will leave the research center on Day 4 of the study.

FE:
For the study it is necessary that the volunteer stays in the research center
for at least 1 period of 13 days (12 nights). This will be followed by 3 short
visits to the research center. These short visits will take place on Day 13,
Day 15 and Day 22

Day 1 and Day 8 are the days when the volunteer receives the study compound.
The volunteer is expected at the research center 2 days before the first
administration of the study compound. The volunteer will leave the research
center on Day 11 of the study.

Based on the results of the first 2 doses, it will be decided if a third dose
is needed. If a third is needed, it is necessary that the volunteer stays in
the research center for a second period of 5 days (4 nights). This will be
followed by 3 short visits to the research center. These short visits will take
place on Day 6, Day 8 and Day 15. Day 1 is the day when the volunteer receives
the third administration of the study compound. The volunteer is expected at
the research center 1 day before administration of the study compound. The
volunteer will leave the research center on Day 4 of the study.

MAD:
For the study it is necessary that the volunteer stays in the research center
for 1 period of 13 days (12 nights). This will be followed by 2 short visits to
the research center. These short visits will take place on Day 15 and Day 22.
Day 1 is the day when the volunteer receives the study compound. The volunteer
is expected at the research center 2 days before administration of the study
compound. The volunteer will leave the research center on Day 11 of the study.

SAD:
The volunteer will be given GDC-6599 or placebo as tablets orally with 240 mL
of water or as a suspension (a drink). After administration of the suspension,
the vial will be rinsed twice with 30 mL of water, which the volunteer will
also be required to drink. Thereafter he/she are also required to drink an
additional amount of water, for a total administration of 240 mL of liquid.

FE:
The volunteer will be given GDC-6599 or placebo as tablets orally with 240
milliliters (mL) of water.

GDC 6599 will be given after a fasting period of 10 hours, or 30 minutes after
a high-fat breakfast, or possibly 30 minutes after a low-fat breakfast.

MAD:
The volunteer will be given GDC-6599 or placebo as tablets orally with 240
milliliters (mL) of water.

In Group MAD-1, GDC-6599 will be given in a fasted state. In Groups MAD-2 and
MAD-3, GDC-6599 will be given in a fasted or fed state, depending on the
results of the FE part.

Blood draw
Drawing blood may be painful or cause some bruising. The use of the indwelling
cannula can sometimes lead to inflammation, swelling, hardening of the vein,
blood clotting, and bleeding in the environment 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.

In total, we will take about 260 (SAD) 450 to 500 (FE) 370 (MAD) milliliters
(mL) (8 days), 420 mL (15 days), or 500 mL (29 days) (MAD) of blood from the
volunteer. 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 will be placed on the arms, chest and legs.
To monitor your heart rate, electrodes will be placed on the chest and abdomen.
Prolonged use of these electrodes can cause skin irritation.

Itch/pain test
A small amount of a liquid test agent is applied to areas about the size of 1
centimeter on the forearm. These areas are then scanned with a laser imaging
camera for up to 21 minutes. The test agent, a mustard oil allyl isothiocyanate
(AITC), may cause some mild skin redness, change in skin color, blistering, or
pain and itching at the area of skin where it is applied. Most of the reactions
described above should resolve within a few hours. However, in some
individuals, the skin changes (eg, redness and/or swelling) can last for 2
weeks, sometimes even up to several months. An example of the latter is a risk
of *scarring*, ie, one participant (out of 86 total) had skin discoloration of
the skin tested, which lasted 79 days. There is a rare risk of having an
allergic skin reaction to AITC (contact dermatitis, which is a type of eczema
triggered by contact with some chemicals).

Fasting/Meals
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.

The high-fat breakfast is a big breakfast containing eg, 2 fried eggs, fried
potatoes and bacon. The volunteer must consume the whole breakfast. 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 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.