A Phase 1 Study to Evaluate the Potential Drug-Drug Interaction between GS-4224 and Probe Inhibitors, Inducers and Substrates in Healthy Subjects

GS-4224 is an experimental compound that may eventually be used for the
treatment of chronic hepatitis B (CHB). Hepatitis B is a viral infection that
affects the liver and can lead to cirrhosis and liver cancer. After an
infection with the hepatitis B virus not all patients have a strong enough
immune reaction to completely clear the virus from the body. Between 5% and 10%
of adults and up to 90% of children with a hepatitis B virus infection develop
CHB as a result. CHB can lead to liver diseases including cirrhosis and liver
cancer. GS-4224 reacts with a protein on the cell surface (programmed cell
death-ligand 1 or PD-L1) that decreases the activity of a specific type of
immune cells (cytotoxic T-cells) in the body. By blocking this protein, the
activity of the specific immune cells increases, and the body can better fight
the infection with the hepatitis B virus increasing the chance to clear the
infection with the hepatitis B virus, even if this is a chronic infection.

Group 1:
Voriconazole is a medication used to treat fungal infections. In this study it
is used because it decreases the activity of CYP3A4, an enzyme that helps to
break down chemicals in the body.
Itraconazole is a medication that is also used to treat fungal infections. In
this study it is used because it decreases the activity of CYP3A4 and P-gp,
enzymes that either speed up the breakdown or decrease the intestinal
absorption of compounds like GS-4224.
Group 2:
Rifampin, also known as rifampicin, is a medication used to treat bacterial
infections such as tuberculosis. In this study it is used because it strongly
increases the activity of the following proteins:
• CYP3A4: an enzyme that helps to break down chemicals in the body
• P-gp: a protein that acts as a pump to remove damaging materials from the cell
• BCRP: transports chemicals from inside the cell to the outside
Group 3:
Rifabutin is an antibiotic medication used to treat bacterial infections such
as tuberculosis. In this study it is used because it increases the activity of
the following proteins:
• CYP3A4: an enzyme that helps to break down chemicals in the body
• P-gp: a protein that acts as a pump to remove damaging materials from the cell
• BCRP: transports chemicals from inside the cell to the outside
Group 4:
Midazolam is a medication used to treat sleep disorders and is also used for
anesthesia. In this study it is used as a model to measure the activity of
CYP3A4, an enzyme that helps to break down chemicals in the body. First, we
will examine how fast your body breaks down midazolam. Second, we will measure
to what extent GS-4224 can slow down this break down process.
Group 5:
GS-9688 is another new compound that is under investigation and can potentially
be used to treat CHB. GS-9688 can bind to a cell receptor (TLR8) that plays an
important role in the immune response. By binding to this receptor, GS-9688 can
stimulate the production of proteins that influence the communication between
immune cells (interleukins). This can result in the activation of immune cells
(natural killer cells) that can then attack the invading viruses.

The purpose of this study is to investigate how quickly and to what extent
GS-4224 is absorbed and eliminated from the body. We study this when the study
compound is administered alone and together with compounds that influence the
activity of a specific group of enzymes (CYP3A4, P­gp, and BCRP). In Group 1
these compounds are voriconazole and itraconazole. GS-4224 was administered to
healthy human subjects in a study before but is not currently approved by any
health authorities for use in any indications. Voriconazole and itraconazole
are not new compounds; they are already available on the market in several
dosages and formulations.

We will also investigate how safe the experimental compound GS-4224 (alone and
combined with voriconazole and with itraconazole) is and how well it is
tolerated when it is administered to healthy volunteers.

We will also investigate how safe the experimental compound GS-4224 (alone and
combined with rifampin) is and how well it is tolerated when it is administered
to healthy volunteers.

We will also investigate how safe the experimental compound GS-4224 (alone and
combined with rifabutin) is and how well it is tolerated when it is
administered to healthy volunteers.

We will also investigate how safe the experimental compound GS-4224 (alone and
combined with midazolam) is and how well it is tolerated when it is
administered to healthy volunteers.

We will also investigate how safe the experimental compound GS-4224 (alone and
combined with GS-9688) is and how well it is tolerated when it is administered
to healthy volunteers. In addition, we will study if administration of these
compounds has an effect on several (immunological) processes.

This study will be performed in approximately 94 healthy male and nonpregnant,
nonlactating female volunteers. The study will be performed in up to 5 parts,
Group 1 to Group 5. Whether all five groups will be performed will be decided
based on the results from the previous groups.

Group 1 consists of 2 subgroups of 9 volunteers each.
Group 2 consists of 2 subgroups of 9 volunteers each.
Group 3 consists of 18 volunteers. There will be 2 subgroups of 9 volunteers
each.
Group 4 consists of two subgroups with in total 15 volunteers.
Group 5 consists of 4 subgroups with 25 volunteers in total.

Group 1:
GS-4224, voriconazole and itraconazole are given as tablets and capsules by
mouth with 240 milliliters (mL) of water.
The actual research consists of 1 period during which volunteers will stay in
the research center for 24 days (23 nights).
Group 2:
GS-4224 and rifampicin are given as tablets and capsules by mouth with 240
milliliters (mL) of water.
The actual research consists of 1 period during which volunteers will stay in
the research center for 18 days (17 nights).
Group 3:
GS-4224 and rifabutin are given as tablets and capsules by mouth with 240
milliliters (mL) of water.
The actual research consists of 1 period during which volunteers will stay in
the research center for 18 days (17 nights).
Group 4:
GS-4224 and midazolam are given as tablets and capsules by mouth with 240
milliliters (mL) of water.
The actual research consists of 1 period during which volunteers will stay in
the research center for 13 days (12 nights).
Group 5:
GS-4224 and GS-9688 are given as tablets and capsules by mouth with 240
milliliters (mL) of water.
The actual research consists of 1 period during which volunteers will stay in
the research center for 17 days (16 nights).

See Protocol and ICF's.

Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising, lightheadedness, fainting, and very
rarely, infection at the site of the needle stick.

This study includes periods of fasting. Fasting could cause dizziness,
headache, stomach discomfort, and/or fainting.

In total, there will be taken no more than 500 mL of blood. This amount does
not cause any problems in adults.

To make a heart tracing, electrodes (small, plastic patches) will be pasted at
specific locations on the arms, chest and legs. Prolonged use of these
electrodes can cause skin irritation.