A randomized, double-blind, placebo-controlled, alternating panel single ascending dose, sequential multiple ascending dose, and food effect study of FM101 in healthy male and female volunteers

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat in the
liver not caused by excessive alcohol consumption. Some NAFLD patients also
develop inflammation in the liver, this is called non-alcoholic steatohepatitis
(NASH). The inflammation leads to damage and scar tissue (fibrosis) in the
liver. This results in a higher risk for developing liver cirrhosis, cancer and
eventually liver failure. FM101 is a new compound that may eventually be used
for the treatment of NASH.

Adenosine is a signaling substance that is involved in many functions in the
body. It is released with cell damage and also elevated levels of adenosine
have been found in cells after inflammation, lack of oxygen and cancer.
Adenosine attaches to, so called, adenosine receptors (receivers) which are
present on cells in the body, after which a signal tells the cell to start
working or work less.. There are different types of these adenosine receptors.
The adenosine A3 receptor is the only one that is increased in inflamed and
cancerous cells. FM101 is a selective A3 adenosine receptor modulator. This
means that FM101 changes (modulates) how the receptor works, so when adenosine
binds to the cell, the cell starts to work less.. FM101 is expected to block
the action of adenosine in the liver and thus stop the worsening of NASH or
even reduce fibrosis in the liver.

The purpose of this study is to investigate how safe the new compound FM101 is
and how well it is tolerated when it is administered to healthy volunteers.
FM101 has not been administered to humans before. It has been previously tested
in the laboratory and on animals. FM101 will be tested at various dose levels.

It will also be investigated how quickly and to what extent FM101 is absorbed
and eliminated from the body (this is called pharmacokinetics). In addition,
the effect of FM101 on the body will be investigated.

The effects of FM101 will be compared to the effects of a placebo. A placebo is
a medicine that looks like the study compound but without any active
ingredient.

Part A:
The actual study will consist of 3 periods during which the volunteer will stay
in the research center for a minimum of 6 days (5 nights) and a maximum of 7
days (6 nights). The planned period of confinement may be changed, depending on
emerging results during the study. This will be discussed with the volunteer.

This part of the study consists of 2 subgroups which start 1 day apart. For
Period 2 and 3 it will only be known in which subgroup you will participate
after the start of Period 1. For Period 1, the volunteer will receive the study
compound the day after his/her arrival and the volunteer will leave the
research center on day 5 after their arrival. For Period 2 and 3, if he/she is
placed in the first subgroup the volunteer will receive the study compound on
the day after their arrival, and the volunteer can leave the research center on
day 5 after their arrival. If the volunteer is placed in the second subgroup,
he/she will receive the study compound on the second day after their arrival,
and the volunteer can leave the research center on day 6 after their arrival.

The volunteer is expected at the research center at 10:00 h in the morning
prior to the day when will be decided in which subgroup he/she will be placed
(this will be decided by change). Administration of the study compound will
take place 1 or 2 days after the volunteers arrival. The volunteer will leave
the research center on Day 5 after administration of the research compound, of
each period of the study. The volunteer is expected in the research center for
an additional visit on Day 7 after administration of the research compound of
each period. There will be a washout period of at least 3 weeks between
administrations of the study compound.

FM101 or placebo will be given as a drink. The volume of this drink will depend
on the doses but will not be more than 240 mL. Depending on the dose you will
receive, the study compound will be given to you in a dispenser (syringe) or in
a bottle. Before and a after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

Part B:
The actual study will consist of 2 periods during which the volunteer will stay
in the research center for 6 days (5 nights).
The planned period of confinement may be changed, depending on emerging results
during the study. This will be discussed with the volunteer.

Day 1 is the first day of administration of the study compound in each period.
The volunteer is expected at the research center at 14:00 h in the afternoon
prior to the day of first administration of the study compound in each period.
The volunteer will leave the research center on Day 5 of each period of the
study. The volunteer is expected in the research center for an additional visit
on Day 7 of Period 2. There will be a washout period of at least 7 days between
administration of the study compound.

FM101 or placebo will be given as a drink. The volume of this drink will depend
on the doses but will not be more than 240 mL. Depending on the dose you will
receive, the study compound will be given to you in a dispenser (syringe) or in
a bottle. Before and after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

Part C:
The actual study will consist of 1 period during which the volunteer will stay
in the research center for 11 days (10 nights).
The planned period of confinement may be changed, depending on emerging results
during the study. This will be discussed with the volunteer.

Day 1 is the first day of administration of the study compound. The volunteer
is expected at the research center at 14:00 h in the afternoon prior to the day
of first administration of the study compound.
The volunteer will leave the research center on Day 10 of the study. He/she is
expected in the research center on Day 14 for a visit.

Part C, Groups 1 and 2:
FM101 or placebo will be given as a drink daily for 7 days. The volume of this
drink will depend on the doses but will not be more than 240 mL. Depending on
the dose you will receive, the study compound will be given to you in a
dispenser (syringe) or in a bottle. Before and after administration of the
study compound, a Listerine strip will be provided to mask the taste of the
study compound.

Part C, Group 3:
FM101 or placebo will be given as a drink twice daily for 6 days (Days 1 to 6)
and a single morning dose on Day 7.
The volume of this drink will depend on the doses but will not be more than 240
mL. Depending on the dose you will receive, the study compound will be given to
you in a dispenser (syringe) or in a bottle. Before and after administration of
the study compound, a Listerine strip will be provided to mask the taste of
the study compound.

Part A:
FM101 or placebo will be given as a drink. The volume of this drink will depend
on the doses but will not be more than 240 mL. Depending on the dose you will
receive, the study compound will be given to you in a dispenser (syringe) or in
a bottle. Before and a after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

Period Day# Group 1* Group 2*
1 1 75 mg FM101 or placebo 150 mg FM101 or placebo
2 22 300 mg FM101 of placebo 600 mg FM101 of placebo
3 43 1200 mg FM101 of placebo 2400 mg FM101 of placebo

#: The days are counted from the first day of administration of the study
compound (Day 1)
* In case the dose level will be lower or higher than planned, the volunteer
will be informed verbally.

Part B:
FM101 or placebo will be given as a drink. The volume of this drink will depend
on the doses but will not be more than 240 mL. Depending on the dose you will
receive, the study compound will be given to you in a dispenser (syringe) or in
a bottle. Before and a after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

During the first 4 hours after administration of the study compound the
volunteer will not be allowed to lie down (except when indicated as such by one
of the investigators), as this may influence the uptake of the study compound.

All volunteers will receive the study compound once with a breakfast and once
without breakfast. The order in which this will occur will be determined by
chance. In one period the volunteer will receive a high-fat breakfast with a
standard composition, which must be started exactly on time and should be
finished within 30 minutes.

Order Period 1 (Day -1 t/m 4) Washout period Period 2 (Day -1 t/m 4)*
Day 1 Day 1
1 FM101 # mg + fasted FM101 # mg + high fat breakfast
2 FM101 # mg + high fat breakfast FM101 # mg + fasted

*: Day -1 of Period 2 is 7 days after administration of the study compound of
Period 1
#: The volunteer will be told which dose level he/she will receive before the
first administration.

Part C, Groups 1 and 2:
FM101 or placebo will be given as a drink. The volume of this drink will depend
on the doses but will not be more than 240 mL. Depending on the dose you will
receive, the study compound will be given to you in a dispenser (syringe) or in
a bottle. Before and a after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

During the first 4 hours after administration of the study compound the
volunteer will not be allowed to lie down (except when indicated as such by one
of the investigators), as this may influence the uptake of the study compound.

Group Day Treatment
1 1-7 # mg FM101 or placebo
2 1-7 # mg FM101 or placebo

#: The volunteer will be told which dose level he/she will receive before the
first administration.

Part C, Group 3:
FM101 or placebo will be given as a drink twice daily for 6 days (Days 1 to 6)
and a single morning dose on Day 7. The volume of this drink will depend on the
doses but will not be more than 240 mL. Depending on the dose you will receive,
the study compound will be given to you in a dispenser (syringe) or in a
bottle. Before and a after administration of the study compound, a Listerine
strip will be provided to mask the taste of the study compound.

During the first 4 hours after administration of the study compound the
volunteer will not be allowed to lie down (except when indicated as such by one
of the investigators), as this may influence the uptake of the study compound.

Group Day Treatment
3 1-7 # mg FM101 or placebo

#: The volunteer will be told which dose level he/she will receive before the
first administration.

As FM101 will be administered to man for the first time in this study, side
effects of FM101 in man have not been reported to date. However, FM101 has been
studied extensively in the laboratory and in animals.

The most frequent side effect of FM101 in dogs receiving doses from 250 to 1000
mg/kg per day was vomiting. Changes in feces (loose, muddy, watery stools) were
observed at the highest doses of 500 mg/kg and 1000 mg/kg. These symptoms
disappeared when treatment was stopped.

Dosing with a 1000 mg/kg in rats resulted in irregular breathing and salivation
in some rats. During the first 2 weeks of dosing with 500 mg/kg and 1000 mg/kg
changes in feces were observed, but these symptoms disappeared during the next
2 weeks of dosing.

The study compound may also have side effects that are still unknown.

Possible discomforts due to procedures:

Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.

In total, we will take a maximum of 450 milliliters (mL) 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.

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