Single-center, open-label study with 14C-radiolabeled ACT-246475 to investigate its mass balance, pharmacokinetics, and metabolism following single subcutaneous administration to healthy male subjects.

ACT-246475 a new compound that may eventually be used for the treatment of
acute myocardial infarction (heart attack). On average it takes between 2 and 4
hours for treatment to start after the first symptoms of an heart attack are
noticed. While quick treatment of suspected heart attacks could prevent death,
and reduce damage to the heart. During a heart attack one of the blood vessels
of the heart becomes obstructed with a blood clot, and if this is not treated
quickly, the heart muscle can die, leading to permanent damage or even death.
Platelets are a type of blood cell responsible for blood clotting. Platelets
form blood clots in case of damage to the blood vessels. ACT-246475 reduces
platelet activation in the blood. In case of a heart attack, reducing the
formation of blood clots at the start of a (suspected) heart attack during the
first symptoms could prevent or reduce damage.

ACT-246475 is in development and it is not registered as a drug but has been
given to humans before.

This study will be performed in 6 healthy male volunteers.

The purpose of this study is to investigate how quickly and to what extent
ACT-246475 is absorbed, distributed, metabolized (broken down) and eliminated
from the body (pharmacokinetics). ACT-246475 will be labelled with 14 Carbon
(14C) and is thus radioactive (also called radiolabeled). In this way
ACT-246475 can be traced in blood, urine and feces. It will also be
investigated how safe ACT-246475 is and how well it is tolerated when it is
administered to healthy male volunteers.

The study will consist of 1 period during which the volunteer will stay in the
research center location Martini Hospital for at least 5 days (4 nights).

Day 1 is the 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
administration of the study compound (on Day -1).

The duration of the stay in the research center will depend on the amount of
radioactivity left in urine and feces at the end of the study (Day 4). The
amount of radioactivity in urine and feces will be measured daily from Day 1
onwards. If, from Day 4 onwards, the radioactivity levels in urine and feces
are below the pre-defined levels, the volunteer is allowed to leave the
research center. The volunteer should be aware that when the radioactivity
levels are still above the pre defined levels on Day 4, the stay in the
research center will be extended with a maximum of 6 days (until Day 10).

On the day that the volunteer leaves the research center volunteers health will
be checked for the last time.
The volunteer will be contacted by telephone for a last safety follow-up call,
30 to 32 days after administration of the study compound on Day 1. During this
phone call the volunteer will be asked how he is feeling and if anything
happened to him since he has left the research center.

The volunteer will receive a single dose of 16 mg/3.7 MBq radiolabeled
ACT-246475 as an injection of 1 milliliter under the skin (subcutaneous) in the
upper leg. The volunteer must remain in a sitting position from approximately 5
minutes before until 4 hours after administration of the study compound, except
for the measurement of the vital signs and ECG, which will be conducted when
the volunteer is lying down, or during blood sampling or for going to the
toilet.

The study compound may cause side effects. Because ACT-246475 is an
investigational drug, all of it side effects may not be known. There may be
rare and unknown side effects.

In the first study with the study compound administered subcutaneously, one
volunteer suffered, after a single subcutaneous dose of 1.6 mg, from serious
headache and hypotension, leading to hospitalization for additional exams and
treatments, and the study was prematurely terminated. The volunteer recovered
spontaneously.
In this study, apart from headache and hypotension, other complaints were also
reported: diarrhea, weakness (asthenia), abdominal pain, belching (eructation),
nausea, vomiting, chest pain, fatigue, feeling cold, inflammation of a vein
(phlebitis) at the injection site, accommodation disorder, light sensitivity
(photophobia), vision blurred, altered state of consciousness, hypersensitivity
for and fear of (loud) sounds (phonophobia).

In a subsequent study in healthy volunteers with subcutaneous doses between 1
and 32 mg of ACT-246475 or placebo, the following complaints were reported:
headache, dizziness, rhinorrhea, nausea and increased perspiration, without a
relationship to the administered dose.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. In total, we will take about 493 milliliters of blood from
the volunteer. This amount does not cause any problems in adults. To compare: a
blood donation involves 500 milliliters of blood being taken each time.

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

Exposure to radiation
In this study radiolabeled ACT-246475 will be used. The amount of radioactivity
in this dose will be approximately 3.7 MBq (MBq = megaBecquerel, this is a unit
to express the amount of radioactivity in the study compound). The average
environmental background radiation burden in The Netherlands is approximately
2.5 mSv per year (mSv = milliSievert, this unit indicates the burden on the
human body; thus the effect on the human body of the amount of radioactivity
administered). The additional radiation burden in this study due to the
administration of approximately 3.7 MBq radiolabeled ACT-246475 is calculated
to be 0.02 mSv. This is approximately 1% of the average annual radiation burden
in The Netherlands.

If the volunteer participate in scientific research involving exposure to
radiation more often, the volunteer should discuss with the responsible doctor
whether participation at this moment would be safe.