A Phase 1, Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses Oral Doses of APX001, to Investigate the Effect of Food on APX001 and to Investigate the Drug-Drug Interaction Potential of APX001

APX001 is a new investigational compound that may eventually be used for the
treatment of fungal infections. APX001 is a so-called prodrug, which is rapidly
metabolized to APX001A after intake. APX001A is able to bind to an enzyme
called GWT1, which is produced by fungi. By binding to GWT1, the cell wall of
the fungus will be affected, biofilm formation by the fungus will be inhibited
and the fungus will produce fungal growth defects. APX001 in development and is
not registered as a drug but has been given to humans before.

The medication I the CYP substrates are known medications that are used for
several indications.

The study will be performed in 3 parts, Parts 1, 2 and 3. In all parts, the
purpose is to investigate to what extent APX001 is tolerated. In addition, it
will be investigated how quickly and to what extent APX001 is absorbed and
eliminated from the body (this is called pharmacokinetics). The differences
between the 3 parts are summarized below.

During Part 1, the effect of single doses of APX001 will be investigated. Also
the effect of food on the pharmacokinetics of APX001 will be investigated.

During Part 2, the effect of multiple doses of APX001 will be investigated.

During Part 3, the potency of interaction between APX001 and other drugs during
treatment with multiple doses of APX001 will be investigated.

This study will be performed in 46 healthy male or female volunteers, divided
over 4 groups.

The pre-study screening will occur within 3 weeks before the start of the study.

Group 1a
For Group 1a, the actual study will consist of 4 periods during which the
volunteer will stay in the clinical research center in Groningen (location
Martini Hospital) for 4 days (3 nights) followed by one day during which the
volunteer will visit the clinical research center in Groningen (location
Martini Hospital) for a short visit. The time interval between the first days
of each period is at least 13 days.

For each period, Day 1 is the first day of administration of the study
compound. In each period, the volunteer is expected at the clinical research
center at 14:00 h in the afternoon prior to the day of administration of the
study compound. The volunteer will be required not to have consumed any food or
drinks during the 4 hours prior to arrival in the clinical research center
(with the exception of water).

In each of the 4 periods, the volunteer will leave the clinical research center
on Day 3 and will come back for a short ambulant visit on Day 8.

The post-study screening will take place on 12 to 16 days after the last
dosing. The appointment for the post-study screening will be made with you
during the study.

For Group 1a, the participation to the entire study, from the pre-study
screening until the post study screening, will be approximately 11 weeks.

Group 1b
For Group 1b, the actual study will consist of 2 periods during which the
volunteer will stay in the clinical research center in Groningen (location
Martini Hospital) for 4 days (3 nights) followed by one day during which you
will visit the clinical research center in Groningen (location Martini
Hospital) for a short visit. The time interval between the first days of each
period is at least 13 days.

For each period, Day 1 is the first day of administration of the study
compound. In each period, the volunteer is expected at the clinical research
center at 14:00 h in the afternoon prior to the day of administration of the
study compound on Day 1. The volunteer will be required not to have consumed
any food or drinks during the 4 hours prior to arrival in the clinical research
center (with the exception of water).

In both periods, the volunteer will leave the clinical research center on Day 3
and will come back for a short ambulant visit on Day 8.

The post-study screening will take place on 12 to 16 days after the last
dosing. The appointment for the post-study screening will be made with you
during the study.

For Group 1b, the participation to the entire study, from the pre-study
screening until the post study screening, will be approximately 7 weeks.

For Group 2 the pre-study screening will occur within 3 weeks before the start
of the study.

The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (location Martini Hospital) for 17
days (16 nights), followed by one day during which the volunteer will visit the
clinical research center in Groningen (location Martini Hospital) for a short
visit.

Day 1 is the first day of administration of the study compound. The volunteer
is expected at the clinical research center at 14:00 h in the afternoon prior
to the day of administration of the study compound on Day 1. The volunteer will
be required not to have consumed any food or drinks during the 4 hours prior to
arrival in the clinical research center (with the exception of water).

The volunteer will leave the clinical research center on Day 16. The volunteer
will return to the clinical research center for a short ambulant visit on Day
21.

The post-study screening will take place on Day 12 to 16 days after the last
dosing. The appointment for the post-study screening will be made with the
volunteer during the study.

The participation to the entire study, from the pre-study screening until the
post study screening, will be approximately 7 weeks.

For Group 3 the pre-study screening will occur within 4 weeks before the start
of the study.

The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (location Martini Hospital) for 19
days (18 nights), followed by one day during which you will visit the clinical
research center in Groningen (location Martini Hospital) for a short visit.

Day 1 is the first day of administration of the study compound. The volunteer
are expected at the clinical research center at 14:00 h in the afternoon prior
to the day of administration of the study compound on Day 1. The volunteer will
be required not to have consumed any food or drinks during the 4 hours prior to
arrival in the clinical research center (with the exception of water).

The volunteer will leave the clinical research center on Day 17. The volunteer
will return to the clinical research center for a short visit on Day 22.

The post-study screening will take place on 12 to 16 days after the last
dosing. The appointment for the post-study screening will be made with the
volunteer during the study.

The participation to the entire study, from the pre-study screening until the
post study screening, will be approximately 9 weeks.

For Group 1a, the study will consist of 4 periods during which the volunteer
will receive APX001 or placebo once per period. APX001 or placebo will be given
as an intravenous infusion in the first period. In the other 3 periods, APX001
or placebo will be given as an oral tablet.

For Group 1b, the study will consist of 2 periods during which the volunteer
will receive APX001 or placebo once per period. APX001 or placebo will be given
as an oral tablet.

For Group 2, the study will consist of 1 period during which the volunteer will
receive APX001 or placebo once daily for 14 consecutive days. APX001 or placebo
will be given as an oral tablet. The dose for the next group will only be
increased if the lower dose of the previous group was found to be well
tolerated and after approval by the local Medical Ethics Review Committee.

For Group 3, the study will consist of 1 period during which the volunteer will
receive once a cocktail of so-called CYP substrates (see also the Table below
for details) on Day 1. Thereafter the volunteer will receive APX001 once daily
for 13 consecutive days, followed by one day on which the volunteer will
receive once APX001 combined with a cocktail of CYP substrates. APX001 will be
given as an oral solution and the CYP substrate cocktail will be given as oral
tablets and capsules.

The possible adverse effects of the investigational procedures (e.g. the use of
the indwelling cannula) are described in Chapter 8 of the information booklet.

All potential drugs cause adverse effects; the extent to which this occurs
differs. APX001 has been administered to man in a currently ongoing study. Thus
far APX001 has been well tolerated with doses up to 350 mg administered via an
intravenous infusion. There were no safety concerns arisen from this study.
APX001 has been studied in animals. The most frequently observed adverse
effects in animals were: vomiting, decreased activity, drowsiness, retching,
decreased food consumption and increased reticulocyte (immature red blood cell)
counts.

Because APX001 may react with light, protective measures will be taken to
prevent exposure to direct sunlight.

The volunteer should be aware that the aforementioned adverse effects and
possibly other, still unknown adverse effects, may occur during the study.
However, with the doses used in this study no serious adverse effects are
expected.

The possible adverse events of the CYP substrates can be found in the package
leaflets that subjects will receive.