An Open-Label, Randomized, Crossover Pilot Study to Evaluate the Pharmacokinetics and Relative Bioavailability of JZP-324 Formulations vs. Xyrem in Healthy Subjects

JZP-324 is a new investigational compound that is being evaluated for the
treatment of narcolepsy. Narcolepsy is a sleeping disorder that involves
excessive daytime sleepiness and, in some people, a sudden loss of muscle tone
usually triggered by strong emotion (cataplexy). One of the current medications
for excessive daytime sleepiness and cataplexy in narcolepsy is Xyrem® (sodium
oxybate, also known as the sodium salt of gamma-hydroxybutyric acid [GHB]).
This is an oral solution that contains a high amount of sodium at the highest
approved dose. Sodium oxybate/GHB is a substance that has depressant or
sedating effects in people.

JZP-324 contains the same active substance as Xyrem, but reduces the daily
intake of sodium. Another potential advantage of JZP-324 is that it is expected
to be taken once a night, while Xyrem should be taken twice a night. JZP 324
has been administered to humans in Part 1 of the study.

Part 1:
The purpose of the study is to compare 5 different JZP-324 formulations to
Xyrem. It will be investigated how quickly and to what extent JZP-324 is
absorbed and eliminated from the body (this is called pharmacokinetics) when
compared to Xyrem (currently marketed drug for the treatment of narcolepsy).
This comparison is called the relative bioavailability. The safety of JZP-324
and to what extent JZP-324 is tolerated will also be investigated.

Four of the 5 JZP-324 formulations are granules which will be taken dry by
mouth and immediately washed down with water (including JZP324 DR1, JZP324 DR2,
JZP324-SR1 and JZP324-SR2). These granules are developed such that the active
compound is slowly distributed over the body after intake (delayed release [DR]
or sustained release [SR]). One of the 5 JZP-324 formulations (JZP324-IR) is an
oral solution similar to Xyrem. This JZP-324 oral solution is developed such
that the active compound is immediately absorbed by the body after intake
(immediate release [IR]) to elicit sleep.


Part 2:
The purpose of Part 2 of the study is to compare 4 different formulations of
JZP-324. It will be investigated how quickly and to what extent these
formulations of JZP 324 are absorbed and eliminated from the body (this is
called pharmacokinetics). The safety of JZP-324 and to what extent JZP-324 is
tolerated will also be investigated.

Each of the JZP-324 formulations contains granules which will be taken dry by
mouth. These granules are developed such that the active compound is slowly
distributed over the body after intake (delayed release [DR] or sustained
release [SR]). Each dose of granules is washed down by an oral solution of
JZP-324. This oral solution is developed such that the active compound is
immediately absorbed by the body after intake (immediate release [IR]) to
elicit sleep. The type of granules and/or the dose of JZP 324 in the granules
is different for each formulation.


Part 3:
The purpose of Part 3 of the study is to investigate how quickly and to what
extent escalating doses of JZP 324 are absorbed and eliminated from the body.
The safety of JZP-324 and to what extent JZP-324 is tolerated will also be
investigated when administered in escalating doses.

The JZP-324 formulation contains granules which will be taken dry by mouth.
These granules are developed such that the active compound is slowly absorbed
and then distributed throughout the body after intake. Each dose of granules is
washed down by an oral solution of JZP-324. This oral solution is developed
such that the active compound is immediately absorbed by the body after intake
to elicit sleep. Three different doses of the JZP-324 formulation will be
evaluated.

Part 1:
Day 1 is the first day of administration of study compound (JZP-324 or Xyrem).
The volunteer is expected at the clinical research center at 14:00 h in the
afternoon prior to the day of first administration of the study compound. The
volunteer is 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).

Each treatment with JZP-324 or Xyrem is separated by a period of 1 day. The
volunteer will receive JZP-324 or Xyrem on Days 1, 3, 5, 7, 9 and 11. During
the study the volunteer will stay for 13 days (12 nights: from Day -1 to Day
12) in the clinical research center.

On the final study day (Day 12) the volunteer will undergo a post study
evaluation. If the participation in the study is ended earlier than Day 12 for
any reason, the volunteer will be asked to undergo the post-study evaluations
to check on safety and to complete any final tests.

Participation from screening until the last study day will last maximally 33
days.


Part 2:
Day 1 is the first day of administration of study compound. The volunteer is
expected at the clinical research center at 14:00 h in the afternoon prior to
the day of first 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).

Each treatment is separated by a period of 1 day. The volunteer will receive
the study compound on Days 1, 3, 5 and 7. During the study the volunteer will
stay for 9 days (8 nights: from Day -1 to Day 8) in the clinical research
center.

On the final study day (Day 8) the volunteer will undergo a post study
evaluation. If the participation in the study is ended earlier than Day 8 for
any reason, the volunteer will be asked to undergo the post study evaluations
to check on safety and to complete any final tests.

Participation from screening until the last study day will last maximally 29
days.


Part 3:
In this study, the subjects will receive a total of 3 escalating doses of
JZP-324. The subjects will receive each dose once; each dose in a separate
period.

The dose for the next period will only be increased if the lower dose of the
previous period was found to be safe and well tolerated. To evaluate the safety
of the dose given in the 1st period, the 2nd period will start approximately
1.5 weeks after the 1st period. To evaluate the safety and pharmacokinetics of
the dose given in the 2nd period, the 3rd period will start approximately 3.5
weeks after the 2nd period.

The actual study will consist of 3 periods during which the subject will stay
in the research center for 3 days (2 nights).

During each period, Day 1 is the day of administration of the study compound.
The subjects are expected at the clinical research center at 14:00 h in the
afternoon prior to each day of administration of the study compound (so on Day
-1). The subjects are 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). They will leave the research center on Day 2 of each
period.

On Day 2 of each period, subjects will undergo a follow up evaluation. Also, if
the participation in the study is ended earlier than Day 2 of Period 3 for any
reason, the subjects will be asked to undergo a follow up evaluation to check
on safety and to complete any final tests.

Part 1:
In this study, the volunteer will receive a total of 6 treatments of study
compound. During the study the volunteer will receive 5 JZP-324 treatments and
1 Xyrem treatment every other day for 12 days. The order in which the volunteer
will receive the treatments will be determined by chance to match one of 6
predefined sequences. The volunteer will receive each treatment once.

Planned treatments:

• Treatment A: 7.19 g of JZP324-DR1 granules (active moiety equivalent to 4.5 g
sodium oxybate).
• Treatment B: 7.79 g of JZP324-DR2 granules, (active moiety equivalent to 4.5
g sodium oxybate).
• Treatment C: 5.94 g of JZP324-SR1 granules, (active moiety equivalent to 4.5
g sodium oxybate).
• Treatment D: 6.10 g of JZP324-SR2 granules, (active moiety equivalent to 4.5
g sodium oxybate).
• Treatment E: 9 mL of JZP324-IR solution containing 3.195 g of potassium
oxybate and 1.665 g of sodium oxybate
(active moiety equivalent to 4.5 g sodium oxybate).
• Treatment F: 9 mL of Xyrem solution (4.5 g sodium oxybate).


Part 2:
In this study, the volunteer will receive a total of 4 treatments with JZP-324
every other day for 8 days. Each treatment contains a total dose of the active
ingredient which is equivalent to 4.5 g sodium oxybate. The order in which the
volunteer will receive the treatments will be determined by chance to match one
of 4 predefined sequences. The volunteer will receive each treatment once.

Planned treatments:
G: 5.54 g JZP324 DR2 granules and 2.6 mL JZP324-IR oral solution
H: 5.70 g JZP324 DR3 granules and 1.5 mL JZP324-IR oral solution
I: 4.56 g JZP324 DR3 granules and 3.0 mL JZP324-IR oral solution
J: 4.38 g JZP324 SR3 granules and 2.6 mL JZP324-IR oral solution


Part 3:
In this study, the subjects will receive a total of 3 escalating doses of
JZP-324. The subjects will receive each dose once; each dose in a separate
period. Please refer to the table below to see the planned dose level of the
study compound for each period.

The dose for the next period will only be increased if the lower dose of the
previous period was found to be safe and well tolerated. To evaluate the safety
of the dose given in the 1st period, the 2nd period will start approximately
1.5 weeks after the 1st period. To evaluate the safety and pharmacokinetics of
the dose given in the 2nd period, the 3rd period will start approximately 3.5
weeks after the 2nd period.

Planned treatments:
K: 3.0 mL JZP-324-IR oral solution and 4.56 g JZP-324-DR granules
L: 4.67 mL JZP-324-IR oral solution and 7.09 g JZP-324-DR granules
M: 6.0 mL JZP-324-IR oral solution and 9.12 g JZP-324-DR granules

The study compound may cause side effects. The active substance in JZP-324 is
the same as the active substance in Xyrem (oxybate). The risks associated with
JZP-324 are expected to be similar to those associated with Xyrem.

In a previous study with volunteers receiving 6 g or 8 g doses of sodium
oxybate, 3 volunteers were discontinued early due to adverse events, including
an abnormal heart rhythm (an atrioventricular [AV] block), a urinary tract
infection, and vomiting. The hearth rhythm abnormality was considered to be
rather characteristic for that volunteer than a direct effect of sodium oxybate
on the heart.

In other study, volunteers received 4.5 g doses of sodium oxybate as an oral
solution or immediate release (IR) tablets. Two volunteers in this study were
discontinued early because of serious adverse events in the 3rd and 4th
treatment period.
• One volunteer intermittently stopped breathing briefly (apnea), which was of
severe intensity. This adverse event began approximately 1 hour after receiving
4.5 g sodium oxybate as IR tablets and lasted for approximately 3 hours. In
previous treatment periods, this volunteer experienced mild somnolence.
• The other volunteer had a respiratory arrest within approximately 1 hour
after receiving 4.5 g sodium oxybate as oral solution. After breathing got
going, the respiration was depressed for approximately 1 hour and this was
considered a serious adverse event. In previous treatment periods, this subject
had experienced mild to moderate somnolence, and mild vomiting, dizziness, and
headache.
These adverse events were considered to be related to study compound by the
investigator. Therefore the volunteer will be monitored carefully.

After treatment with the formulations consisting of granules, the volunteer
might be able to see residual granules in the stools that were not completely
absorbed by the body. This is not harmful.

Because some of the formulations are designed to be slowly distributed and
absorbed by the body, the effects of JZP-324 on the level of alertness may be
prolonged. On the final study day, a physical examination including a brief
neurological examination (on alertness and coordination) will be conducted.
This test is not only done to test capability to drive a car but also to test
if the volunteer is alert with good coordination and orientation during
walking/cycling/driving. Because there is a risk of delayed effects of the
delayed/sustained release formulation, the volunteer is not allowed to drive a
car/machine on Day 12 (part 1) and Day 8 (part 2).

Xyrem
In clinical studies with Xyrem in subjects with narcolepsy, the most common
adverse effects (those that occurred in greater than or equal to 5% of
subjects) were nausea, dizziness, vomiting, sleepiness, enuresis (inability to
control urination especially during sleep), and tremor (muscle twitching).
Overall, the adverse effects observed in clinical studies with healthy
volunteers are similar to those seen in patients.

Less common adverse effects (those that occurred in greater than or equal to 2%
but less than 5% of subjects with narcolepsy) were diarrhea, stomach pain, dry
mouth, pain in arms and legs, feeling drunk, edema peripheral (swelling of
legs), increased cataplexy in people with cataplexy (a sudden loss of muscle
tone usually triggered by strong emotion), muscle spasms, paresthesia (tingling
and prickling sensation), disturbance in attention (cannot concentrate), sleep
paralysis (not able to move when falling asleep or at awakening),
disorientation (loss sense of direction, position), anxiety (feeling of worry),
irritability (easily annoyed), sleep walking, and hyperhidrosis (sweating a
lot).

The rare but serious adverse effects (that occurred in less than 2%) in
Xyrem-treated subjects were reduced or stopped breathing, sleep apnea (short
periods of no breathing while sleeping), loss of consciousness or coma,
psychosis (seeing or hearing things that are not real), and thoughts of killing
themselves or trying to kill themselves.

As with taking any drug, there is a risk of allergic reaction. Some symptoms of
allergic reactions are: rash, difficulty breathing, and wheezing, sudden drop
in blood pressure, a fast heart rate, sweating, and swelling around the mouth,
throat or eyes. During the stay in the clinical research center the volunteers
will be monitored continuously for any symptoms of an allergic reaction.

The following adverse effects may occur in relation to the investigational
procedures:
Drawing Blood Risks: Risks associated with drawing blood from the arm include
lightheadedness, pain, bruising, and bleeding at the site of needle puncture,
inflammation of the vein, and, on rare occasions, infection. Scarring damage to
a vein is also possible.

Intravenous (IV) Risks: During the placement of an IV catheter into a vein, the
volunteer may experience pain and/or bruising at the site on the arm where the
catheter is placed and blood is taken. In the event the IV fails to work
properly, a needle stick may be inserted directly into a vein to obtain blood
draws for one or more time-points. The volunteer may experience dizziness,
lightheadedness, and/or fainting. Localized bruising, clot and infections may
occur. Scarring damage to a vein is also possible.

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