A Randomized, Double-Blind, Crossover, Comparative Pharmacokinetic Trial of Deulevodopa (TEV-50939) and Levodopa, both Administered with Carbidopa in Healthy Subjects

During this study, the study compound deulevodopa (TEV-50939; formerly SD-1077)
in combination with carbidopa (which is registered as Lodosyn®) will be
compared to the reference compound levodopa.

Deulevodopa is a new investigational compound that may eventually be used for
the treatment of Parkinson*s disease. Parkinson*s disease is a progressive
disorder of the nervous system that affects movement. Characteristic features
of the disease include shaking, rigidity and slowness of movements and
difficulty in walking and gait. The symptoms of the disease are related to
depletion of dopamine in a specific part of the brain (substantia nigra).
Administration of levodopa, a metabolic precursor of dopamine, relieves
symptoms of Parkinson*s disease. When levodopa is administered orally, the
major part is rapidly metabolized to dopamine before it has reached the brain.
Only a small amount will reach the brain unchanged and produce a therapeutic
effect. Therefore, large doses of levodopa are required. These large doses may
often be accompanied by nausea and other adverse effects attributable to
dopamine formed in tissues outside the brain. Carbidopa is a compound which
inhibits metabolism of levodopa to dopamine outside the brain. When carbidopa
is combined with levodopa administration, more levodopa is available for
transport to the brain and less dopamine is formed outside the brain. In turn,
the amount of adverse effects is reduced. Deulevodopa is a new compound
similar to levodopa. The aim of development of deulevodopa is to achieve a
dopamine precursor that is an improved version of levodopa and can be
administered in a fixed combination with carbidopa. This is the first time that
deulevodopa is being given to humans. Levodopa and carbidopa are not new drugs,
and are already available in the market under several dosages and formulations
for the treatment of Parkinson*s disease. Despite available treatments for
Parkinson*s disease, an unmet need remains for drugs that can provide superior
efficacy, over longer periods of time, and with favorable treatment-induced
side effect profile.

Deulevodopa in combination with carbidopa is a combination in development for
the treatment of patients with Parkinson*s disease.

The effects of deulevodopa taken with carbidopa have not yet been tested in
humans, and there are no available clinical data on the adverse effects of this
medicine. Deulevodopa is similar to levodopa and like levodopa, is a precursor
for dopamine. Furthermore, deulevodopa given with carbidopa behaves similar to
levodopa with carbidopa in animal studies.

During this study it will be investigated:

• how much of the study compound gets into the bloodstream after a single dose,
and how long the body takes to get rid of the study compound (this is called
pharmacokinetics)
• if single doses of the study compound have any important adverse effects
(this is called tolerability)

This study will be performed in one group of 16 healthy male and female
volunteers. This group consists of 2 subgroups. The first subgroup consists of
2 volunteers. From these, 1 volunteer will receive a combination of carbidopa
and deulevodopa and 1 volunteer will receive a combination of carbidopa and
levodopa. After dosing, the safety and tolerability of carbidopa and
deulevodopa and carbidopa and levodopa will be closely monitored for at least
24 hours. Only if there are no concerns about the safety and tolerability, the
remaining 14 subjects will be dosed.

Before the study the subject will undergo a pre-study screening during which
the subject will be subjected to a number of medical examinations. Similar
examinations will be performed after the study at the post-study screening. The
pre-study screening will be no more than 28 days before the beginning of the
study.

The actual study will consist of 2 periods. During each period the subject will
stay in the clinical research center in Zuidlaren for 3 days (2 nights). Day 1
is the day on which the study compound will be administered. The time interval
between the Day 2 of Period 1 and Day 1 of Period 2 is at least 7 days.

The subject is expected at the clinical research center at 14:00 h in the
afternoon of Day -1, which is the day prior to the day of administration of the
study compound. The subject 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 subject will leave the clinical research center on Day 2 after completion
of all assessments.

The post-study screening will take place 7 days after the end of participation
in this study. The appointment for the post-study screening will be made with
the subject during the study.

Participation to the entire study, from the pre-study screening until the post
study screening, will be a maximum of 43 days.

During the study the subject will receive the study compound after an overnight
fast (at least 10 hours no eating and drinking). In Period 1, the subject will
receive a single dose of 37.5 mg carbidopa as a one and a half LODOSYN® tablet
with approximately 200 milliliters of (tap) water first and 30 minutes
thereafter, the subject will receive 150 mg deulevodopa or 150 mg levodopa as
250 milliliter oral solution. If the subject has received a combination of
carbidopa and levodopa in Period 1, the subject will receive a combination of
carbidopa and deulevodopa in Period 2. If the subject has received a
combination of carbidopa and deulevodopa in Period 1, the subject will receive
a combination of carbidopa and levodopa in Period 2. After administration of
the study compound administered as an oral solution (deulevodopa or levodopa),
the vial will be rinsed with 200 milliliters of water, which the subject will
also be required to drink.

The side effects in humans of deulevodopa taken with carbidopa are expected to
be similar to those of levodopa and carbidopa.

The side effects of levodopa and carbidopa taken together have been well
characterized from drugs that are currently used to treat patients with
Parkinson*s disease (for example, SINEMET® and Lodosyn®).

Like other medicines, the combination of carbidopa and levodopa given together
can cause side effects, although not everybody gets them.

In previously conducted studies in healthy volunteers given single doses of
levodopa and carbidopa at doses higher than those administered in this study
(up to 50 milligram carbidopa and up to 250 milligram levodopa) demonstrated
most common side effects were mild to moderate headache and nausea. With the
doses used in this study, no serious adverse effects are expected.

The following side effects have been reported with carbidopa and levodopa given
together (for example, Sinemet® and/or Lodosyn®), mainly in studies in patients
with Parkinson*s Disease:

• allergic reactions, the signs may include hives (nettle rash), itching, rash,
swelling of the face, lips, tongue or throat. This may cause difficulty in
breathing or swallowing
• chest pain
• uneven (irregular) heart beat or palpitations
• dizziness on standing-up quickly
• bleeding from your gut which may be seen as blood in your feces or darkened
feces (gastro-intestinal bleeding)
• blood problems, the signs may include pale skin (pallor), tiredness, fever,
sore throat or mild bruising and prolonged bleeding after injury
• stiff muscles, high fever
• mental changes including delusions, hallucinations and depression (with or
without suicide thoughts)
• fits (convulsions)

The most common reported side effects are:
• abnormal movements such as twitching or spasms
• nausea

Other side effects include
• fainting, anorexia, high blood pressure
• inflammation of the veins, being sick (vomiting), diarrhea, discoloration of
urine, sweat or saliva
• on-off phenomenon, characteristic of some people with long-standing
Parkinson*s disease
• dizziness, sleepiness (including excessive drowsiness or sudden sleep onset
episodes), pins and needles
• dream abnormalities, confusion, feeling agitated, increased sexual drive,
shortness of breath, hair loss
• an excessive desire to gamble
• abnormal liver function tests

Side effects that have been reported with medicines containing levodopa are:

Nervous system:
• loss of control over the voluntary movements of everyday life
• numbness, increased hand tremor, muscle twitching, muscle cramp, irregular
movement of jaw muscles resulting in difficulty opening the mouth
• difficulty sleeping, feeling anxious or high, falling over and abnormal
walking patterns
• headache

Eyes:
• drooping eyelid and dilated pupil
• changes in vision, irregular movement of the eye

Digestive system:
• indigestion, dry mouth, bitter taste
• swelling of the salivary glands, difficulty swallowing, grinding of the teeth
• hiccups, abdominal pain and distress, constipation, wind
• burning sensation of the tongue

Sexual:
• persistent abnormal erection of the penis

Urinary:
• difficulty passing urine or incontinence (inability to control urine flow)

Skin:
• changed patches of pigmented skin, including, irritated or irregular moles,
or moles in which changes have been noted (melanoma)

General:
• weight gain or loss, swelling in the limbs
• flushing, hot flushes, increased sweating
• feeling weak, faint or tired
• hoarseness, general feeling of being unwell
• increased energy or activity, unusual breathing pattern

Deulevodopa has been administered to animals before. The safety of deulevodopa
was compared with that of levodopa in animal models and found to be comparable.
Overall, side effects were only observed in doses that are several times higher
than those ever expected in human subjects. These side effects consisted of
dyspnea, rigor and convulsions.

Carbidopa belongs to a group of medicines called *aromatic amino acid
decarboxylase inhibitors, and it helps levodopa work more effectively by
slowing the speed at which levodopa is broken down outside the brain.
Subsequently the incidence of levodopa induced nausea and vomiting is less.