PRX-00023 Therapy in Localization-Related Epilepsy

Introduction:

PRX-00023 is a selective 5HT1A agonist being developed as an oral therapeutic treatment for
epilepsy.

Objective:

To initiate a pilot clinical trial assessing the safety, tolerability and efficacy of the
5HT1A receptor agonist PRX-00023 in patients with localization-related epilepsy. PRX-00023 is
a 5HT1A receptor agonist that has shown promise in clinical trials of depression. Patients
with localization-related epilepsy have reduced 5HT1A receptor binding on 18FCWAY positron
emission tomography (PET). Increasing neurotransmitter activity at 5HT1A receptor sites might
ameliorate seizures. Moreover, depression is a common co-morbidity in people with epilepsy.
Altered 5HT1A receptor binding has been found in depression.

Study Population:

Thirty adults with localization-related epilepsy.

Design:

A randomized, double-blind, placebo-controlled cross-over, phase II clinical trial. Subjects
will be screened under protocol 01-N-0139 and will undergo medical and epilepsy history and
physical examination, vital signs, ECG, clinical laboratory studies including standard
clinical chemistry and hematology studies, urinalysis, pregnancy test for females of
childbearing potential, and MRI scan and eo EEG monitoring will be performed if not
previously completed successfully, and measurement of plasma AED levels (for those AEDs in
which an assay is available at NIH).

The trial will have a baseline phase, which will last up to 6 weeks. Baseline may occur
concurrent with screening procedures. The baseline phase will include measurement of seizure
frequency (patient will record via seizure calendar). In addition the following will be
administered, unless previously completed: Columbia Suicide Severity Rating Scale,
neuropsychological and mood evaluations, FCWAY PET (if not already performed), EEG,
measurement of plasma AED levels (if assay available), and pregnancy test (for women of child
bearing potential), saliva samples will be obtained for genetic testing (if not previously
obtained) and blood samples will be obtained during the PET procedure for cortisol and ACTH
levels.

Following baseline, patients will begin the treatment phase (consisting of Period 1 and
Period 2). Patients will be randomized to PRX-00023 (120mg BID) or matching placebo. After
completion of the first treatment period, patients will undergo a washout period after which
patients will be crossed over to the alternate treatment period.

Outcome measures:

1. Seizure frequency counts during the 3-month placebo and active treatment phases

2. Neuropsychological and mood indices

3. Safety assessment will include adverse events, vital signs, laboratory signs and
physical examination.

- INCLUSION CRITERIA:

1. Enrolled in protocol 01-N-0139

2. Age 18 to 65

3. Localization-related epilepsy diagnosed by standard clinical criteria that has
not responded to treatment with up to two standard antiepileptic drugs either
sequentially or in combination.

4. Patients must be able to provide informed consent.

5. Patients must be able to remain on their baseline AED drugs and doses for the
duration of the study

6. Patients must be able to use seizure calendars to record seizures throughout the
trial.

7. Experiences 4 seizures within a 6-week period

EXCLUSION CRITERIA:

1. Pregnancy or lactation

2. Women of child-bearing potential and men who are unable or unwilling to take adequate
contraceptive precautions, including one of the following:

- hormonal contraception (birth control pills, injected hormones or vaginal ring);

- intrauterine device;

- barrier methods (condom or diaphragm) combined with spermicide;

- surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner

3. Current treatment for another significant medical disorder, such as diabetes, or heart
disease, or an untreated disorder, that is discovered during the screening examination
and might interfere with the study and is determined by the PI to warrant exclusion of
the participant.

4. An abnormality on clinical laboratory tests, physical examination, EEG or ECG that
might increase the risk associated with trial participation or investigational product
administration, such as hepatic enzyme elevation greater than twice normal, or
hematocrit lower than 30.

5. A level 4 or 5 on the Columbia Suicide Severity Rating Scale rating for symptoms
during the last month

6. Concomitant treatment with more than 2 AEDs

7. Evidence for a potentially progressive neurologic disorder, such as an astrocytoma

8. Use of sublingual lorazepam for seizure clusters more than once per wee

9. Use of any of the following prohibited medications/classes with less than required
interval period:

- Any other Investigational drugs; required interval period (weeks prior to
baseline) is 4

- benzodiazepines; required interval period (weeks prior to baseline) is 4

- MAO Inhibitors anti depressant; required interval period (weeks prior to
baseline) is 4

- Buspirone; required interval period (weeks prior to baseline) is 2

- other psychotropic medicines; required interval period (weeks prior to baseline)
is 2

- potent CYP3A4 inducers/inhibitors; required interval period (weeks prior to
baseline) is 2 for:

- Itraconazole

- ketoconazole

- HIV antivirals

- clarithromycin

- phenytoin

- Prornolol is 2