Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures

This randomized, double-blind, placebo controlled trial is designed to look at safety and
efficacy of cenobamate adjunctive therapy as compared to placebo on PGTC seizures in subject
with idiopathic generalized epilepsy. Subjects will be randomized to receive either
cenobamate or placebo on a 1:1 basis. The study will have three periods, pre-randomization
period where a baseline seizure frequency is established, treatment period and follow up
period. The treatment period consists of a 10 week titration phase where subjects are
titrated slowly until they reach the target dose and a maintenance phase. During the
titration phase, subjects will receive 12.5 mg study drug, followed by 25 mg, 50 mg, 100 mg,
and 150 mg study drug every two weeks. During the maintenance phase, subjects will receive
the target dose of 200 mg study drug. Subjects will take their once daily dose of study drug
at approximately the same in the morning with or without food. If tolerability issues arise,
subjects can switch to evening dosing. There is also an option to down-titrate to 150 mg
study drug, one time only. If tolerability issues continue, subjects may be discontinued.
Upon completion of the maintenance phase, eligible subjects will have an opportunity to
enroll in an open-label safety study. Subjects who discontinue early or do not wish to
participate in this additional study will complete the three week follow up period. Subjects
may receive a one week down titration to 100 mg and return for a follow up visit 2 weeks
later.

Throughout the study, subjects will keep a diary containing the type and frequency of
seizures. This will be the primary efficacy measure.

Inclusion Criteria:

1. Subject is male or female and aged ≥18 years.

2. Written informed consent signed by the subject or legal guardian, prior to entering
the study, in accordance with the International Council for Harmonisation (ICH) Good
Clinical Practice (GCP) guidelines. If the written informed consent is provided by the
legal guardian because the subject is unable to do so, a written or verbal assent from
the subject must also be obtained. As required by country-specific regulations, only
the subject may sign the Informed Consent Form (ICF) in accordance with ICH
guidelines.

3. Female subjects of childbearing potential are willing to use an acceptable form of
birth control

4. Subject has a clinical diagnosis of PGTC seizures (with or without other subtypes of
generalized seizures) in the setting of idiopathic generalized epilepsy.

5. Subject experiences at least 3 PGTC seizures in 12 weeks during the Pre-Randomization
Period.

6. Subject has had a routine electroencephalogram (EEG) within 5 years prior to Visit1
(Screening/Baseline) or during the Pre-Randomization Period with
electroencephalographic features consistent with idiopathic generalized epilepsy;
other concomitant anomalies must be explained by adequate past medical history.

7. Subject has undergone computed tomography (CT) or magnetic resonance imaging (MRI)
within 10 years prior to Visit 1 (Screening/Baseline) or during the Pre-Randomization
Period that ruled out a progressive cause of epilepsy.

8. Subject is currently receiving 1 to a maximum of 3 concomitant AEDs with fixed dosing
regimens for a minimum of 30 days prior to Visit 1 (Screening/Baseline).

1. Benzodiazepines (except diazepam, see Exclusion Criterion No.7) taken at least
once per week during the 30 days prior to Visit 1 (Screening/Baseline) for
epilepsy, anxiety, or sleep disorder will be counted as 1 AED and the dosage must
be continued unchanged throughout the study. Therefore, only a maximum of 2
additional approved AEDs will be allowed. (See Exclusion Criterion No. 10 for
intermittent benzodiazepine rescue parameters.)

2. Subjects receiving felbamate as a concomitant AED must meet the following
criteria: i. Have a 2-year history of felbamate use and a history of a fixed
dosing regimen for a minimum of 60 days prior to Visit 1 (Screening/Baseline).
ii. No prior or known history of hepatotoxicity or hematologic disorder due to
felbamate.

9. Subject with an implanted vagal nerve or deep brain stimulator will be allowed if the
stimulator was implanted at least 5 months prior to Visit 1 (Screening/Baseline) and
the stimulator parameters are not changed for 30 days prior to Visit 1 and for the
duration of the study.

10. Subject taking a ketogenic diet will be allowed as long as the diet has been stable
for at least 3 months prior to Visit 1 (Screening/Baseline) and will remain stable for
the duration of the study.

Exclusion Criteria:

1. Female subjects who are pregnant (or planning to become pregnant during the study),
lactating, or breast-feeding.

2. Subject has a history o f status epilepticus that required hospitalization within 12
months prior to Visit 1 (Screening/Baseline).

3. Subject has PGTC seizure clusters where individual seizures cannot be counted or
classified.

4. Subject has a history of non-epileptic psychogenic seizures.

5. Subject has a concomitant diagnosis of Partial Onset Seizures (POS).

6. Subject has a clinical diagnosis of Lennox-Gastaut syndrome.

7. Subject is currently taking (within the 30 days prior to Visit 1 [Screening/Baseline])
any of the following medications: diazepam (for any reason other than as intermittent
benzodiazepine rescue medication), phenytoin, mephenytoin, fosphenytoin,
phenobarbital, primidone, ethotoin, clopidogrel, fluvoxamine, amitriptyline,
clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, or efavirenz.

8. Subject has participated in previous cenobamate clinical studies.

9. Subject has a history of vigabatrin use within 5months prior to Visit 1
(Screening/Baseline), or the subject plans to begin treatment with vigabatrin during
the study.

a) A subject with a history of vigabatrin use that ended more than 5 months prior to
Visit1 may be enrolled after documented evidence of no vigabatrin-associated
clinically significant abnormality in an automated visual perimetry test.

10. Subject has a history of intermittent use of rescue benzodiazepines (i.e., 1 to 2
doses over a 24-hour period is considered a 1-time rescue) 4 or more times within the
30 days prior to Visit 1 (Screening/Baseline).

11. Subject has received an investigational drug or device within 30 days prior to Visit 1
(Screening/Baseline).

12. Subject has a history of drug or alcohol dependency or abuse within 2 years prior to
Visit 1 (Screening/Baseline).

13. Subject tests positive, via urine drug screen at Visit 1 (Screening/Baseline), for
illicit drugs (e.g., tetrahydrocannabinol, amphetamines) or for a drug that has not
been prescribed (e.g., certain opiates).

14. Subject has a history of any serious drug-induced hypersensitivity reaction
(including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis,
or DRESS) or any drug-related rash requiring hospitalization.

15. History of AED-associated rash that involved conjunctiva or mucosae.

16. History of more than one non-serious drug-related hypersensitivity reaction that
required discontinuation of the medication.

17. Subject has evidence of clinically significant abnormalities or disease (e.g.,
psychiatric, cardiac, respiratory, gastrointestinal, hepatic [aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) more than 2 times the upper
limit of normal (ULN), or total or direct bilirubin not more than ULN], or renal
disease) that, in the opinion of the Principal Investigator, could affect the
subject's safety or conduct of the study.

18. Presence of congenital short QT syndrome or relevant replicated change in QT/QTc
interval less than 340 msec on ECG.

19. Subject has any significant active Central Nervous System (CNS) infection,
demyelinating disease, degenerative neurologic disease or any CNS disease deemed to be
progressive during the course of the study that may confound the interpretation of the
study results.

20. Subject has a creatinine clearance less than 50 mL/min, as calculated by
Cockcroft-Gault equation.

21. Subject has an absolute neutrophil count less than 1500/µL.

22. Subject has platelet count lower than 80,000/µL in subjects treated with valproate.

23. Subject has a history of positive antibody/antigen test for hepatitis A, hepatitis B,
hepatitis C, or HIV.

24. Subject has any suicidal ideation (with intent with or without a plan) at Visit 1
(Screening/Baseline) or Visit 4 (Randomization) (i.e., answering YES to Question 4
and/or Question 5 on the Suicidal Ideation section of the C-SSRS).

25. Subject has more than 1 lifetime suicide attempt.

26. Subject is a staff member or immediate family member of study staff. Any potential
exception to the inclusion as well as exclusion criteria allowing de minimis
(clinically trivial and meaningless) variations must be approved by the Medical
Monitor.