Phase 3 Study of Adjunctive Ganaxolone in Adults With Drug-resistant Partial Onset Seizures and Open-label Extension

This is a 2-cohort study comprised of 2 phases in each cohort. Phase 1 is a double-blind
phase followed by Phase 2, an open-label phase. Cohort 1 will provide tolerability, safety,
and PK information for ganaxolone 1200mg/d, 1800mg/d and placebo. Cohort 2 will investigate
the efficacy, tolerability and safety of ganaxolone 1800mg/d compared to placebo. Cohort 1
(N= approximately 50) will enroll into a 67-week study comprised of a 4-week prospective
baseline period plus 4 week retrospective baseline followed by two treatment phases: a 9-week
randomized DB placebo-controlled treatment phase followed by a 52-week open label (OL)
treatment phase. Cohort 2 (N=150) will enroll into a 72-week study comprised of a 8-week
prospective baseline period followed by two treatment phases: a 14-week randomized DB
placebo-controlled treatment phase followed by a 52-week open label (OL) treatment phase.

Inclusion Criteria:

- Able to give informed consent in writing, or have a legally authorized representative
able to do so

- Willing to enter and participate for the full term of the double blind phase and
willing to enter into the open-label phase

- Male or female outpatients > 18 years of age

- Have a confident diagnosis of drug-resistant epilepsy with partial-onset seizures
(POS), with or without secondary generalization, for ≥2 years. Have residual POS
despite having been treated in the past with at least 2 approved anti-epilepsy drugs
(AEDs) either alone or in combination

- Based on history, subjects would be anticipated to have at least 3 POS during each
4-week Baseline period and unlikely to have 21 or more consecutive POS-free days

- Currently being treated and maintained with a stable regimen of 1, 2, or 3 AEDs

- Able and willing to maintain daily seizure calendar

- Able and willing to take drug with food twice daily

- Sexually active women of childbearing potential must use acceptable birth control and
have a negative pregnancy test at all visits

Exclusion Criteria:

- Have had previous exposure to ganaxolone

- Known sensitivity or allergy to any component in the study drug, progesterone, or
other related steroid compounds

- Exposure to any investigational drug or device < 30 days prior to screening, or plans
to take another investigational drug at any time during the study

- Time of onset of epilepsy treatment < 2 years prior to enrollment

- Have generalized epilepsy, such as Lennox-Gastaut syndrome, juvenile myoclonic
epilepsy, absence epilepsy, or non-epileptic seizures within the last 12- month period
prior to study entry

- Have less than 3 POS seizures in a 28-day period or more than 21 consecutive
seizure-free days during the Baseline period

- Have only simple partial seizures without any observable motor component

- Have innumerable seizures or status epilepticus within the last 12-months prior to
screening

- Have more than 100 POS per 4-week Baseline period

- Have seizures secondary to illicit drug or alcohol use, infection, neoplasm,
demyelinating disease, degenerative neurological disease, or central nervous system
(CNS) disease deemed progressive, metabolic illness, or progressive degenerative
disease

- Current use of vigabatrin is not permitted. If prior use of vigabatrin, must have
documented stable visual fields

- Current use of ezogabine is not permitted. If prior use, must have been off the
medication for at least 3 months prior to screening and have had documented normal
fundoscopic exam by ophthalmologist

- Are planning surgery, or to be evaluated for surgery, during the double blind phase to
control seizures including VNS implantation

- Are suffering from acute or progressive neurological disease, moderate or severe
psychiatric disease, or severe mental abnormalities that are likely to require changes
in drug therapy during the double blind portion of the study or interfere with the
objectives of the study or the ability to adhere to the protocol requirements

- Have a history of an actual suicide attempt in the last 5 years or more than 1
lifetime suicide attempt

- Have a positive urine drug screen at Screening or meet criteria for current or
historical Substance Use Disorder (DSM-V criteria) within the past 5 years.

- Have any medical condition that, in the investigator's judgment, is considered to be
clinically significant and could potentially affect subject safety or study outcome,
including but not limited to: clinically significant cardiac, renal, pulmonary,
gastrointestinal, hematologic or hepatic conditions; or a condition that affects the
absorption, distribution, metabolism or excretion of drugs

- Have elevated ALT (SGPT) or AST (SGOT) greater than 3 times upper limits of normal, or
total bilirubin greater than 1.5 time ULN

- Have a history of malignancy within the past 2 years, with the exception of basal cell
carcinoma

- Are currently following or planning to follow a ketogenic diet

- Use of dietary supplements or herbal preparations are not permitted if subject has
been using them consistently for less than 6 months prior to screening, or does not
plan on remaining on stable doses for the duration of the double blind phase. Use of
St. John's Wort is not permitted

- Females who are pregnant, currently breastfeeding or planning to become pregnant
during the duration of the study

- A history of chronic noncompliance with drug regimens

- Inability to withhold grapefruit and grapefruit juice from diet during the entire
clinical trial