Abstracts

Ganaxolone (GNX), a neurosteroid, has been evaluated for the treatment of epilepsy in several Phase II clinical trials, including an inpatient trial in children with treatment-refractory seizures (see companion abstract). The present study evaluated GNX in children with treatment-refractory seizures in an outpatient setting., Forty-five children (25 male, 20 female), ages 2 to 15 years, with seizures refractory to conventional antiepileptic drugs enrolled in an open-label, flexible dose-escalation study of GNX. Thirty-five had epileptic spasms with a historical diagnosis of infantile spasms (IS). After a pre-dosing observation period (OP), ganaxolone was titrated over a 9-week period at doses from 1 mg/kg BID to 12 mg/kg TID, followed by an 8-week maintenance period., Twenty-seven (60%) of 45 patients completed the study. For all seizure types, twelve (27%) patients were responders ([ge]50% seizure reduction). Of the 35 with spasms, 1 patient experienced remission and 10 others were responders. Of 9 with absence seizures, 2 experienced remission and 1 other was a responder. Of 6 with partial seizures, 1 experienced remission and 2 others were responders. Of 12 with tonic seizures, 3 were responders. Neither of the patients with myoclonic seizures completed treatment. Central nervous system adverse events (CNS AEs) occurring in [underline][gt][/underline] 5% of subjects were agitation (38%), adverse change in seizures (36%) and somnolence (24%). Subjects experienced respiratory/ear infections: pharyngitis (36%), otitis media (16%) and bronchitis (11%). Non-serious AEs leading to discontinuation were adverse change in seizures (6), agitation (4), increase in seizures and agitation (1), nausea (1), and somnolence (1). One withdrew due to insufficient clinical response. A total of 7 patients reported 9 serious AEs (7 possibly related and 2 unrelated). The majority (6/9) occurring in 5 patients were a change in seizure frequency and/or nature, including 1 who experienced 2 episodes of status epilepticus. Of the 5, 2 discontinued GNX. There was 1 event each of severe otitis, increased seizure frequency plus somnolence, and GNX accidental overdose., A substantial proportion of these drug-refractory children showed improvement with GNX (overall responder rate 27%; 31% in patients with a historical diagnosis of IS). Controlled trials are necessary to determine whether the worsening seen in some patients is a treatment-related effect or represents the natural disease course. Many subjects exhibited respiratory and ear infections, which is expected in a pediatric population. Transitory CNS AEs were common, but did not result in discontinuation in the majority of subjects. The results support controlled trials with GNX., (Supported by Marinus Pharmaceuticals, Inc.)