Abstracts

The neurosteroid ganaxolone (GNX) is an allosteric modulator of the GABA[sub]A[/sub] receptor complex distinct from the benzodiazepine site. GNX has protective activity in diverse animal seizure models. Previous clinical studies have indicated that oral GNX is safe and well-tolerated. This study evaluated GNX as add-on therapy in hospitalized children continuing to have seizures despite treatment with available marketed antiepileptic drugs., Fifteen children (9 male, 6 female), ages 5 to 15 years, enrolled in an open-label flexible dose-escalation study of GNX for the treatment of partial or generalized seizures refractory to conventional antiepileptic drugs. Dosing of GNX [szlig]-cyclodextrin suspension ranged from a starting dose of 1 mg/kg BID to a maximum maintenance dose of 12 mg/kg TID. Dose titration was conducted during a 16-day inpatient hospitalization followed by a 2-month maintenance period, after which patients continued treatment, or withdrew treatment over 2 weeks., Thirteen of the 15 subjects were evaluated at Maintenance Week 4 (MW 4). Two patients were withdrawn prior to evaluation, one due to non-compliance and one to adverse events. The responses of the 13 patients were substantial ([underline][gt][/underline] 50% seizure reduction) in 4 (one becoming seizure free), moderate (25-49% reduction) in 3 and insufficient ([lt] 25% reduction) in 6 patients. Of the 8 patients evaluated at Maintenance Week 8 (MW 8), the responses were substantial in 4 (one of whom was a nonresponder at MW 4), moderate in 2 and insufficient in 2 patients. Three of the 4 eligible patients continued GNX in extension treatment. A total of 17 adverse events (AEs) were reported during the escalation and maintenance phases, 16 attributable to the central nervous system and 1 to the digestive system. Somnolence was the most frequently reported AE. Severity of AEs was either mild or moderate. One patient with a history of abnormal behavior including frequent episodes of agitation experienced a serious adverse event (agitation, hostility, and hallucination requiring extended hospitalization) after a 3 mg/kg TID dose of GNX. These events were considered moderate in severity and possibly related to GNX. The patient was withdrawn from the study, and the events resolved after 11 days., GNX was well-tolerated. A portion of the subjects in this drug-refractory population seemed to respond to GNX (5 of 15 demonstrated at least a 25% decrease in seizure frequency at both time points, and 6 demonstrated at least a 25% decrease in seizure frequency at MW 8). Additional controlled studies are required to confirm the efficacy of GNX for the treatment of children with drug refractory partial or generalized seizures., (Supported by Marinus Pharmaceuticals, Inc.)