Abstracts

Rationale: Ganaxolone (GNX) is a synthetic analog of the endogenous GABA modulator allopregnanolone. GNX 1500mg/day has been shown as safe and effective for the treatment of epilepsy in a 10 wk, double-blind (DB), placebo (PBO)-controlled study of adjunctive therapy in adult outpatients with uncontrolled partial onset seizures (POS) (Tsai,J., Antiepileptic Drug Trials X, Coral Gables, FL, April 2009). A 2 year, open-label extension (OLE) to the DB study was conducted to assess the long-term safety, tolerability and efficacy of GNX. Methods: Adults (N=124) aged 18 to 69 yrs having POS with or without secondary generalization were enrolled in the OLE at 24 US sites. Subjects received GNX 1500mg/day as 500mg tid or maximally tolerated dose regardless of prior treatment in the DB study. Up to 3 concomitant AEDs at stable doses were permitted. Results: Of 131 completers in the DB study, 124 (95%) entered the OLE and were dosed for a mean of 262 days. Preliminary analysis shows GNX to be safe and well-tolerated for extended use. The most frequent (>10%) adverse events (AEs) in the OLE were fatigue, headache, dizziness, convulsion, fall, contusion, somnolence, and nasal congestion; most were mild or moderate in severity. SAEs were reported in 17 subjects; 7 were related to the disease being studied. There were no trends of changes in chemistry, vital signs or ECGs that would limit clinical use. No mean changes in weight were observed up to 12 mo; 4 subjects (3%) reported weight increase as an AE. Preliminary analysis of OLE data shows subjects experienced a reduction in mean weekly seizure frequency from baseline to endpoint of 11.8%. The reduction in mean weekly seizure frequency measured at Wk 52 (observed cases) was 32.0%. Mean weekly seizure frequency decreased by 13.6% after 10 wks of open-label treatment for the group that received PBO in the DB study and began GNX in the OLE. This result is similar to the 17.6% decrease seen with GNX treatment in the DB study. DB GNX subjects who continued on GNX in the OLE maintained their response. The overall responder rate (defined as 50% improvement over DB baseline) in the OLE was 21.1%; the rate for observed cases at 52 wks was 42.9%. Conclusions: Preliminary analysis of data from a 2 year OLE of GNX for adjunctive treatment of refractory POS shows GNX maintained seizure control with extended use and was safe and generally well tolerated.