Abstracts

Rationale: Ganaxolone is a neurosteroid and synthetic derivative of the endogenous neuromodulator, allopregnanolone, that has been evaluated for the treatment of epilepsy in several Phase 2 clinical trials, including a proof-of-concept study in adult partial onset seizures utilizing a pre-surgical trial design. In the present Phase 2 study, ganaxolone was evaluated as adjunctive therapy in adult patients who had uncontrolled partial onset seizures despite taking up to 3 concomitant AEDs. Methods: One hundred and forty-seven adults (100 females, 47 males), aged 18 to 69 years, with partial onset seizures with or without secondary generalization refractory to conventional antiepileptic drugs were randomized in a 2:1 ratio (98 ganaxolone: 49 placebo) at 24 US sites. After an 8-week baseline period, subjects were titrated up to 1500 mg/day (500 mg tid) over a 1-2 week dose-titration period and maintained at that dose for an additional 8 weeks. Subjects were allowed to adjust their dose downward if needed. Subjects completing the study were eligible for an open-label extension (OLE) study. Results: One hundred and thirty-one subjects completed the study and 95% of those entered the OLE study. Both mean weekly seizure frequency, the primary endpoint, and percent change from baseline in weekly seizure frequency were statistically significantly different with ganaxolone treatment compared with placebo (P=0.0251 and P=0.0144, respectively); ganaxolone treatment produced an 18% decrease in weekly seizure frequency, compared with a 2% increase for placebo, over the 10-week treatment period. Responder rates (proportions of subjects with greater than 50% reduction in seizures) were numerically larger in the ganaxolone treatment group (24%) vs. placebo (15%) but the difference did not reach statistical significance (P=0.1926). Overall, ganaxolone was safe and well tolerated. Ninety-five percent of subjects were able to titrate up to 1500 mg/day during the first week and 78% maintained this dose. Discontinuation rates due to adverse events were similar between the ganaxolone (7.1%) and placebo (6.1%) groups. The most commonly reported adverse events were CNS-related and were mild to moderate in severity. The most commonly reported adverse events reported by ganaxolone-treated subjects were dizziness (16%), fatigue (16%), and somnolence (13%). Ganaxolone-treated subjects had numerically lower reports of headache (8.2% vs 12.2%), nasopharyngitis (5.1% vs 10.2%), and falls (5.1% vs 12.2%), compared with the placebo group. Safety parameters, including hematology, chemistry, urinalysis, vital signs, and ECGs, displayed no trends that would limit clinical use. Conclusions: Ganaxolone treatment improved partial onset seizure control over placebo and was generally safe and well tolerated. Current positive results support continued development of ganaxolone for adult patients with partial onset seizures..