Abstracts

Rationale: Antiepileptics are usually administered chronically over years, so safety and tolerability are important in choice of agent. Ganaxolone (GNX), a synthetic analog of the endogenous GABA modulator allopregnanolone, is a first-in-class neurosteroid in development for treatment of epilepsy, PTSD and Fragile X syndrome. Preclinical toxicology studies show did not identify any organ toxicities nor any effects on reproductive assays. A 10 wk double-blind (DB), placebo-controlled trial showed GNX 1500mg/day was safe and effective as adjunctive therapy for adults with uncontrolled partial onset seizures (POS)(Tsai, J., Antiepileptic Drug Trials X, Coral Gables, FL, April 2009). A 2-yr, 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 enrolled in the OLE at 24 US sites. Subjects received GNX 1500mg/day (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: Most eligible subjects who completed the DB trial (124/131; 95%) entered the OLE, and were dosed for a mean of 262 days. Eighty-eight percent of subjects (109/124) reached and 71% (88/124) finished on the target dose of 1500 mg/day. 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. Twelve subjects (12/124; 10%) discontinued due to an AE, four of which were related to the diagnosis under study. There were no trends for important changes in clinical chemistry, hematology, vital signs or ECGs overall, except for a mild decrease in CO2. Few subjects had clinically meaningful changes in chemistry parameters: hyponatremia 0.2% ; hyperkalemia 0.1%; elevated SGOT 0.2% and elevated SGPT 0.1% including one subject with SGOT and SGPT >5xULN at Day 57. Three subjects had measurements of QTc intervals greater than 450 ms and more than 5% increased over baseline. Mean change in weight from the initial GNX treatment to endpoint was 0.3 + 4.3 kg, range -12 to 16; median 0.4 kg. Four subjects (3%) reported weight increase as an AE and one of them discontinued from the study. SAEs were reported in 17 subjects; 7 were related to the disease being studied. Conclusions: Analysis of data from a two-year open-label extension of a study of GNX for adjunctive treatment of refractory POS shows GNX was safe and generally well tolerated. There were no trends of clinically important changes in chemistry, hematology, vital signs or ECGs that would be predicted to limit clinical use.