Abstracts

Rationale: Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy associated with multiple seizure types, characteristic electroencephalography (EEG) abnormalities (slow spike wave or generalized paroxysmal fast activity), and developmental delay. Although rare (cumulative prevalence at 10 years 2.6:10,000), the disorder causes severe physical, cognitive, emotional, and social consequences. In ~ 25% of cases LGS evolves from West syndrome/infantile spasms, but a host of genetic and acquired causes exists.   Despite six approved antiepileptic drugs (AEDs) to treat LGS in the US or EU, all with potential serious adverse effects, most patients continue to experience disabling seizures.Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one; GNX) is a positive allosteric modulator of the GABAA receptor. Although a synthetic analog of the endogenous progesterone metabolite, allopregnanolone, GNX lacks both nuclear progesterone receptor activity and hormonal effects with chronic dosing. GNX activates synaptic and extrasynaptic GABAA receptors at a site distinct from benzodiazepines and barbiturates; it does not induce tolerance. GNX has anticonvulsant activity with an acceptable safety and tolerability profile in doses of 900 to 1800 mg in adults and children.We hypothesized that GNX could reduce the frequency of major seizures in children with treatment-refractory LGS, and potentially increase seizure free days. Methods: Eight LGS patients (aged 2-15 years) with severe, treatment-resistant generalized tonic-clonic and drop seizures, all receiving stable doses of AEDs were enrolled at 4 US centers. Patients received oral GNX, either titrated to a maximum of 63 mg/kg/day if under 30kg, or 1800 mg/day. The primary objective was to study safety and tolerability of GNX and the primary efficacy endpoint was median percentage change in the 28-day frequency of major (generalized tonic, clonic, tonic-clonic or tonic-spasm) seizures at 26 weeks. The secondary efficacy endpoint was median percentage change in the 28-day seizure free days at 26 weeks. The efficacy analyses were by modified intention to treat (>= 1 major seizure during baseline). Tests that the percentage changes differed from zero were done by the Wilcoxon signed rank test. Results: The median percentage change at 26 weeks for major seizures was -32%, range -80% to +40%, p=0.195. The median percentage change at 26 weeks for seizure-free days was an increase of 33%, range 0 to +170% p=0.031. Five of the 8 subjects reported adverse events potentially associated with GNX use: a single episode of somnolence in 3 subjects, 3 episodes of vomiting in a 4th subject, and an episode of behavioral change and increased seizure activity in a 5th subject. Three subjects reported no adverse events.  No serious adverse events were reported for these subjects. Conclusions: This open-label study suggests that GNX can reduce seizure frequency, increase seizure free days, and is generally safe and well tolerated. These findings support further testing of GNX in children with LGS. Funding: This study was funded by Marinus Pharmaceuticals