Abstracts

Rationale: Up to 40% of patients with epilepsy continue to experience breakthrough seizures, despite efforts to optimize available therapies. SAGE-217, a first in class, next generation neuroactive steroid GABAA receptor positive allosteric modulator, is currently in Phase I clinical development, with the goal of initially testing safety and efficacy in genetically defined epilepsy subpopulations among other potential indications. Here we present results of an in vitro electrophysiological characterization of SAGE-217 and in vivo studies in the Fmr1 knock out mouse, a genetically defined animal model that exhibits a seizure phenotype in response to auditory stimuli. Methods: Potentiation of GABA EC20-evoked currents by SAGE-217 was assessed using electrophysiological recordings from heterologous mammalian and amphibian cells that expressed one of nine distinct recombinant human GABAA receptors. Protection against audiogenic seizures was tested in Fmr1 knockout FVB mice, an animal model of Fragile X syndrome. Fmr1 knockout, but not wild type, FVB mice exhibit convulsive seizures in response to a 121 dB tone. In addition, locomotor activity (LMA) was measured for 30 min prior to the audiogenic seizure testing. Results: SAGE-217 potentiated GABA EC20-evoked currents at 9 different receptor subtypes, in particular including the benzodiazepine insensitive a4߳d and a6߳d receptors, representing two of the most highly expressed extra-synaptic receptors. SAGE-217 EC50 ranged from 184 to 1,260 nM and percent change in maximal current (Emax) ranged from 291 to 1,590 %. In vivo, SAGE-217 (0.1, 0.3, 1, 5 mg/kg, IP, 45 min pretreatment time) dose-dependently reduced seizure score in Fmr1 KO mice (Fig. 1) from 1.830.34 (vehicle) to 0.67 0.33 (0.1 mg/kg), 0.270.27 (0.3 mg/kg) or 0 (1 and 5 mg/kg). SAGE-217 significantly reduced distance moved at 5 mg/kg (737.6319.4 cm vs 5,095404.8 cm), but not at the lower doses. Conclusions: SAGE-217 is a GABAA receptor potentiator that is broadly active in vitro and exhibits robust anticonvulsant activity against audiogenic seizures in the Fmr1 knockout model. A greater than 10 fold margin between anticonvulsant activity and sedation was observed. These data support further investigating the utility of SAGE-217 for the treatment of refractory epilepsy, particularly in genetically defined populations. Funding: None