Abstracts

Rationale: Status epilepticus (SE) is a potentially life-threatening condition characterized by unremitting seizures that last for at least 5 minutes (Trinka et al., 2015). If a patient fails to respond to first-line therapy with benzodiazepines, phenytoin, an anti-epileptic drug, is a common choice for second-line therapy (Al-Mufti and Claassen, 2014). We report pre-clinical results comparing the electrographic activity of phenytoin with SAGE-689, a potent and selective next generation neuroactive steroid (NAS) in a rat model of SE. Methods: We investigated the effect of selective GABAA receptor positive allosteric modulator SAGE-689 and the sodium channel blockers phenytoin and lamotrigine, each in the rat lithium-pilocarpine model of SE with EEG recording. Results: Phenytoin (5 and 15 mg/kg, IV) administered within 2 minutes of SE onset failed to reduce behavioral convulsions or aberrant EEG spike probability. When phenytoin was administered at 50 mg/kg IV, sustained arrest of behavioral convulsions was observed; all (4 of 4) animals that received 50 mg/kg exhibited a loss of righting reflex (LRR) up to 30 minutes after dosing and 3 of 4 animals exhibited LRR for 4 hours. However, only a temporary reduction in spike probability was observed, notwithstanding brain concentrations as high as 37,0004.2 ng/g. Lamotrigine (3, 10, and 30 mg/kg, IV), another antiepileptic drug that blocks sodium channels, also failed to reduce spike probability at all doses when administered immediately after SE onset, despite brain concentrations as high as 26,5000.6 ng/g. Lamotrigine was not sedating at any dose level tested. In contrast, SAGE-689 (5 and 15 mg/kg, IV) dose-dependently reduced aberrant spike probability when administered 60 minutes after SE onset, a time when benzodiazepines may not be effective (Kapur and MacDonald, 1997). Furthermore, co-administration of subactive doses of SAGE-689 and diazepam also resulted in a significant reduction in spike probability (seizure activity). Conclusions: SAGE-689 significantly reduced seizure activity in a rodent model of SE, while phenytoin and lamotrigine did not at the doses tested. Interestingly, both SAGE-689 and phenytoin induced behavioral sedation, highlighting the value of using preclinical EEG to monitor potential ongoing seizure activity in non-convulsive subjects. These data identify important differences between SAGE-689 and two clinically used therapies in SE, and support the further development of SAGE-689 for the treatment of SE. Funding: This study was funded by Sage Therapeutics, Inc.