Preclinical Pharmacology and Pharmacodynamic Interactions of SAGE-547: Relevance to Super Refractory Status Epilepticus (SRSE). (P6.068)

Objective: The objective was to characterize the primary pharmacological profile of SAGE-547 at synaptic and extrasynaptic GABA A receptors in vitro, relative to other GABAergic modulators, and to examine the combination effects of SAGE-547 with pentobarbital, an anesthetic commonly used to treat super refractory status epilepticus (SRSE). Background: SAGE-547 injection is a proprietary formulation of the endogenous neurosteroid allopregnanolone, being studied as a potential adjunctive therapy for the treatment of SRSE, a condition where seizures persist or recur for >24 hours despite multiple therapeutic interventions. In preclinical models, prolonged seizures reduce the surface expression of synaptic GABA A receptors, exacerbating neuronal excitability and limiting target sites for GABAergic treatments (eg. benzodiazepines). Design/Methods: GABA-evoked currents were examined in vitro with whole cell patch clamp recordings in cells expressing recombinant a1b2g2 or α4β3δ GABA A receptor subunits. The rat lithium-pilocarpine model of refractory status epilepticus (RSE) was used to examine the in vivo anticonvulsant activity of SAGE-547 when administered in the presence or absence of pentobarbital (Pouliot 2013). Results: SAGE-547 was >10,000-fold more potent at modulating both synaptic (α1β2γ2) and extrasynaptic (α4β3d) GABA A receptor currents in vitro compared to pentobarbital and was the most potent modulator of α4β3d receptor currents when compared to benzodiazepines, propofol, and pentobarbital. SAGE-547 and pentobarbital had a synergistic interaction at both synaptic (α1β2γ2) and extrasynaptic (α4β3δ) GABA A receptors in vitro and the combination robustly reduced seizure activity in a rat model of RSE. Conclusions: SAGE-547 more potently modulated extrasynaptic GABA A receptors (which remain available to treatment during prolonged seizures) when compared to diazepam, midazolam, pentobarbital, or propofol in vitro. Combination of SAGE-547 with pentobarbital potently reduced seizure activity in a rat model of RSE, consistent with their synergistic interactions in vitro. Disclosure: Dr. Hammond has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Hammond holds stock and/or stock options in Sage Therapeutics, which sponsored research in which Dr. Hammond was involved as an investigator. Dr. Hammond has received research support from Sage Therapeutics. Dr. Ackley has received personal compensation for activities with SAGE Therapeutics as an employee. Dr. Ackley has received research support from SAGE Therapeutics. Dr. Quirk has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Belfort has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Belfort has received research support from Sage Therapeutics. Dr. Doherty has received personal compensation for activities with Sage Therapeutics, Inc. as an employee. Dr. Doherty has stock and/or stock options in Sage Therapeutics.