Next-generation neuroactive steroid SAGE-217 in a multiple-ascending dose study (P3.009)

Objective: To study safety and tolerability of SAGE-217 Oral Solution in a multiple ascending dose (MAD) clinical study. Background: SAGE-217 is a next-generation neuroactive steroid (NAS) and a positive allosteric modulator (PAM) of synaptic and extrasynaptic GABA A receptors, with similar pharmacology to the NAS allopregnanolone. SAGE-217 exhibits robust anticonvulsant and anxiolytic activity in a variety of preclinical models. SAGE-217 possesses a pharmacokinetic (PK) profile optimized for once daily oral administration. Design/Methods: In this Phase 1, MAD study, three double-blind, placebo-controlled cohorts of healthy volunteers were randomized 9:3, SAGE-217:placebo at doses of 15mg, 30mg, and 35mg administered once daily in the morning (AM) for seven days. After a suitable washout, subjects in the 30 mg cohort returned for seven days of evening (PM) dosing. Pre-defined stopping criteria mainly related to sedation (defined by the Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S)) were utilized to define the maximum tolerated dose (MTD). Electroencephalogram (EEG) recordings assessed electrical activity in the brain. Results: SAGE-217 was well tolerated, with no serious adverse events. Reported adverse events were mild or moderate in intensity. The MTD was established as 30mg by the MOAA/S stopping criterion. SAGE-217 produced concentration dependent pharmacodynamic effects as measured by elevation of beta-band EEG (GABA A receptor modulation) at all doses tested (15–35 mg). Furthermore, these pharmacodynamics effects were sustained throughout the 7-day dosing period. Conclusions: In this MAD study, SAGE-217 was well tolerated for both AM and PM dosing, with slightly less sedation in the PM cohort. Evidence of target engagement at all doses supports the further development of SAGE-217 as a potential therapy for essential tremor and postpartum depression. A phase 2 clinical program is planned to evaluate SAGE-217 in multiple indications. Study Supported by: This study was supported by Sage Therapeutics, Inc. Disclosure: Dr. Nomikos has received personal compensation for activities with Sage Therapeutics, Inc. Dr. Colquhoun has received personal compensation for activities with Sage Therapeutics, Inc., as an employee. Dr. Quirk has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Raines has received personal compensation for activities with 2-b-Analytics as an employee and Sage Therapeutics, Inc., as a consultant. 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. Dr. Hoffman has received personal compensation for activities with Sage Therapeutics, Inc. as an employee. Dr. Hoffman holds stock and/or stock options in Sage Therapeutics, Inc. Dr. Sankoh has received personal compensation for activities with Sage Therapeutics, Inc. as an employee. Dr. Kanes has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Kanes holds stock and/or stock options in Sage Therapeutics.