Next-generation neuroactive steroid SAGE-217 in a multiple-ascending dose study

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 GABAA 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 (GABAA 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.