The pharmacokinetics of SAGE-217 in Phase 1 SAD and MAD studies (P3.008)

Objective: To assess SAGE-217 Oral Solution pharmacokinetics (PK) in single ascending dose (SAD) and multiple ascending dose (MAD) clinical studies Background: SAGE-217 is a novel, orally bioavailable neuroactive steroid (NAS). SAGE-547 Injection, a proprietary, aqueous formulation of the NAS allopregnanolone, has shown positive signals in essential tremor (ET), super-refractory status epilepticus (SRSE), and postpartum depression (PPD) studies. SAGE-217 has similar pharmacology to allopregnanolone, as a positive allosteric modulator of GABA A receptors, and demonstrates anticonvulsant and anxiolytic activities in a variety of preclinical models. Design/Methods: SAGE-217 was evaluated in SAD and MAD studies. For the SAD study, SAGE-217 was administered to 72 healthy volunteers, at doses between 0.25 and 66 mg, in nine double-blind, cohorts, which were randomized 6:2, SAGE-217:placebo. A 10 th cohort assessed the effect of food on the PK of single SAGE-217 doses. In the MAD study, three double-blind cohorts of healthy volunteers were randomized 9:3 SAGE-217:placebo, at doses of 15 mg, 35 mg, and 30 mg, administered once daily for 7 days. An open-label cohort assessed potential induction of the CYP3A4 and CYP2B6 enzymes, using simvastatin and bupropion as probes. Results: PK profiles obtained in Phase 1 SAD and MAD studies of SAGE-217 were consistent with once daily, oral dosing and display dose linearity over the ranges studied (0.25–66 mg SAD;15–35 mg MAD). The SAGE-217 half-life ranged from 10–25 hours. In the MAD study, slight SAGE-217 accumulation, commensurate with the long half-life, was observed. A modest reduction in C max but no change in AUC was observed in fed versus fasting patients. There was no evidence for induction of CYP3A4 or CYP2B6. Conclusions: Favorable PK results support once daily oral administration and advancing the clinical development of SAGE-217 as a potential therapy for ET and PPD. 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. 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. Wald has received personal compensation for activities with qPharmetra and Sage Therapeutics as an employee and a consultant. Dr. Raines has received personal compensation for activities with 2-b-Analytics as an employee and Sage Therapeutics, Inc., as a consultant. 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. Kane has received personal compensation for activities with Sage Therapeutics as an employee. Dr. Kane holds stock and/or stock options in Sage Therapeutics.