The neuroactive steroid (NAS) sage-217 in major depressive disorder: the landscape development program of an investigational, oral, positive allosteric modulator (PAM) of GABAA receptors.

Introduction: Major depressive disorder (MDD) is an episodic disorder associated with 1-aminobutyric acid (GABA) dysregulation. Depression is widely considered a chronic condition, with low remission rates with available medications. SAGE-217 is an investigational, oral NAS GABAAR PAM. In a pivotal, double-blind, randomized study inMDD(NCT03000530), SAGE-217 demonstrated rapid (Day 2) and sustained (Day 42) reductions in depressive symptoms versus placebo. SAGE-217 improved objective sleep efficiency versus placebo in a Phase 1 study in healthy volunteers (NCT03284931). Objectives: The Phase 2/3 development program aims to test the hypothesis that a majority of patients with MDD can be treated acutely and episodically, while having a positive effect on comorbid insomnia, thereby challenging the notion that most patients with depression require chronic treatment. Methods: Mountain (NCT03672175) examines efficacy and safety of 14-day dosing with SAGE-217 or placebo. Shoreline (NCT03864614) examines safety and tolerability of an initial 14-day SAGE-217 treatment and repeat-use over one year. Redwood (NCT04007367) assesses the time-to-relapse in a fixed, repeated treatment regimen of 14-day SAGE-217 treatment periods every two months. Rainforest (NCT03771664) examines the effect of SAGE-217 in comorbid MDD and insomnia. Results: Study designs and results from the SAGE-217 development program will be presented. Previous results showed the potential utility of SAGE-217 for acute, short-course treatment of MDD, with a positive impact on sleep in healthy volunteers. Conclusions: The Landscape Program aims to provide evidence for treatment effects in major depressive episodes and may support an episodic treatment paradigm in the event of symptom recurrence, with potential for positive impacts on co-morbid insomnia. Disclosure: CMS is an employee of Sage Therapeutics, Inc. with stock/stock options. [ABSTRACT FROM AUTHOR]