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Introduction: An estimated 300 million people worldwide are affected with major depressive disorder (MDD). Dysregulation of ɣ-aminobutyric acid (GABA) signaling is associated with MDD. SAGE-217 is an investigational, oral, neuroactive steroid and GABAA receptor positive allosteric modulator that has demonstrated reductions in depressive symptoms in a Phase 2 doubleblind, randomized, placebo-controlled study in MDD. Objectives: The objective of this Phase 3, double-blind, randomized, placebo-controlled study was to evaluate the efficacy and safety of SAGE-217 in the treatment of adult subjects with MDD. Methods: Subjects withMDDwere randomized 1:1:1 to SAGE-217 30 mg, 20 mg, or placebo capsules. Subjects were treated for 14 evenings, then followed frequently for 4-weeks and intervals through 182-days. The primary endpoint was change from baseline in Hamilton Depression Rating Scale (HAM-D) total score at Day 15 compared with placebo. Safety and tolerability were assessed by standard clinical assessments. Results: The initial 4-week follow-up of this Phase 3 study will be completed at the end of 2019. Data will be reported onHAM-D time points Days 3-42 (including Day 15), HAM-D response (≥50% reduction) and remission (≤7), Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and Hamilton Anxiety Rating Scale (HAM-A) scores. Safety and tolerability data will also be reported. Conclusions: This Phase 3 study aims to confirm and extend the previous results in a larger study population utilizing two dose groups versus placebo. These results have the potential to be an important milestone in the development of SAGE-217 in the treatment of individuals with MDD. [ABSTRACT FROM AUTHOR]

Background: Over 4.5% of the global population is estimated to suffer from major depressive disorder (MDD) annually. A double-blind, randomized, placebo-controlled Phase 3 study (NCT03672175; MOUNTAIN) evaluated the efficacy and safety of 20mg or 30mg of SAGE-217, an investigational, oral, neuroactive steroid GABAA receptor positive allosteric modulator, compared with placebo in MDD. Methods: Patients (N=581),18-65 years old, diagnosed with MDD of qualifying severity [Hamilton Rating Scale for Depression (HAM-D) total score =22, and Montgomery-Åsberg Depression Rating Scale (MADRS) score =32], were randomized 1:1:1 to SAGE-217 20mg, SAGE-217 30mg, or placebo for two weeks of dosing, with follow-up through 182 days. HAM-D was assessed throughout the study [change from baseline (CFB), response (reduction =50%), and remission (score =7)]. CFB at Day 15 was the primary endpoint. Safety and tolerability were assessed by the adverse event (AE) frequency and severity. Results: SAGE-217 30mg did not achieve a statistically significant HAM-D CFB versus placebo at Day 15 (primary endpoint; 30mg, -12.6; placebo -11.2; p=0.115). At Days 3, 8, and 12, SAGE-217 30mg demonstrated statistically significant HAM-D CFB versus placebo (p=0.018 for each time point). Post hoc analyses of SAGE-217 30mg patients with measurable drug concentration showed significant HAM-D CFB versus placebo at all time points through and including Day 15 (p=0.048 for each time point). The most common AEs (=5%) in either SAGE-217 group were headache, dizziness, somnolence, fatigue, diarrhea, sedation, and nausea. Conclusions: SAGE-217 achieved rapid (by Day 3) improvements in depressive symptoms and demonstrated numerical reduction in HAM-D at Day 15. [ABSTRACT FROM AUTHOR]

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]