OBJECTIVES

: Major depressive disorder (MDD) can be a disabling and potentially life-threatening condition, and fatigue is an important somatic symptom of MDD. A Phase 2, double-blind, randomized, placebo-controlled study of the investigational, orally-bioavailable GABA_A receptor positive allosteric modulator SAGE-217 in MDD included patient reported measures of depressive symptoms and fatigue.

METHODS

: Seven US centers enrolled 89 subjects with MDD and a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥ 22. Subjects were randomized 1:1 to receive 30 mg SAGE-217 or placebo on Days 1-14, with follow up for 4 weeks. The reduction in depressive symptoms, compared to placebo, was assessed by HAM-D total score change from baseline at Day 15. The 41-item Remission from Depression Questionnaire (RDQ) and 16-item Fatigue Associated with Depression Questionnaire (FAsD) were patient reported at Day 15 and were assessed as change from baseline. Safety and tolerability were assessed by standard safety parameters, including adverse event (AE) reporting.

RESULTS

: At the Day 15 primary endpoint, SAGE-217 achieved a greater least-squares mean reduction from baseline in HAM-D total score versus placebo (-17.4 versus -10.3; p<0.0001). SAGE-217 also demonstrated statistically significant reductions in FAsD (-1.6 vs. -1.0; p=0.017) and RDQ (-27.3 vs. -14.9; p=0.004) least-squares mean total scores versus placebo at Day 15. Higher proportions of patients met the FAsD total score criteria for established minimally important difference (0.62) for SAGE-217 versus placebo (71% vs 57%). There were no deaths, serious or severe AEs reported. The most common SAGE-217 group AEs reported (≥5%) included headache, dizziness, nausea, and somnolence. The treatment emergent AE of fatigue was experienced by two SAGE-217 subjects and zero placebo subjects.

CONCLUSIONS

: Subjects with MDD receiving SAGE-217 reported meaningful improvements in patient reported measures of depression and fatigue compared to subjects receiving placebo in this randomized, double-blind study.