The gamma-aminobutyric acid type A receptor positive allosteric modulators brexanolone injection and SAGE-217 in the treatment of mood disorders: Results from recent placebo-controlled studies

Introduction:

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and acts through synaptic and extrasynaptic GABA_A receptors (GABAARs) to mediate phasic and tonic inhibition. Dysregulation of GABAergic signaling is thought to be associated with mood disorders such as postpartum depression (PPD) and major depressive disorder (MDD). The investigational positive allosteric modulators (PAMs) of GABAARs, brexanolone injection (BRX) and oral SAGE-217, are in development as potential treatments for PPD and PPD/MDD, respectively.

Methods:

Three double-blind, randomized, placebo-controlled (DBRPCT) studies of women diagnosed with moderate to severe PPD (HAM-D ≥26 in Studies A/B; HAM-D score 20 – 25 in Study C) were treated with 60-hour infusions of placebo or BRX 90 µg/kg/hour (BRX90) or BRX 60 µg/kg/hour (BRX60, Study B only).

Results:

In a pooled analysis 102, 38, and 107 patients were treated with BRX90, BRX60, and placebo respectively. At Hour 60 (primary endpoint), significantly greater least square mean (LSM) HAMD reductions were achieved with BRX90 (-17.0) and BRX60 (-19.1) vs. placebo (-12.8; p < 0.001 for both). Significant differences from placebo were seen as early as Hour 24 (BRX90, p = 0.001; BRX60, p = 0.009) and maintained through Day 30 (BRX90, p = 0.021; BRX60, p = 0.004). The most common adverse events (≥10%) with BRX were headache, dizziness, and somnolence.

A DBRPCT study evaluated the oral synthetic SAGE-217 in 89 patients (45 SAGE-217, 44 placebo) with moderate-to-severe MDD (HAM-D ≥22). Patients received either SAGE-217 30 mg or placebo daily for 14 days. At Day 15 (primary endpoint), a significantly greater LSM HAM-D reduction was achieved with SAGE-217 (-17.4) vs. placebo (-10.3; p < 0.001). The significant difference from placebo was observed as early as Day 2 (p = 0.022) and maintained through Day 28 (p = 0.024). The most common adverse events (≥5%) with SAGE-217 were headache, nausea, dizziness, and somnolence.

Conclusion:

Brexanolone injection and SAGE-217 are novel GABAAR-PAMs that showed rapid (1 – 2 days) and sustained reductions (over the study period) in depressive symptoms. These results support regulatory filings for brexanolone injection in the treatment of PPD and the continued development of SAGE-217 in MDD.