ET is associated with impaired GABAergic signaling in the cerebellum. SAGE-324 is a neuroactive steroid GABA_A receptor positive allosteric modulator, with a broader GABA_A pharmacology, distinct from other mechanisms currently in development for ET.

ET patients with a qualifying upper limb tremor by The Essential Tremor Rating Assessment Scale (TETRAS; combined upper limb total score ≥8 on performance subscale Part 4) and not taking ET medications were enrolled. Patients received a single dose of SAGE-324 suspension in 2 dose groups (45 mg or 60 mg) and underwent tremor assessments for 24 hours post-dose as inpatients, using TETRAS and upper extremity accelerometry as inpatients. Follow-up at Days 7 and 14 was outpatient. Plasma PK parameters were evaluated.  Safety and tolerability were assessed by adverse event reporting and standard clinical assessments. 

SAGE-324 was generally well-tolerated in both dose groups (45 mg, n=6 or 60 mg, n=5); no serious or severe adverse events were reported. Both dose groups demonstrated maximal mean percent reduction from baseline in tremor as measured by TETRAS (45 mg: 26% SD 11.2%; 60 mg: 43% SD 23.0%) and accelerometry (45 mg: 48% SD 20.4%; 60 mg: 55% SD 13.9%) that corresponded with mean maximum plasma concentrations (C_max).  

In this Phase 1b study, SAGE-324 was generally well tolerated and demonstrated decreases in tremor. A clear PK/PD relationship was observed. This study supports future evaluation of SAGE-324 in a Phase 2 study in ET.