Objective: This single dose, open-label, Phase 1b study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SAGE-324 in otherwise healthy patients with Essential Tremor (ET).

Background: Essential Tremor (ET) is a chronic neurological disorder characterized by bilateral postural tremor and tremor that occurs during voluntary movement of the upper limbs. ET is associated with impaired GABAergic signaling in the cerebellum. SAGE-324 is a structurally distinct, investigational, proprietary,  oral, next-generation neuroactive steroid GABA_A receptor positive allosteric modulator currently in development for ET with a pharmacology distinct from benzodiazepines and other GABAergic pharmacotherapies.

Method: Patients with ET and a qualifying upper limb tremor by The Essential Tremor Rating Assessment Scale (TETRAS; combined upper limb total score ≥8 on performance subscale Part 4) were enrolled. Patients were in-patients and received a single dose of SAGE-324 oral suspension (either 45mg or 60mg); they underwent tremor assessments for 24 hours post-dose using TETRAS and upper extremity Kinesia accelerometry. Follow-up at Days 7 and 14 was outpatient. Plasma PK parameters were evaluated.  Safety and tolerability were assessed by incidence of adverse events and standard clinical assessments.

Results: SAGE-324 was generally well-tolerated in both dose groups (45 mg, n=6 or 60 mg, n=5), no serious or severe treatment emergent adverse events were reported. The most common TEAEs (reported in 2 or more subjects in any treatment group) were as follows; Somnolence (2/6 [33.3%] in 45 mg group, 2/5 [40.0%] in 60 mg), Dizziness (2/6 [33.3%] in 45 mg group, 2/5 [40.0%] in 60 mg group). There were no TEAEs leading to study discontinuation. Both dose groups demonstrated mean reductions from baseline in tremor as measured by TETRAS (45 mg 21%, 60 mg, 33% at 4 hours post-dose) and Kinesia (45mg 47%, 60mg 47% at 4 hours post-dose).  Changes in tremor amplitude  followed plasma concentrations of SAGE-324 showing a good PK/PD relationship.

Conclusion: In this Phase 1b study, single doses of SAGE-324 were generally well tolerated by patients with essential tremor; decreases in tremor amplitude were observed. A clear PK/PD relationship was observed. This study supports a future Phase 2 study of SAGE-324 in ET.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/an-open-label-phase-1b-study-of-the-neuroactive-steroid-gabaa-receptor-positive-allosteric-modulator-sage-324-in-essential-tremor/