Objective: To examine use of γ-aminobutyric acid (GABA) type A receptor (GABA-A-R) positive allosteric modulators (PAMs) in the treatment of essential tremor (ET) in early phase clinical trials of brexanolone injection (BRX), an investigational, intravenous formulation of allopregnanolone, and novel, investigational, orally-bioavailable, GABA-A-R PAMs in subjects with ET.

Background: ET is a chronic neurological disorder characterized by involuntary rhythmic shaking. The etiology of ET is largely unknown, but reduced GABA-A-R levels and decreased GABAergic activity have been observed in ET. GABA-A-R PAMs can reduce tremor levels but are not specifically indicated for ET. Neuroactive steroids, such as allopregnanolone, are PAMs of both synaptic and extrasynaptic GABA-A-Rs, suggesting potential for efficacy in treating ET.

Method: A randomized, double-blind, placebo-controlled, 2-period, cross-over study of BRX versus placebo was conducted in 25 subjects with ET, who had a qualifying score on The Essential Tremor Rating Scale (TETRAS). Subjects received 12-hour infusions of BRX or placebo in crossover fashion and were assessed for tremor symptoms by TETRAS and accelerometry through 24 hours. SAGE-217, a novel, orally-bioavailable PAM, was tested in a three-part, multicenter, Phase 2 study in subjects with ET. During the course of the study, 32 subjects were treated for 7 or 14 days to examine the effect of SAGE-217 capsule on tremor severity.

Results: In the BRX trial, greater decreases from baseline in tremor as measured by accelerometry and TETRAS were observed up to 24 hours after the start of infusion compared to placebo. Statistically significant improvements in total upper limb (UL) kinetic tremor scores during BRX treatment were observed at 6 (p=0.020), 10 (p=0.040), and 12 hours (p=0.034) versus placebo. BRX was generally well tolerated in the 2-period cross-over study, and all adverse events were mild or moderate in severity. Across all studies, SAGE-217 treatment resulted in decreased total UL and kinetic tremor as measured by TETRAS and accelerometry. SAGE-217 capsule was generally well tolerated throughout the study.

Conclusion: Improved tremor symptoms in studies of BRX and SAGE-217 suggest the potential utility, and support further development, of the GABA-A-R PAM mechanism in ET.

References: [1] Kaul I, Bullock A, Li S, Silber C, Kanes S. SAGE-217 Capsules in Essential Tremor: An Open-label, Phase 2 Pilot Clinical Trial [abstract]. J Movement Disorders June 2018;33, Suppl 1:S14–S117. [2] Ellenbogen A, Raines S, Kanes S. Exploratory Trial Results for SAGE-547 in Essential Tremor [abstract]. Neurology April 2016;86 (16 Supplement).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gaba-a-receptor-positive-allosteric-modulators-phase-2-proof-of-concept-studies-of-brexanolone-injection-and-sage-217-in-essential-tremor/