Exploratory Trial for Essential Tremor Treatment

In a study of 2857 patients with essential tremor, 33% received no treatment for their tremor. Of those patients who did receive treatment, 33% experienced no benefit from beta-blockers and 35% discontinued due to side effects. In addition, 17% reported no benefit from primidone and 23% discontinued due to side effects.¹

“It’s a huge unmet need to have something available for essential tremor that will control tremor without causing significant side effects that end up being more bothersome than the tremor itself,” stated Kelly Lyons, PhD.

Essential tremor, one of the most common neurological disorders, has a relatively unknown etiology. Reduced levels of γ-aminobutyric acid (GABA) type A receptors (GABAAR) and decreased GABAergic activity, however, have been observed in these patients.

Researchers studied the effects of SAGE-547, a potent positive allosteric modulator of GABAAR, to evaluate a possible role in restoring GABA dysfunction. SAGE-547 is a proprietary formulation of allopregnanolone in Captisol®.²

In stage one of this double-blind, placebo-controlled, two-period crossover, proof-of-concept study, 25 patients with essential tremor were exposed to a dose-escalating infusion of SAGE-547 or placebo in crossover fashion. Seventeen patients chose to participate in stage two, an additional 10-hour infusion of open-label SAGE 547 at a higher dose. Endpoints were determined by accelerometer, The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale, pharmacokinetic profile of allopregnanolone, and Stanford Sleepiness Scale.

Accelerometer measurements noted significant reductions in kinetic tremor scores for SAGE-547 compared to placebo (P<0.05), as did TETRAS clinician ratings of kinetic tremor. Also in stage one, patients in both groups had no difference in adverse events. In stage two, tremor scores were similar to stage one, although patients reported more sleepiness at the higher dose. One patient discontinued the study due to hypotension and patients commonly experienced fatigue and dizziness.

Although there was little evidence of increased efficacy during stage two, increased sedation was seen at the higher dose. In addition, some patients experienced tolerance to the increased level of sleepiness after 6 hours. Overall, SAGE-547 was well tolerated with signals of activity compared to placebo.

“[T]his doesn’t mean SAGE-547 would necessarily be a treatment for essential tremor – it’s a drug that’s given by IV, it has a very short half-life – but the mechanism itself is one that we’re very interested in.” Our intent, explained Steve Kanes, MD, PhD, “is to identify and develop compounds with similar pharmacology that would be more amenable to treating patients like those with essential tremor – long half-life drugs, ones with good neurobioavailability, ones that would improve the overall symptoms and potentially the quality of life of patients with essential tremor.”

“It’s a huge unmet need to have something available for essential tremor that will control tremor without causing significant side effects that end up being more bothersome than the tremor itself,” stated Kelly Lyons, PhD.

Reference: Ellenbogen A, et al. Exploratory Trial Results for SAGE-547 in Essential Tremor. Poster presentation P4.297, Apr 19, 2016. AAN Annual Meeting, Vancouver, British Columbia.