SAGE Therapeutics has announced results from a successful exploratory clinical trial of SAGE-547 to evaluate the GABAA mechanism of action as a treatment for essential tremor, a debilitating neurological disorder that causes involuntary, rhythmic shaking with no known cause that is estimated to affect more than 10 million people in the United States.
In a randomized, double-blind, placebo-controlled, crossover trial of 25 patients affected by essential tremor, where patients were exposed to the target steady state dose for only two hours, several clinician-rated and accelerometer-rated measures showed significant reductions in tremor. These changes included a significant reduction in accelerometer-measured upper limb kinetic tremor (p=0.046) which is one of the major manifestations of tremor impacting morbidity. Overall clinician ratings of large tremor motions, as well as smaller movements such as writing and spiral drawing, also showed improvement (p=0.056). In addition, SAGE-547 demonstrated a clinically meaningful reduction of tremor amplitude as measured by accelerometer (at least a 30% reduction from baseline) in 33% of patients, compared with 16% of patients in the placebo arm.
Seventeen of these patients were exposed to higher doses of SAGE-547 in an open-label extension with 44% demonstrating at least a 30% reduction in tremor amplitude from baseline. The most common adverse events at higher doses were fatigue and dizziness. Hypotension led to discontinuation of one patient. No serious adverse events were observed on therapy or during the 30-day follow-up period.
“The information obtained in this exploratory study, including the activity signal supporting the role of the GABAA mechanism in essential tremor, greatly increases our confidence in a future program for essential tremor,” said Jeff Jonas, M.D., chief executive officer, SAGE Therapeutics. “This study exemplifies SAGE’s unique approach to clinical development. By generating efficient, targeted, signal-finding data in humans, SAGE-547 provides us with the unique ability to rapidly explore new indications for our leading library of compounds and to determine where our development efforts are most likely to benefit the many patients who are in need of new and improved treatment options.”
The trial was designed as a signal-finding study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the GABAA mechanism in patients with essential tremor. The study was powered at 80% for p=0.05. The goals of the study were to evaluate the feasibility of using the GABAA mechanism and, if positive activity signals were obtained, inform the clinical pathway and design of a second-generation SAGE molecule for the chronic treatment of this disorder.
Patients (n=25) received either blinded SAGE-547 or placebo in two crossover treatment periods. SAGE-547 was administered as a step-up infusion to a steady state dosage. Seventeen of the 25 patients volunteered to participate in an open-label, dose-escalation extension to study the range of pharmacodynamic effects of the GABAA modulator mechanism in conscious patients. Patients were monitored for up to 30 days following treatment.
The study was designed to enroll patients with moderate to severe essential tremor as assessed by a clinician rating scale, The Essential Tremor Rating Scale (TETRAS). Tremor outcome was measured during the trial by TETRAS and accelerometry, a direct physical measure of tremor amplitude and frequency. Patients enrolled in the trial were required to have had diagnosed essential tremor for at least two years and to be off medication, or on a stable dose of medication for their tremor, for at least 28 days prior to screening.