A Randomized Double-Blind Placebo- and Positive-Controlled Crossover Study to Evaluate the Effects of Single Doses of SD-809 (Deutetrabenazine) and Tetrabenazine on the Corrected QT Interval (P2.347)

BACKGROUND: SD-809 (deutetrabenazine) is a VMAT-2 inhibitor in clinical development for treatment of hyperkinetic movement disorders. In a thorough QT (TQT) study, 50 mg of tetrabenazine (TBZ) prolonged the corrected QT (QTc) interval by approximately 8 msec. QT prolongation predisposes to life-threatening ventricular arrhythmias. OBJECTIVE: Evaluate the pharmacokinetics and pharmacodynamics (QTc) of SD-809 and TBZ. DESIGN/METHODS: In this double-blind, placebo- and positive-controlled, six-period crossover study, 48 healthy subjects were randomized to one of six treatment sequences. Treatments were separated by a 5-day washout and included single oral doses of SD-809 12 and 24 mg, TBZ 50 mg, moxifloxacin 400 mg and placebo controls. Triplicate 12-lead ECGs were recorded pre-dose and at 12 time points over 24 hours following drug administration. The primary outcome measures were the placebo-adjusted change from baseline in QTcF (ΔΔQTcF) for each SD-809 dose and TBZ. Moxifloxacin was utilized for assay sensitivity. Safety was assessed with adverse event monitoring and clinical laboratory tests. RESULTS: Forty-two subjects completed all treatments. The maximal mean (90[percnt] CI) ΔΔQTcF for SD-809 12 and 24 mg was 2.8 (0.7, 4.8) and 4.5 (2.4, 6.5) msec, respectively, whereas for TBZ 50 mg it was 7.6 (5.6, 9.5) msec. No subjects treated with SD-809 experienced a QTcF interval > 450 msec whereas one subject treated with TBZ experienced one. SD-809 24 mg provided comparable exposure (AUCinf) to circulating drug as 50 mg of TBZ, but with a lower Cmax. Assay sensitivity was demonstrated with moxifloxacin. Study treatments were generally well tolerated, as no severe or serious adverse events were reported. CONCLUSIONS: In this TQT study, SD-809 up to 24 mg increased QTcF by Disclosure: Dr. Stamler has received personal compensation for activities with Auspex Pharma as an employee. Dr. Offman has received research support from Auspex. Dr. Bradbury has received personal compensation for activities with Auspex Pharmaceuticals as an employee. Dr. De Boer has received personal compensation for activities with Auspex as an employee.