127 Cardiovascular Safety Assessment of Deutetrabenazine in Healthy Volunteers and Implications for Patients With Huntington Disease or Tardive Dyskinesia

Abstract

Introduction: Deutetrabenazine is approvedfor treating Huntington disease (HD) chorea and is beingevaluated for tardive dyskinesia (TD). OBJECTIVE(S): To assess the effect of deutetrabenazine oncardiac repolarization. METHOD(S): A QT interval study was performed to evaluateeffects of deutetrabenazine 12 and 24 mg on cardiacrepolarization, as assessed by time-matched change frombaseline, placebo-adjusted, in Fridericia-corrected QTinterval (deltaQTcF). Moxifloxacin (400 mg) and tetrabenazine (50 mg) were the positive control and comparator, respectively. An exposure-response analysis wasdeveloped from this study to predict maximal effects onQTcF at maximum recommended dosing based onCYP2D6 status, an approach consistent with regulatoryguidance at predicting QT interval effects. RESULT(S): Maximal deltaQTcF between the least-squaresmean (90% two-sided confidence interval) of deutetrabenazine 12 and 24 mg (n = 45 in each group) were 2.8(0.7-4.8) ms and 4.5 (2.4-6.5) ms, respectively. ThedeltaQTcF increase with tetrabenazine (n = 45) was 7.6(5.6-9.5) ms. Assay sensitivity was verified with moxifloxacin (n = 47), which produced a maximal effect ondeltaQTcF of 14.0 (11.9-16.0) ms. A linear model wasdeveloped that described a correlation between plasmaconcentrations from pivotal HD andTD trials (n = 101)and QT interval prolongation. Using that model and theindividual predicted Cmax for HD and TD patients, theplacebo-adjusted change from baseline inQTcF fordeutetrabenazine at maximal recommended daily doses was found to be 5.4 (2.5-9.5) ms. CONCLUSION(S): Patients receiving the maximal recommended doses of deutetrabenazine are predicted to havea QTcF increase below the level of regulatory concern.