Cardiovascular Safety Assessment of Deutetrabenazine in Healthy Volunteers and Implications for Patients With Huntington Disease or Tardive Dyskinesia (P4.080)

Objective: To assess the effect of deutetrabenazine on cardiac repolarization. Background: Deutetrabenazine is approved for the treatment of Huntington disease (HD) chorea and tardive dyskinesia (TD). Patients with HD and TD may be prescribed medications that increase the risk of QT interval prolongation. Due to the risk of torsade de pointes, which can result in sudden cardiac death, evaluation of drug-induced QT prolongation is important. Design/Methods: A single-site, randomized, double-blind, crossover study was performed to evaluate effects of single-dose deutetrabenazine 12 and 24 mg on cardiac repolarization, as assessed by time-matched, placebo-adjusted change from baseline in Fridericia-corrected QT interval (ΔΔQTcF). Moxifloxacin (400 mg) and tetrabenazine (50 mg) were the positive control and comparator, respectively. An exposure–response analysis was developed to predict maximal effects on QTcF at maximum recommended dosing based on CYP2D6 status. Results: Maximal ΔΔQTcF between the least-squares mean (90% two-sided confidence interval) of deutetrabenazine 12 and 24 mg (n=45 in each group) were 2.8 (0.7–4.8) and 4.5 (2.4–6.5) ms, respectively. The ΔΔQTcF for tetrabenazine (n=45) was 7.6 (5.6–9.5) ms, consistent with drug labeling. Assay sensitivity was verified with moxifloxacin (n=47), which produced a maximal effect on ΔΔQTcF of 14.0 (11.9–16.0) ms. A linear model was developed that described a correlation between plasma concentrations and QT interval change from pivotal HD and TD trials (n=101). Using that model and individual predicted C max values for each patient, the placebo-adjusted change from baseline in QTcF for deutetrabenazine at maximal recommended daily doses was found to be 5.4 (2.5–9.5) ms. Conclusions: Patients receiving maximal recommended doses of deutetrabenazine are predicted to have a QTcF increase below 10 ms. In clinical trials of deutetrabenazine for the treatment of HD chorea and TD, cardiovascular AEs were uncommon and similar to placebo. Effects on QT interval were small. Study Supported by: This study was funded by Teva Branded Pharmaceutical Products Ru0026D, Inc. Petach Tikva, Israel Disclosure: Dr. Cox has nothing to disclose. Dr. Levi has nothing to disclose. Dr. Rabinovich-Guilatt has nothing to disclose. Dr. Truong has nothing to disclose. Dr. Stamler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Auspex Pharmaceuticals.