Assessment of the deutetrabenazine exposure-response relationships for patients with moderate-to-severe tardive dyskinesia

Abstract: Background: Deutetrabenazine (Teva) is indicated for chorea associated with Huntington’s disease and tardive dyskinesia (TD). Individual optimization of treatment based on efficacy and tolerability, is reached by dose titration. Previous dose-response analyses of the double-blind studies in TD confirmed that deutetrabenazine doses of 24 and 36 mg are efficacious. The present exposure-response analysis was conducted to determine if there was an increase in efficacy associated with higher plasma exposure concentrations of deutetrabenazine and active metabolites, α-HTBZ and β-HTBZ. Methods An exposure-response (E-R) analysis evaluated the relationships between exposures and endpoints assessed in phase 3 study participants with moderate-to-severe TD who received a total daily dose of 12-48mg. PK exposure parameters (average and maximal concentrations) were determined for the sum total of the active metabolites (total (α+β)-HTBZ) for each patient. Phase 3 primary [individual total motor AIMS score] and secondary [proportion of patients with improvement on Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC)] endpoints were modeled. Results The relationship between ∆AIMS and exposures of total-(α+β) HTBZ showed that higher exposure to total (α+β)-HTBZ can lead to greater decreases in AIMS score compared to baseline. Similarly, positive relationship between CGIC and PGIC scores occurred with PK-increased exposure. Conclusion The results of this E-R analysis indicate that patients with higher concentrations of deutetrabenazine’s active metabolites show better treatment response in terms of AIMS score (motor control). This analysis supports titration to higher doses (up-to-48mg) in patients with TD to explore optimal motor control and overall clinical response.Short Description: Deutetrabenazine is indicated for chorea associated with Huntington’s disease and tardive dyskinesia (TD). Individual optimization of treatment based on efficacy and tolerability, is reached by dose titration. An exposure-response analysis evaluated the relationships between exposure to deutetrabenazine’s active metabolites and changes in the clinical endpoints from the phase 3 studies of patients with TD; and found that those with higher active metabolite concentrations showed better treatment response, supporting titration to higher doses up to 48mg.Name of Sponsoring Organization(s): Teva Pharmaceuticals USA