Exposure–Response Analysis to Compare Changes in the Clinical Endpoints for Tardive Dyskinesia and Chorea in Huntington Disease Following Once-Daily and Twice-Daily Tablet Formulations of Deutetrabenazine

This work was sponsored by Teva Pharmaceuticals Background Deutetrabenazine is an FDA-approved treatment in adults for tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD) and comes in a twice-daily (BID) formulation (Austedo, Teva) and once-daily (QD) formulation (Austedo XR, Teva). Exposure-Response models using predicted exposure of deutetrabenazine’s active metabolites following BID and QD formulation administration, and therapeutic responses in the phase 3 TD and HD studies of the BID formulation were leveraged to predict changes in clinical efficacy endpoints following QD formulation administration in patients. Methods ER models were applied using simulated average plasma concentration under steady-state conditions (Cavg,ss) of total (α+β)-HTBZ after BID and QD formulation administration to obtain predicted improvements in mean change from baseline in AIMS-TMS at week-12 for patients with TD, and mean change from baseline in UHDRS-TMC score at week-12 for patients with HD. Results Predicted placebo-corrected mean changes in AIM-TMS in TD patients with Cavg,ss for total-daily-doses 12mg, 24mg, and 48mg were -1.75, -2.06, -2.68 and -1.72, -2.00, -2.57 for BID and QD formulations, respectively. Predicted placebo-corrected mean changes in UHDRS-TMC scores in HD patients with Cavg,ss were -2.67, -2.95, and -3.50; and -2.65, -2.90, and -3.40 for total-daily-doses 12mg, 24mg, and 48mg for the BID and QD formulations. Conclusions Modeling predicted a ≥2-point decrease from baseline in the AIMS-TMS and a 2-3 point decrease in the UHDRS-TMC score with maintenance daily doses of 24mg and 48mg deutetrabenazine using both the BID and QD formulations indicating similar efficacy to BID is expected upon administration of the QD formulation.