Evaluation of the Safety of Deutetrabenazine at Higher Doses to Treat Chorea in Huntington’s Disease (4310)

Objective: To evaluate the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat Huntington’s disease (HD)–associated chorea in ARC-HD.

Background: In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat HD chorea was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (week 8), and, at investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 36 mg twice daily.

Design/Methods: In this post-hoc analysis, patient counts and safety assessments were attributed to patients when they received a dose either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.

Results: All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years), but only 49 subjects were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.

Conclusions: Some patients with HD require doses higher than 48 mg/day to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.

Disclosure: Dr. Frank has received research support from First-HD, and ARC-HD.Dr. Vaughan has nothing to disclose. Dr. Stamler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Former employee of Teva Pharmaceuticals; salary and benefits from Auspex Pharmaceuticals. Patents pending: US20160346270, US20160287574.. Dr. Oakes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Research Support: Auspex (for the FIRST-HD and related studies), Vaccinex Inc., Prana Pharmaceuticals, Biogen, Inc., NIH. Honoraria: Raptor Pharmaceuticals, Voyager Inc.. Dr. Oakes has received research support from Research Support: Auspex (for the FIRST-HD and related studies), Vaccinex Inc., Prana Pharmaceuticals, Biogen, Inc., NIH. Honoraria: Raptor Pharmaceuticals, Voyager Inc..Dr. Davis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an Employee of Teva Pharmaceuticals. Dr. Gross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals, USA. Dr. Gordon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals. Dr. Savola has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Former employee of Teva Pharmaceuticals International, GmbH, Basel, Switzerland.. Dr. Wieman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Former employee of Teva Pharmaceuticals.. Dr. Eberly has nothing to disclose. Dr. Kayson has nothing to disclose. Dr. Whaley has nothing to disclose. Dr. Goldstein has nothing to disclose. Dr. Testa has received research support from Co-Principal Investigator: First-HD. Consultant: Lundbeck, with honoraria donated to the Medical College of Virginia Foundation.