The Safety of Deutetrabenazine for Chorea in Huntington Disease: An Open-Label Extension Study

Abstract

Background Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease. Objective We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease. Methods This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study. Results Of 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up. Conclusions Adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea. Clinical Trial Registration ClinicalTrials.gov identifier: NCT01897896.The members of "The Huntington Study Group/ARC-HD Investigators and Coordinators" are listed in the Acknowledgements section.

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease

“…Ethics approval and informed consent were not required for this integrated analysis as they were obtained for the original clinical studies previously published [ 13 – 17 ], which were in accordance with the Declaration of Helsinki.…”

“…The pivotal studies included two 12-week, double-blind, randomized, placebo-controlled trials of patients with TD (ARM-TD and AIM-TD) [ 13 , 14 ] and a 12-week, double-blind, randomized, placebo-controlled trial of patients with HD (First-HD) [ 15 ]. Open-label extension (OLE) studies in TD (RIM-TD) and HD (ARC-HD) were also conducted to evaluate the long-term safety and efficacy of deutetrabenazine treatment [ 16 , 17 ].…”

“…This study is an integrated safety analysis of deutetrabenazine combining data across separate studies in TD (3 studies, 514 patients included) and HD (2 studies, 129 patients included) to further assess the safety of deutetrabenazine and identify any potentially emerging safety signals within the first 12–15 weeks of exposure. Safety data beyond week 15 from the OLE studies have been published previously [ 16 , 17 ] and were not included in these integrated safety analyses. Because of differences between patients with HD and patients with TD, data from each indication were analyzed separately but presented side by side, because physicians may find it informative when considering potential risks of treatment.…”

Latest advances on new promising molecular-based therapeutic approaches for Huntington’s disease

“…Tetrabenazine and deutetrabenazine are the only small-molecule drugs approved by the Food and Drug Administration (FDA) and also in China to manage HD chorea. [ 91 , 92 , 93 ] modulating dopamine by selectively inhibiting vesicular monoamine transporter type 2 (VMAT2). [ 94 ] In addition to controlling the symptoms of chorea, several clinical trials (NCT04301726, NCT0471398) are also conducted to elucidate the efficacy of deutetrabenazine to control symptoms of dysphagia, functional speech and gait dynamics in HD patients, while no results have been published up to now.…”

Pharmacogenetics in the Treatment of Huntington’s Disease: Review and Future Perspectives

“…Drowsiness, sedation, extrapyramidal symptoms, depression, akathisia, and parkinsonism are common side effects of VMAT2 inhibitors. There is also an increased risk of suicidality, QT prolongation, and neuroleptic malignant syndrome [ 15 , 16 ].…”