Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease

Abstract

BackgroundVesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods.MethodsData from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests.ResultsCompared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant.ConclusionsThis indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.Trial registrationClinicalTrials.gov NCT01795859 and NCT00219804.

Therapeutic Advances for Huntington’s Disease

“…Deutetrabenazine contains a deuterium atom and is a novel inhibitor of VMAT2. In indirect treatment comparison studies, deutetrabenazine was found to have a favorable tolerability profile compared to tetrabenazine [41]. In mouse models, TBZ ameliorated chorea and other motor symptoms, and reduced striatal neuronal cell loss [38].…”

Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

“…Comparing deutetrabenazine with tetrabenazine for the treatment of TD using meta‐analytic techniques is not possible as there are no randomised placebo‐controlled studies of tetrabenazine for TD; however, in an indirect comparison of deutetrabenazine and tetrabenazine for Huntington's disease, tetrabenazine and deutetrabenazine did not differ significantly on motor scores or adverse events, but depression and somnolence scales favoured deutetrabenazine significantly . Another indirect analysis comparing tolerability of deutetrabenazine and tetrabenazine in Huntington's disease demonstrated that deutetrabenazine was associated with a significantly lower risk of moderate to severe adverse events and neuropsychiatric adverse events including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia and parkinsonism; deutetrabenazine also had a significantly lower rate of dose reduction or dose reduction/suspension …”

Huntington’s Disease Clinical Trials Corner: April 2020

“…There are two other VMAT2 inhibitors on the market: tetrabenazine (3-times daily) and deutatrabenazine (twice-daily), both of them approved by FDA for chorea associated with HD. Apart from dosage regimen, it is unclear if there are differences between these two modestly effective drugs, which have comparable safety profiles with risks of suicidality, parkinsonism and QT prolongation [10][11][12].…”