Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea

Frank, Samuel; Stamler, David; Kayson, Elise; Claassen, Daniel O.; Colcher, Amy; Davis, Charles S.; Duker, Andrew P.; Eberly, Shirley; Elmer, Lawrence; Furr-Stimming, Erin; Gudesblatt, Mark; Hunter, Christine; Jankovic, Joseph; Kostyk, Sandra K.; Kumar, Rajeev; Loy, Clement T.; Mallonee, William M.; Oakes, David; Scott, Burton L.; Sung, Victor; Goldstein, Jody; Vaughan, Christina; Testa, Claudia; Investigators, Alternatives for Reducing Chorea in Huntington Disease

doi:10.1001/jamaneurol.2017.1352

Cited by 196 publications

(25 citation statements)

References 17 publications

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“…Additionally, the authors of First-HD performed a study titled ARC-HD, and in one portion of the study, patients were entered to the study on a stable dose of tetrabenazine and were allowed to switch to deutetrabenazine in an open-label fashion. 18 Though the goal of this study was to show that patients could switch from tetrabenazine to deutetrabenazine safely without loss of efficacy from a chorea standpoint, the efficacy and safety data could also be used as an indirect comparison between the two drugs as the same patients will have taken both drugs. There were 37 patients enrolled in this study, and each patient switched overnight from tetrabenazine to deutetrabenazine in ~2:1 conversion.…”

Section: Deutetrabenazine Vs Tetrabenazinementioning

confidence: 99%

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Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease

Dean¹,

Sung²

2018

DDDT

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Deutetrabenazine was recently approved for the treatment of chorea in Huntington’s disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine’s drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.

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Section: Deutetrabenazine Vs Tetrabenazinementioning

confidence: 99%

“…A higher overnight switch ratio was not evaluated in this study, and a study with a higher deutetrabenazine-to-tetrabenazine ratio would be interesting from a safety and efficacy standpoint to know whether efficacy is further improved without sacrificing the favorable safety profile that has been seen in studies thus far. 18 …”

Section: Dosage and Administrationmentioning

confidence: 99%

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease

Dean¹,

Sung²

2018

DDDT

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“…***P ≤ 0.001. dopamine accumulations or interrupting the dopaminergic receptors in the brain. For example, tetrabenazine is characterized by its ability to inhibit the vesicular monoamine transporter 2 (VMAT-2) in the central nervous system (CNS) and can prevent serotonin, dopamine, and norepinephrine in the cytoplasm from uptake into presynaptic vesicles (Wyant et al, 2017;Frank et al, 2017). TCMs with few side effects possess multiple components, targets and efficacies.…”

Section: Discussionmentioning

confidence: 99%

Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells

et al. 2020

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The pathogenesis of Huntington's disease (HD), an inherited progressive neurodegenerative disease, is highly associated with the cytotoxicity-inducing mutant huntingtin (mHtt) protein. Emerging evidence indicates that autophagy plays a pivotal role in degrading aggregated proteins such as mHtt to enhance neuronal viability. In this study, by employing preparative high-performance liquid chromatography (pre-HPLC), ultra-high performance liquid chromatography diode-array-detector quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q-TOF-MS) and nuclear magnetic resonance (NMR), three escins, escin IA (EA), escin IB (EB) and isoescin IA (IEA), were isolated and identified from the seed of Aesculus chinensis Bge. (ACB). After EGFP-HTT74-overexpressing HT22 cells were treated with EA, EB and IEA at safe concentrations, the clearance of mHtt and mHtt-induced apoptosis were investigated by Western blot, immunofluorescence microscopy and flow cytometry methods. In addition, the autophagy induced by these escins in HT22 cells was monitored by detecting GFP-LC3 puncta, P62 and LC3 protein expression. The results showed that EA, EB and IEA could significantly decrease mHtt levels and inhibit its induced apoptosis in HT22 cells. In addition, these three saponins induced autophagic flux by increasing the ratio of RFP-LC3 to GFP-LC3, and by decreasing P62 expression. Among the tested escins, EB displayed the best autophagy induction, which was regulated via both the mTOR and ERK signaling pathways. Furthermore, the degradation of mHtt and the commensurate decrease in its cytotoxic effects by EA, EB and IEA were demonstrated to be closely associated with autophagy induction, which depended on ATG7. In conclusion, we are the first to report that the escins, including EA, EB and IEA are novel autophagy inducers that degrade mHtt and inhibit mHtt-induced apoptosis in vitro and in vivo. As a result of these findings, the triterpenoid saponins in ACB might be considered to be promising candidates for the treatment of HD in the future.

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“… 24 Furthermore, an open-label study has demonstrated that patients with HD can safely be converted from tetrabenazine three times daily to deutetrabenazine twice-daily with good adherence. 25 …”

Section: Discussionmentioning

confidence: 99%

Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington’s Disease–associated Chorea Initiated on Tetrabenazine

Sung

Iyer

Gandhi

et al. 2018

JHEOR

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Background: Huntington’s disease (HD) is a multifaceted neurodegenerative disorder characterized by involuntary movements, specifically chorea, as well as behavioral and psychiatric disturbance, and cognitive dysfunction. Tetrabenazine was the first approved treatment for chorea, although tolerability concerns exist. Objectives: To characterize demographic and clinical characteristics of HD patients with chorea based on tetrabenazine use and examine treatment persistence with tetrabenazine in a real-world setting. Methods: Patients with a claim for HD-associated chorea (ICD-9-CM code 333.4) between 1/1/08 and 9/30/15 were selected from the MarketScan® Commercial and Medicare Supplemental databases. The first diagnosis date during the study period was considered the index date, with ≥6 months of continuous medical and prescription coverage before and after the index date. Treatment persistence was defined as the number of days from initiation to discontinuation or end of follow-up period. Discontinuation was defined as a gap in therapy of ≥60 days. Results: 1644 patients met selection criteria (mean age ± standard deviation: 54.5 ± 15.5), of which 151 (9.2%) were treated with tetrabenazine during the study period. The average (median) daily dose of tetrabenazine during the treatment period was 45.5 (42.3) mg/day. A total of 41.8% (59/141) of HD patients who initiated tetrabenazine experienced a ≥60-day gap in tetrabenazine therapy, with a median time to discontinuation of 293.5 days. During the 6-month post-index period after HD diagnosis, HD patients incurred higher all-cause healthcare costs ($20 204) vs the 6-month pre-index period ($6057), driven by higher hospitalization and pharmacy costs. Conclusions:A small percentage of HD patients with chorea were treated with tetrabenazine and discontinuation rates were high among those receiving treatment, with a median time to discontinuation of 9 months.

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Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea

Cited by 196 publications

References 17 publications

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease

Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells

Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington’s Disease–associated Chorea Initiated on Tetrabenazine

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Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea

Cited by 196 publications

References 17 publications

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington&#39;s disease

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington&#39;s disease

Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells

Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington’s Disease–associated Chorea Initiated on Tetrabenazine

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Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease