Dataset Information

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

ABSTRACT:

Aims

To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects.

Methods

We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting.

Results

Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449.

Conclusions

These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD.

SUBMITTER: Chen S

PROVIDER: S-EPMC6495663 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

Chen Sheng S Zhang Xiao-Jie XJ Xie Wen-Jie WJ Qiu Hong-Yan HY Liu Hui H Le Wei-Dong WD

CNS neuroscience & therapeutics 20150630 8

<h4>Aims</h4>To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects.<h4>Methods</h4>We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites w ...[more]

PMID: 26122704

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Project description:Abstract Background: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder resulting from exposure to dopamine receptor-blocking agents (DRBAs), such as antipsychotics. Valbenazine is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is being evaluated for the treatment of TD and other movement disorders. Clinical studies include a Phase 3 trial of valbenazine in adults who had TD and underlying schizophrenia/schizoaffective disorder or mood disorder (KINECT 3; NCT02274558). The primary end point of this trial was met as demonstrated by a significant difference between valbenazine 80?mg/day and placebo for the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score (Items 1–7) change from baseline. Additional analyses of AIMS data from this trial were conducted to assess treatment response in subjects with TD. Methods: In this 6-week, double-blind, placebo-controlled trial, subjects were randomized 1:1:1 to once-daily treatment with valbenazine 80?mg, valbenazine 40?mg, or placebo. Treatment response was defined as ?50% reduction in the AIMS total score. AIMS responders were analyzed by study visit (Weeks 2, 4, and 6) in the intent-to-treat (ITT) population and in subgroups categorized by underlying psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder). Numbers needed to treat (NNTs) were calculated for AIMS responders (valbenazine vs placebo) at Week 6. Significance testing was not conducted in the subgroups. Results: At Week 6 in the ITT population (N = 225), AIMS responder rates were significantly higher with valbenazine than with placebo: 80?mg, 40.0% (P < .0001; NNT = 4); 40?mg, 23.8% (P = .0200; NNT=7); placebo, 8.7%. Treatment with valbenazine 80?mg versus placebo also resulted in significantly higher responder rates at Week 2 (23.4% vs 5.3%, P = .0016) and Week 4 (28.8% vs 9.7%, P = 0.0039). Subjects treated with valbenazine 40?mg also had higher response rates at Week 2 (14.3% vs 5.3%) and Week 4 (15.6% vs 9.7%) relative to placebo-treated subjects, but the differences were not statistically significant. In subjects with schizophrenia/schizoaffective disorder (n = 148) or mood disorder (n = 77), AIMS responder rates were higher with valbenazine than placebo at all study visits. The highest responder rates were found at Week 6 and similar in the schizophrenia subgroup (80?mg, 40.9%, NNT = 4; 40?mg, 26.2%, NNT = 6; placebo, 9.3%) and mood subgroup (80?mg, 38.5%, NNT = 4; 40?mg, 19.0%, NNT=9; placebo, 7.7%). Conclusion: These study results, based on a rigorous definition of treatment response, indicate that substantial TD improvements occurred more frequently with valbenazine than placebo in adults diagnosed with schizophrenia/schizoaffective disorder or mood disorder. A significant difference between the 80-mg dose and placebo for the AIMS response was observed as early as 2 weeks of treatment.

Dataset Information

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

Aims

Methods

Results

Conclusions

Publications

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

Similar Datasets

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