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NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study.

ABSTRACT: Tardive dyskinesia is a persistent movement disorder induced by chronic neuroleptic exposure. NBI-98854 is a novel, highly selective, vesicular monoamine transporter 2 inhibitor. We present results of a randomized, 6-week, double-blind, placebo-controlled, dose-titration study evaluating the safety, tolerability, and efficacy of NBI-98854 for the treatment of tardive dyskinesia.Male and female adult subjects with moderate or severe tardive dyskinesia were included. NBI-98854 or placebo was given once per day starting at 25 mg and then escalated by 25 mg to a maximum of 75 mg based on dyskinesia and tolerability assessment. The primary efficacy endpoint was the change in Abnormal Involuntary Movement Scale from baseline at week 6 scored by blinded, central video raters. The secondary endpoint was the Clinical Global Impression of Change-Tardive Dyskinesia score assessed by the blinded investigator.Two hundred five potential subjects were screened, and 102 were randomized; 76% of NBI-98854 subjects and 80% of placebo subjects reached the maximum allowed dose. Abnormal Involuntary Movement Scale scores for NBI-98854 compared with placebo were significantly reduced (p = 0.0005). Active drug was also superior on the Clinical Global Impression of Change-Tardive Dyskinesia (p < 0.0001). Treatment-emergent adverse event rates were 49% in the NBI-98854 and 33% in the placebo subjects. The most common adverse events (active vs. placebo) were fatigue and headache (9.8% vs. 4.1%) and constipation and urinary tract infection (3.9% vs. 6.1%). No clinically relevant changes in safety assessments were noted.NBI-98854 significantly improved tardive dyskinesia and was well tolerated in patients. These results support the phase 3 clinical trials of NBI-98854 now underway.

SUBMITTER: O'Brien CF

PROVIDER: S-EPMC5049616 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study.

O'Brien Christopher F CF Jimenez Roland R Hauser Robert A RA Factor Stewart A SA Burke Joshua J Mandri Daniel D Castro-Gayol Julio C JC

Movement disorders : official journal of the Movement Disorder Society 20150908 12

<h4>Background</h4>Tardive dyskinesia is a persistent movement disorder induced by chronic neuroleptic exposure. NBI-98854 is a novel, highly selective, vesicular monoamine transporter 2 inhibitor. We present results of a randomized, 6-week, double-blind, placebo-controlled, dose-titration study evaluating the safety, tolerability, and efficacy of NBI-98854 for the treatment of tardive dyskinesia.<h4>Methods</h4>Male and female adult subjects with moderate or severe tardive dyskinesia were inclu ...[more]

PMID: 26346941

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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.

Project description:Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired R,R,R-13e [(+)-13e] and S,S,S-13e [(-)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using in vitro and in vivo models (+)-13e displayed high affinity for VMAT2 (Ki = 1.48 nM) and strongly inhibited [3H]DA uptake (IC50 = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. In vivo, (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.

Project description:Abstract Background: Valbenazine is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is being evaluated for the treatment of tardive dyskinesia (TD), a persistent movement disorder resulting from exposure to antipsychotics or other dopamine receptor blocking agents (DRBAs). The efficacy of valbenazine in treating TD was demonstrated in a Phase 3 clinical trial (KINECT 3; NCT02274558), which included subjects with underlying schizophrenia/schizoaffective disorder or mood disorder. Further analyses of data from that trial were conducted to explore the efficacy of valbenazine across diagnostic subgroups. Methods: Subjects in this 6-week, double-blind, placebo-controlled trial were randomized 1:1:1 to once-daily valbenazine 80?mg, valbenazine 40?mg, or placebo. The primary endpoint was change from baseline to Week 6 on the Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) for valbenazine 80?mg vs placebo in the intent-to-treat (ITT) population. AIMs were videotaped and ratings were conducted by central raters blind to study visit and group. Additional outcomes included AIMS total score change (40?mg vs placebo) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI TD) score (80 and 40?mg vs placebo) at Week 6. In addition to being evaluated in the ITT population, these outcomes were analyzed in subgroups categorized by underlying psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder). Results: At Week 6 in the ITT population (N = 225), AIMS score improvement was significantly greater with valbenazine 80?mg than placebo (least squares [LS] mean change from baseline: 80?mg, 3.2; placebo, ?0.1; P < .0001). AIMS score change at Week 6 for valbenazine 40?mg (1.9) was also greater than placebo (P = .0021). Statistical testing was not conducted in the subgroups, but the magnitude of AIMS improvement in these patients was comparable to results in the overall ITT population: schizophrenia/schizoaffective disorder (n = 148; mean change from baseline: 80?mg, ?3.1; 40?mg, ?1.5; placebo, +0.4); mood disorder (n = 77; 80?mg, 3.6; 40?mg, ?2.5; placebo, ?0.7). CGI-TD scores at Week 6 in the ITT population indicated greater global improvement with valbenazine than placebo, but between-group differences were not statistically significant (LS mean scores: 80?mg, 2.9; 40?mg, 2.9; placebo, 3.2). CGI-TD outcomes in the subgroups were as follows: schizophrenia/schizoaffective disorder (mean scores: 80?mg, 3.0; 40?mg, 2.9; placebo, 3.1); mood disorder (80?mg, 2.7; 40?mg, 2.9; placebo, 3.2). Psychiatric status remained stable during the 6-week double-blind treatment period. Conclusion: Once-daily treatment with valbenazine improved TD regardless of underlying psychiatric diagnosis.

Project description:Background:Tardive dyskinesia (TD) is a common side effect of antipsychotic treatment. This movement disorder consists of orofacial and limb-truncal components. The present study is aimed at investigating the role of serotonin receptors (HTR) in modulating tardive dyskinesia by genotyping patients with schizophrenia. Methods:A set of 29 SNPs of genes of serotonin receptors HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, and HTR6 was studied in a population of 449 Caucasians (226 females and 223 males) with verified clinical diagnosis of schizophrenia (according to ICD-10: F20). Five SNPs were excluded because of low minor allele frequency or for not passing the Hardy-Weinberg equilibrium test. Affinity of antipsychotics to 5-HT2 receptors was defined according to previous publications. Genotyping was carried out with SEQUENOM Mass Array Analyzer 4. Results:Statistically significant associations of rs1928040 of HTR2A gene in groups of patients with orofacial type of TD and total diagnosis of TD was found for alleles, and a statistical trend for genotypes. Moreover, statistically significant associations were discovered in the female group for rs1801412 of HTR2C for alleles and genotypes. Excluding patients who used HTR2A, respectively, HTR2C antagonists changed little to the associations of HTR2A polymorphisms, but caused a major change of the magnitude of the association of HTR2C variants. Due to the low patient numbers, these sub-analyses did not have significant results. Conclusion:We found significant associations in rs1928040 of HTR2A and for rs1801412 of X-bound HTR2C in female patients. The associations were particularly related to the orofacial type of TD. Excluding patients using relevant antagonists particularly affected rs1801412, but not rs1928040-related associations. This suggest that rs1801412 is directly or indirectly linked to the functioning of HTR2C. Further study of variants of the HTR2C gene in a larger group of male patients who were not using HTR2C antagonists is necessary in order to verify a possible functional role of this receptor.

Dataset Information

NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study.

Publications

NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study.

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