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Tardive dyskinesia (TD), a persistent and potentially disabling movement disorder, is associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine (VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from two long-term phase 3 studies (KINECT 3 [K3], NCT02274558; KINECT 4 [K4], NCT02405091) and a rollover study (1506, NCT02736955), the long-term outcomes of once-daily VBZ on TD were examined in participants who received 40mg or had a dose reduction from 80 to 40mg.
The effects of VBZ 40mg (as well as VBZ 80mg) were evaluated in the following studies: the pivotal K3 study (6 weeks double-blind, placebo controlled), the extension phase of K3 (42 additional weeks of VBZ, 4 week discontinuation), and the open-label K4 study (48 weeks of VBZ, 4 week discontinuation). Completers from K3 extension and K4 were invited to participate in 1506 (up to 72 additional weeks of VBZ or until commercial availability of VBZ). Few participants reached Week 60 (n=4) or Week 72 (n=0) in the 1506 study before termination. Analyses focused on VBZ 40mg in two populations: pooled K3/K4 (participants who received VBZ 40mg throughout K3 or K4 or who had a dose reduction [80/40mg] during K3 or K4); and 1506 (participants who received VBZ 40mg from beginning of K3 or K4 to last visit in 1506 or who had a dose reduction [80/40mg] at any time). Outcomes for the K3/K4 population included mean change from baseline (CFB) in Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48 of K3 or K4. Outcomes for the 1506 population included a Clinical Global Impression of Severity-Tardive Dyskinesia (CGIS-TD) score ≤2 (“normal, not at all ill” or “borderline ill”).
In the K3/K4 population, AIMS CFB to Week 48 indicated mean TD improvements in participants who received 40mg continuously (40mg, -5.7 [n=54]) and in those who had a dose reduction to 40mg (80/40mg, -6.2 [n=13]). In addition, a majority of these participants had an AIMS response after 48 weeks of treatment (40mg, 53.7%; 80/40mg, 53.8%). In the 1506 population, the percentage of participants who had a CGIS-TD score ≤2 (rating of “normal, not at all ill” or “borderline ill”) at Week 12 was 63.6% (7/11) in the 40mg group and 30.8% (4/13) in the 80/40mg group. Data from Weeks 24 to 60 of 1506 were limited by the small sample sizes (<10 participants each in 40mg or 80/40mg group at each of these visits).
Based on these analyses and results from published studies, VBZ 40mg may be an effective long-term option for some TD patients. Dose reductions from 80 to 40mg, if necessary, did not appear to compromise long-term benefit.
This study was sponsored by Neurocrine Biosciences, Inc.
Valbenazine (VBZ) is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Post hoc response and shift analyses were conducted using Abnormal Involuntary Movement Scale (AIMS) data from KINECT 4 (NCT02405091), a long-term open-label study in which participants received up to 48 weeks of open-label treatment with once-daily VBZ (40 or 80 mg).
KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score <50); no high risk of active suicidal ideation or behavior. Stable doses of concomitant medications to treat psychiatric and medical disorders were allowed. VBZ dosing was initiated at 40 mg, with escalation to 80 mg at Week 4 based on clinical assessment of TD and tolerability; a dose reduction to 40 mg was allowed if 80 mg was not tolerated. AIMS responses, ranging from ≥10% to 100% improvement from baseline in AIMS total score (sum of items 1-7), were analyzed at Week 48 based on scoring by site investigators. AIMS shift, conducted for each item (representing 7 different body regions), was defined as an improvement from a score ≥3 (moderate/severe) at baseline to a score ≤2 (none/minimal/mild) at Week 48.
103 participants had an available AIMS assessment at Week 48 (40 mg, n=20; 80 mg, n=83 [including 9 with a dose reduction]). At Week 48, 94.2% of participants had ≥30% total AIMS score improvement (40 mg, 90.0%; 80 mg, 95.2%) and 86.4% had ≥50% improvement (40 mg, 90.0%; 80 mg, 85.5%). The percentage of participants meeting the remaining AIMS response thresholds ranged from 9.7% (for 100% response) to 97.1% (for ≥10% response). In participants who had an AIMS item score ≥3 at baseline, shifts to a score ≤2 at Week 48 were as follows: 100% for lips, upper extremities, and lower extremities (VBZ 40 mg and 80 mg). Shift rates for the remaining regions were as follows (40 mg, 80 mg): face (100% [9/9], 96.9% [31/32]), jaw (100% [10/10], 97.6% [40/41]), tongue (100% [11/11], 97.9% [47/48]), trunk (87.5% [7/8], 88.9% [16/18]).
After 48 weeks of treatment with once-daily VBZ (40 or 80 mg), >85% of KINECT 4 participants had a clinically meaningful AIMS response (≥30% total score improvement), a robust AIMS response (≥50% total score improvement), or an AIMS shift (from item score ≥3 at baseline to score ≤2 at Week 48). These results suggest that VBZ is an appropriate long-term treatment for many adults with TD.
This study was sponsored by Neurocrine Biosciences, Inc.
Patients treated with antipsychotics, regardless of psychiatric diagnosis, are at risk for developing tardive dyskinesia (TD), a potentially debilitating drug-induced movement disorder. Valbenazine (INGREZZA; VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat TD in adults. Data from KINECT 4 (NCT02405091) were analyzed to evaluate the long-term effects of VBZ in adults with schizophrenia/schizoaffective disorder (SZD) or mood disorder (MD) and moderate or severe TD.
KINECT 4 included open-label treatment (48weeks) followed by washout (4weeks). Entry requirements included: moderate or severe TD, qualitatively assessed at screening by a blinded, external reviewer; DSM diagnosis of SZD or MD; psychiatric stability (Brief Psychiatric Rating Scale score <50). Stable concomitant psychiatric medications were allowed. Dosing was initiated at 40mg, with escalation to 80mg at Wk4 if participants had a Clinical Global Impression of Change-TD score of ≥3 (minimally improved to very much worse) and tolerated 40mg. A reduction to 40mg was allowed if 80mg was not tolerated (80/40mg); participants unable to tolerate 40mg were discontinued. Safety was the primary focus, but the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) was used to evaluate changes in TD. Mean changes from baseline (BL) in AIMS total score (rated by on-site investigators) were analyzed descriptively. Safety assessments included treatment-emergent adverse events (TEAEs) and psychiatric scales (Positive and Negative Syndrome Scale [PANSS], Calgary Depression Scale for Schizophrenia [CDSS], Montgomery-Åsberg Depression Rating Scale [MADRS], Young Mania Rating Scale [YMRS], and Columbia-Suicide Severity Rating Scale [C SSRS]).
Of 163 participants in the analyses, 103 completed the study. Adverse events (n=26) was the most common reason for discontinuation. Analyses included 119 participants with SZD (40mg=37; 80mg=76; 80/40mg=6) and 44 with MD (40mg=8; 80mg=31; 80/40mg=5). At Wk48, mean improvements from BL in AIMS total score were: SZD (40mg, –10.1; 80mg,–10.7); MD (40mg, 10.2; 80mg: –11.6). AIMS total scores at Wk52 (end of washout) indicated a return toward BL levels. Compared to SZD, the MD subgroup had a higher incidence of any TEAE (84% vs 61% [all doses]) but fewer TEAEs leading to discontinuation (7% vs 18%). Urinary tract infection was the most common TEAE in the MD subgroup (18%); somnolence and headache were most common in the SZD subgroup (7% each). Psychiatric status remained stable from BL to Wk48: SZD (PANSS positive, –0.7, PANSS negative, –0.6; CDSS, –0.7); MD (MADRS, –0.3; YMRS, –0.3). Most participants (95%) had no change in C-SSRS score during the study.
Sustained and clinically meaningful TD improvements were observed with VBZ, regardless of primary psychiatric diagnosis. VBZ was generally well tolerated and no notable changes in psychiatric status were observed.
Funding Acknowledgements: Supported by Neurocrine Biosciences, Inc.