Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

OFF-times before, during, and after nighttime sleep periods in Parkinson's disease patients with motor fluctuations and the effects of opicapone: A post hoc analysis of diary data from BIPARK-1 and -2.

INTRODUCTION: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg. METHODS: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits. RESULTS: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05). CONCLUSION: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes.

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. METHODS: KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. FINDINGS: KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. INTERPRETATION: In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. FUNDING: Neurocrine Biosciences.

Effects of intranasal dantrolene nanoparticles on brain concentration and behavior in PS19 tau transgenic mice.

Background: Repurposing dantrolene as a potential disease-modifying treatment for Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 months and 9-12 month old C57BL/6J male mice. Mice received a single intranasal dose of ERFR and, after 20 min, blood and brain samples were collected. Dantrolene concentrations in the plasma and brain were analyzed by High Performance Liquid Chromatography. Animal behavior was examined in PS19 tau transgenic mice, with/without acrolein treatment to exacerbate cognitive deficits. Behavioral tests included cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: Dantrolene concentration in the blood and brain decreased with age, though the decrease was greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction or motor function in the PS19 mice compared to controls after chronic ERFR treatment even with acrolein treatment. Conclusion: Our studies suggest that while we did not find PS19 mice to be a reliable Alzheimer animal model to test the therapeutic efficacy of dantrolene, the results suggest a potential for ERFR to be an effective chronic therapy for Alzheimer's disease and that further studies are indicated.

Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.

OBJECTIVES: Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease. METHODS: Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented. RESULTS: Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased. CONCLUSIONS: Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.

Development of a Bayesian inference model for assessing ventilation condition based on CO2 meters in primary schools.

Outdoor fresh air ventilation plays a significant role in reducing airborne transmission of diseases in indoor spaces. School classrooms are considerably challenged during the COVID-19 pandemic because of the increasing need for in-person education, untimely and incompleted vaccinations, high occupancy density, and uncertain ventilation conditions. Many schools started to use CO2 meters to indicate air quality, but how to interpret the data remains unclear. Many uncertainties are also involved, including manual readings, student numbers and schedules, uncertain CO2 generation rates, and variable indoor and ambient conditions. This study proposed a Bayesian inference approach with sensitivity analysis to understand CO2 readings in four primary schools by identifying uncertainties and calibrating key parameters. The outdoor ventilation rate, CO2 generation rate, and occupancy level were identified as the top sensitive parameters for indoor CO2 levels. The occupancy schedule becomes critical when the CO2 data are limited, whereas a 15-min measurement interval could capture dynamic CO2 profiles well even without the occupancy information. Hourly CO2 recording should be avoided because it failed to capture peak values and overestimated the ventilation rates. For the four primary school rooms, the calibrated ventilation rate with a 95% confidence level for fall condition is 1.96±0.31 ACH for Room #1 (165 m3 and 20 occupancies) with mechanical ventilation, and for the rest of the naturally ventilated rooms, it is 0.40±0.08 ACH for Room #2 (236 m3 and 21 occupancies), 0.30±0.04 or 0.79±0.06 ACH depending on occupancy schedules for Room #3 (236 m3 and 19 occupancies), 0.40±0.32,0.48±0.37,0.72±0.39 ACH for Room #4 (231 m3 and 8-9 occupancies) for three consecutive days.

Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self.

BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αß T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αß T cells (CD4

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

BACKGROUND AND OBJECTIVES: To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Regional cost effectiveness analyses for increasing radon protection strategies in housing in Canada.

The incremental cost effectiveness ratios for implementing a recent recommendation to install a more radon resistant foundation barrier were modelled for new and existing housing in 2016, for each province and territory in Canada. Cost-utility analyses were conducted, in which the health benefit of an intervention was quantified in quality-adjusted life years, to help guide policymakers considering increasing investment in radon reduction in housing to reduce the associated lung cancer burden shouldered by the health care system. Lung cancer morbidity was modelled using a lifetable analysis that incorporated lung cancer incidence and survival time for localized, regional, and distant stages of diagnoses for both non-small cell and small cell lung cancer. The model accounted for surgical or advanced lung cancer treatment costs avoided, and average health care costs incurred for radon-attributable lung cancer cases prevented by the intervention. The incremental implementation of radon interventions in the housing stock was modelled over a lifetime horizon, and a discount rate of 1.5% was adopted. This radon intervention in new housing was cost effective in all but one region, ranging from $18,075/QALY (15,704; 20,178) for the Yukon to $58,454/QALY (52,045; 65,795) for British Columbia. A sequential analysis was conducted to compare intervention in existing housing for mitigation thresholds of 200 and 100 Bq/m3. This intervention in existing housing was cost effective at a mitigation threshold of 200 Bq/m3 in regions with higher radon levels, ranging from $33,247/QALY (27,699; 39,377) for the Yukon to $61,960/QALY (46,932; 113,737) for Newfoundland, and more cost effective at a threshold of 200 than 100 Bq/m3. More lung cancer deaths can be prevented by intervention in new housing than in existing housing; it was estimated that the proposed intervention in new housing would prevent a mean of 446 (416; 477) lung cancer cases annually. The cost effectiveness of increased radon resistance in foundation barriers in housing varied widely, and would support adopting this intervention in new housing across Canada and in existing housing in higher radon regions. This study provides further evidence that the most cost effective way of responding to the geographically variable radon burden is by implementing specific regional radon reduction policies.

RADON INFILTRATION BUILDING ENVELOPE TEST SYSTEM: EVALUATION OF BARRIER MATERIALS.

The performance of radon barrier materials currently available for housing foundations was evaluated using a unique radon infiltration building envelope test system that was designed to test radon prevention and mitigation systems using real world construction techniques. The reduction in radon concentration measured across the air barrier in the foundations has been used to evaluate five representative barrier materials installed in the radon infiltration building envelope test facility. The reduction in radon concentration in the mock house varied from 68% for 6 mil polyethylene to 98% for the spray polyurethane foam. The five representative barrier materials were selected after determining the radon diffusion coefficient and the corresponding radon resistance from samples of 14 barrier materials in a radon diffusion testing chamber. The Canadian experience evaluating whether radon barrier materials would satisfy building code requirements was described.

Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk.

Background: Although engaging in physical exercise has been shown to reduce the incidence of cardiovascular events, the molecular mechanisms by which exercise mediates these benefits remain unclear. Based on epidemiological evidence, reductions in traditional risk factors only accounts for 50% of the protective effects of exercise, leaving the remaining mechanisms unexplained. The objective of this study was to determine whether engaging in a regular exercise program in a real world clinical setting mediates cardiovascular protection via modulation of non-traditional risk factors, such as those involved in coagulation, inflammation and metabolic regulation. Methods and Results: We performed a prospective, cohort study in 52 sedentary patients with cardiovascular disease or cardiovascular risk factors at two tertiary medical centers between January 1, 2016 and December 31, 2019. Prior to and at the completion of an 8-week exercise program, we collected information on traditional cardiovascular risk factors, exercise capacity, and physical activity and performed plasma analysis to measure levels of fibrinolytic, inflammatory and metabolic biomarkers to assess changes in non-traditional cardiovascular risk factors. The median weight change, improvement in physical fitness, and change in physical activity for the entire cohort were: -4.6 pounds (IQR: +2 pounds, -11.8 pounds), 0.37 METs (IQR: -0.076 METs, 1.06 METs), and 252.7 kcals/week (IQR: -119, 921.2 kcals/week). In addition to improvement in blood pressure and cholesterol, patients who lost at least 5 pounds, expended at least 1,000 additional kcals/week, and/or achieved ≥0.5 MET increase in fitness had a significant reduction in plasminogen activator inhibitor-1 [9.07 ng/mL (95% CI: 2.78-15.35 ng/mL); P = 0.026], platelet derived growth factor beta [376.077 pg/mL (95% CI: 44.69-707.46 pg/mL); P = 0.026); and angiopoietin-1 [(1104.11 pg/mL (95% CI: 2.92-2205.30 pg/mL); P = 0.049)]. Conclusion: Modest improvements in physical fitness, physical activity, and/or weight loss through a short-term exercise program was associated with decreased plasma levels of plasminogen activator inhibitor, platelet derived growth factor beta, and angiopoietin, which have been associated with impaired fibrinolysis and inflammation.

Single-Cell Transcriptional Profiling Reveals Sex and Age Diversity of Gene Expression in Mouse Endothelial Cells.

Although it is well-known that sex and age are important factors regulating endothelial cell (EC) function, the impact of sex and age on the gene expression of ECs has not been systematically analyzed at the single cell level. In this study, we performed an integrated characterization of the EC transcriptome of five major organs (e.g., fat, heart-aorta, lung, limb muscle, and kidney) isolated from male and female C57BL/6 mice at 3 and 18 months of age. A total of 590 and 252 differentially expressed genes (DEGS) were identified between females and males in the 3- and 18-month subgroups, respectively. Within the younger and older group, there were 177 vs. 178 DEGS in fat, 305 vs. 469 DEGS in heart/aorta, 22 vs. 37 DEGS in kidney, 26 vs. 439 DEGS in limb muscle, and 880 vs. 274 DEGS in lung. Interestingly, LARS2, a mitochondrial leucyl tRNA synthase, involved in the translation of mitochondrially encoded genes was differentially expressed in all organs in males compared to females in the 3-month group while S100a8 and S100a9, which are calcium binding proteins that are increased in inflammatory and autoimmune states, were upregulated in all organs in males at 18 months. Importantly, findings from RNAseq were confirmed by qPCR and Western blot. Gene enrichment analysis found genes enriched in protein targeting, catabolism, mitochondrial electron transport, IL 1- and IL 2- signaling, and Wnt signaling in males vs. angiogenesis and chemotaxis in females at 3 months. In contrast, ECs from males and females at 18-months had up-regulation in similar pathways involved in inflammation and apoptosis. Taken together, our findings suggest that gene expression is largely similar between males and females in both age groups. Compared to younger mice, however, older mice have increased expression of genes involved in inflammation in endothelial cells, which may contribute to the development of chronic, non-communicable diseases like atherosclerosis, hypertension, and Alzheimer's disease with age.

A long-term, open-label study of valbenazine for tardive dyskinesia.

BACKGROUND: Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine. METHODS: Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs). RESULTS: At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4). CONCLUSIONS: Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

Abnormal involuntary movement scale in tardive dyskinesia: Minimal clinically important difference.

BACKGROUND: A minimal clinically important difference has not been established for the Abnormal Involuntary Movement Scale in patients with tardive dyskinesia. Valbenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Efficacy in randomized, double-blind, placebo-controlled trials was defined as the change from baseline in Abnormal Involuntary Movement Scale total score (sum of items 1-7). OBJECTIVES: To estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor-based method. METHODS: Data were pooled from three 6-week double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Valbenazine doses were pooled for analyses as follows: "low dose," which includes 40 or 50 mg/day; and "high dose," which includes 75 or 80 mg/day. Mean changes from baseline in Abnormal Involuntary Movement Scale total score were analyzed in all participants (valbenazine- and placebo-treated) with a Clinical Global Impression of Change-Tardive Dyskinesia or Patient Global Impression of Change score of 1 (very much improved) to 3 (minimally improved). RESULTS: The least squares mean improvement from baseline to week 6 in Abnormal Involuntary Movement Scale total score was significantly greater with valbenazine (low dose: -2.4; high dose: -3.2; both, P < 0.001) versus placebo (-0.7). An minimal clinically important difference of 2 points was estimated based on least squares mean changes in Abnormal Involuntary Movement Scale total score in participants with a Clinical Global Impression of Change-Tardive Dyskinesia score ≤3 at week 6 (mean change: -2.2; median change: -2) or Patient Global Impression of Change score ≤3 at week 6 (mean change: -2.0; median change: -2). CONCLUSIONS: Results from an anchor-based method indicate that a 2-point decrease in Abnormal Involuntary Movement Scale total score may be considered clinically important. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cardiovascular Profile of Valbenazine: Analysis of Pooled Data from Three Randomized, Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. OBJECTIVE: Using data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication. METHODS: Data were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters. RESULTS: The pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, - 1.8 mmHg), diastolic blood pressure (- 0.1, - 1.6, - 1.2 mmHg), heart rate (- 1.7, - 2.2, - 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment. CONCLUSIONS: Results from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.

Characterizing Treatment Effects of Valbenazine for Tardive Dyskinesia: Additional Results From the KINECT 3 Study.

BACKGROUND: In the KINECT 3 (NCT02274558; October 2014 to September 2015) study, valbenazine efficacy in tardive dyskinesia (TD) was demonstrated based on mean changes from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). Data from this study were analyzed further to provide a more clinically meaningful interpretation of the primary AIMS results. METHODS: The study included adults who had a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or any mood disorder and also met DSM-IV criteria for neuroleptic-induced TD. Study participants received 6 weeks of double-blind treatment with valbenazine (40 or 80 mg/d) or placebo. Post hoc AIMS analyses, based on available data, included Cohen d effect sizes, response analyses with odds ratios (ORs) and numbers needed to treat (NNTs), and shift analyses. RESULTS: At week 6 (N = 202), medium-to-high effect sizes were found for mean improvements in AIMS total score (40 mg/d, d = 0.52; 80 mg/d, d = 0.89). For AIMS total score responses of ≥ 10% to ≥ 70% improvement from baseline, statistical significance was found for valbenazine 80 mg/d versus placebo (P ≤ .01), with ORs (range, 3.0-10.3) and NNTs (range, 3-9) indicating clinical relevance. For response per AIMS item (score ≤ 1 at week 6), significant differences between valbenazine (both doses or 80 mg/d) and placebo were found in the lips, jaw, tongue, and upper extremities. In participants who had an AIMS item score ≥ 1 at baseline, the percentage with a ≥ 1-point improvement at week 6 (shift) was significantly higher with valbenazine (40 and/or 80 mg/d) versus placebo in all 7 body regions. CONCLUSIONS: Consistent with primary published results for KINECT 3, these supplemental analyses indicate that participants treated with valbenazine (40 or 80 mg/d) had statistically significant and clinically relevant improvements in TD severity both overall and in specific body regions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02274558.

The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study.

BACKGROUND: Valbenazine, a highly selective vesicular monoamine transporter 2 inhibitor, is approved for the treatment of tardive dyskinesia. This is the first report of long-term effects in adults with tardive dyskinesia. METHODS: Participants with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder who completed the 6-week, double-blind, placebo-controlled period of KINECT 3 were eligible to enter the 42-week valbenazine extension (VE) period and subsequent 4-week washout period. The extension phase was conducted from December 16, 2014, to August 3, 2016. Participants who received placebo and entered the VE period were re-randomized 1:1 to valbenazine 80 or 40 mg while others continued valbenazine at the KINECT 3 dose. Safety assessments included treatment-emergent adverse events (TEAEs) and scales for suicidal ideation/behavior, treatment-emergent akathisia or parkinsonism, and psychiatric symptoms. Efficacy assessments included the Abnormal Involuntary Movement Scale (AIMS) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD). RESULTS: 198 participants entered the VE period, 124 (62.6%) completed treatment (week 48), and 121 (61.1%) completed the follow-up visit after washout (week 52). During the VE period, 69.2% of participants had ≥ 1 TEAE, 14.6% had a serious TEAE, and 15.7% discontinued due to a TEAE. During washout, 13.1% of participants experienced a TEAE. No apparent risk for suicidal ideation or behavior was found. Long-term valbenazine treatment did not appear to induce or worsen akathisia or parkinsonism. Participants generally remained psychiatrically stable during the study. AIMS and CGI-TD measures indicated sustained tardive dyskinesia improvement, with scores returning toward baseline after 4 weeks of valbenazine washout. CONCLUSIONS: The long-term safety and tolerability of valbenazine were generally favorable, and maintenance of treatment effect was apparent with both doses during this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02274558.