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Introduction Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Compared to younger patients, older patients have a higher risk of TD and may develop symptoms earlier during antipsychotic treatment. Valbenazine, a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved to treat TD in adults of all ages, with no dose adjustment required for older patients. The long-term effects of valbenazine on TD were evaluated in KINECT 4 (NCT02405091), an open-label study in which participants received up to 48 weeks of once-daily treatment with valbenazine. Abnormal Involuntary Movement Scale (AIMS) data from this study were analyzed post hoc to evaluate treatment responses in older (≥55 to 85 years) and younger (18 to Methods 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 Results Of 163 participants in the safety/efficacy population, 103 (63.2%) had an available AIMS assessment at Week 48. At Week 48, the percentages of patients who met the criteria for minimal response (≥10% AIMS total score improvement from baseline) or clinically meaningful (≥30% improvement) response were similar between the older and younger subgroups (≥55 years; Conclusions After 48 weeks of treatment with once-daily valbenazine, >95% of all KINECT 4 participants (older and younger) had a minimal AIMS total score response (≥10% improvement), >90% had a clinically meaningful response (≥30% improvement), and >80% had a robust response (≥50% improvement). Older patients seemed more likely than younger patients to achieve a maximal response, including 100% improvement, although these results may be limited by smaller sample sizes. Shift analyses based on AIMS item scores were supportive of AIMS total score responses. Together, the results presented in this post hoc analysis suggest that valbenazine is an appropriate long-term treatment for both older and younger adults with TD. This research was funded by: This study was sponsored by Neurocrine Biosciences, Inc.

Introduction Older adults have an increased risk of developing tardive dyskinesia (TD), a persistent and often debilitating movement disorder that is associated with antipsychotic treatment. Valbenazine is currently approved to treat TD in adults of all ages, with no dose adjustment required for older patients. Valbenazine has been evaluated in 2 long-term Phase III studies (KINECT 3, KINECT 4) in which adults with TD (18 to 85 years) received once-daily treatment (40 or 80 mg) for up to 48 weeks. Completers from these studies were eligible to enter a long-term, open-label rollover study (NCT02736955) in which global improvements and patient satisfaction were assessed. Data from the rollover study were analyzed post hoc to further investigate the long-term effects of valbenazine in participants categorized by age ( Methods Completers from KINECT 3 or KINECT 4 were re-initiated at 40 mg following washout of prior valbenazine treatment. Dose was escalated after 4 weeks to 80 mg based on tolerability and clinical assessment of TD. Reduction to 40 mg was allowed if 80 mg was not tolerated; participants unable to tolerate 40 mg were discontinued from the study. The study was designed to include 72 weeks of treatment, but few participants reach Week 60 and none reach Week 72 because valbenazine became commercially available. Both doses of valbenazine (40 and 80 mg) were pooled. Analyses were conducted at Week 48 and end-of-treatment (EOT), based on the last available post-baseline value. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD: range, 1 [normal/not at all ill] to 7 [extremely ill]) and Patient Satisfaction Questionnaire (PSQ: range, 1 [very satisfied] to 5 [very dissatisfied]). All outcomes were analyzed descriptively in age subgroups (younger, Results The study included 51 younger participants (mean age, 47.9 years; range, 34-54 years) and 109 older participants (mean age, 62.5 years; range, 55-83 years). A total of 56 participants reached the Week 48 visit ( Conclusions A clinician-based global assessment indicated ongoing, meaningful TD improvements with once-daily valbenazine in both younger and older adults. Patient satisfaction rates remained high, even in patients treated for >1 year. These results, along with the safety results presented separately at this meeting, indicate that valbenazine is an effective long-term treatment for TD. This research was funded by This research was fully funded by Neurocrine Biosciences, Inc.

The effect of 5-amino-4-imidazole-carboximide (AI-CA)-riboside on different pathways of purine metabolism (biosynthesis de novo, salvage pathways, adenosine metabolism, ATP catabolism) was studied in human B lymphoblasts (WI-L2). AICA-Riboside markedly decreased intracellular levels of 5-phosphoribosyl-1-pyrophosphate and in consequence affected purine biosynthesis de novo and purine salvage pathways. AICA-riboside inhibited incorporation of glycine into purine nucleotides, but when formate was used as the precursor of purine biosynthesis de novo, a biphasic effect was observed. The incorporation of formate into purine nucleotides was increased by AICA-riboside at concentrations up to 2 mM but decreased at higher concentrations. Salvage of the purine bases adenine, hypoxanthine, and guanine was markedly inhibited and utilization of extracellular adenosine in B lymphoblasts was reduced by AICA-riboside. AICA-riboside increased ribose 1-phosphate concentrations and increased degradation of prelabeled ATP. No effect on the intracellular levels of orthophosphate was found. Proliferation of WI-L2 lymphoblasts was only slightly affected at concentrations of AICA-riboside below 500 microM but markedly inhibited by higher concentrations.

Intracellular adenosine formation and release to extracellular space was studied in WI-L2-B and SupT1-T lymphoblasts under conditions which induce or do not induce ATP catabolism. Under induced conditions, B lymphoblasts but not T lymphoblasts, release significant amounts of adenosine, which are markedly elevated by adenosine deaminase inhibitors. In T lymphoblasts, under induced conditions, only simultaneous inhibition of both adenosine deaminase activity and adenosine kinase activities resulted in small amounts of adenosine release. Under noninduced conditions, neither B nor T lymphoblasts release adenosine, even in the presence of both adenosine deaminase or adenosine kinase inhibitors. Comparison of B and T cell's enzyme activities involved in adenosine metabolism showed similar activity of AMP deaminase, but the activities of AMP-5'-nucleotidase, adenosine kinase and adenosine deaminase differ significantly. B lymphoblasts release adenosine because of their combination of enzyme activities which produce or utilize adenosine (high AMP-5'-nucleotidase and relatively low adenosine kinase and adenosine deaminase activities). Accelerated ATP degradation in B lymphoblasts proceeds not only via AMP deamination, but also via AMP dephosphorylation into adenosine but its less efficient intracellular utilization results in the release of adenosine from these cells. In contrast, T lymphoblasts release far less adenosine, because they contain relatively low AMP-5'-nucleotidase and high adenosine kinase and adenosine deaminase activities. In T lymphoblasts, AMP formed during ATP degradation is not readily dephosphorylated to adenosine but mainly deaminated to IMP by AMP deaminase. Any adenosine formed intracellularly in T lymphoblasts is likely to be efficiently salvaged back to AMP by an active adenosine kinase. In general, these results may suggest that adenosine can be produced only by selective cells (adenosine producers) whereas other cells with enzyme combination similar to SupT1-T lymphoblasts can not produce significant amounts of adenosine even in stress conditions.