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Background: TV46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone approved for the treatment of schizophrenia in adults. Methods: The RISE study (NCT03503318) compared TV-46000 once monthly (q1m) and once every 2 months (q2m) with placebo (1:1:1) in patients with schizophrenia who underwent stabilization on oral risperidone. The SHINE study (NCT03893825) evaluated the long-term safety, tolerability, and effectiveness of TV-46000 in patients who completed RISE without relapse (rollover; placebo rollover randomized [1:1] to q1m or q2m; TV-46000 rollover continued assigned treatment) or who were newly recruited (de novo; randomized [1:1] to q1m or q2m after oral stabilization). Patient-centered outcomes included the Schizophrenia Quality of Life Scale (SQLS), the 5-Level EuroQoL 5-Dimensions Questionnaire (EQ-5D-5L), the Personal and Social Performance Scale (PSP), and the Drug Attitudes Inventory 10-item version (DAI-10). Results: In RISE, SQLS least-squares mean changes (SE) improved to last assessment (LA) for TV-46000 q1m (– 4.15 [1.03]) and q2m (– 3.28 [1.06]) but worsened for placebo (1.75 [1.07]; P< 0.001 for both). PSP, EQ5D-5L, and DAI-10 showed similar trends. In SHINE, SQLS decreased (improved) at LA for both TV-46000 q1m (− 0.43 [0.98]) and q2m (− 2.16 [0.98]); reductions were observed in the de novo (q2m only) and placebo rollover (q1m and q2m) cohorts, but not for the TV46000 rollover cohort. Results for PSP, EQ5D-5L, and DAI-10 were consistent with those reported in the RISE study. Conclusion: Improvements in patient-centered outcomes were observed across cohorts, with the largest improvements observed for patients who began TV-46000 during SHINE (ie, de novo and placebo rollover cohorts), while gains made during RISE were minimally improved or maintained in the TV-46000 rollover cohort, indicating the benefit of uninterrupted TV-46000 treatment. These data support the effectiveness of TV-46000 to improve patient-centered outcomes in patients with schizophrenia. Plain Language Summary: RISE and SHINE were clinical studies where patients with schizophrenia received TV-46000. TV-46000 is injected under the skin once monthly or once every 2 months to treat schizophrenia in adults. In RISE, patients took pills for the first 3 months, and then received injections under the skin. Some patients received inactive (placebo) injections. Comparing results among groups showed the effectiveness and side effects of TV-46000. Patients who completed RISE could continue into SHINE. SHINE included patients who had not been part of RISE as well. All patients received TV-46000 in SHINE to see if results were the same long term. This report summarizes the results of patient-centered outcomes. These included measures of quality of life and attitudes toward the medicine. In RISE, quality of life and attitudes toward the medicine improved with TV-46000, but worsened with placebo. In SHINE, the patient-centered outcomes also improved. The largest improvements were for patients who began taking TV-46000 during SHINE. This analysis showed that there is a benefit in taking TV-46000 for longer times without breaks. It also showed that TV-46000 improves quality of life and attitudes toward the medicine. [ABSTRACT FROM AUTHOR]

Introduction: In RISE, TV46000 once monthly (q1m) or once every 2 months (q2m) significantly extended time to impending schizophrenia relapse. The current study (SHINE, NCT03893825) evaluated the long-term safety, tolerability, and effect of TV46000. Methods: Patients completing RISE without relapse (rollover) or newly recruited (de novo) were eligible. The de novo and placebo rollover cohorts were randomized 1:1 to q1m or q2m for ≤56 weeks; the TV46000 rollover cohort continued assigned regimen. Exploratory efficacy endpoints included time to impending relapse and patient centered outcomes (PCOs) including Schizophrenia Quality of Life Scale (SQLS). Results: 334 patients were randomized and received TV46000 q1m (n=172) or q2m (n=162), for 202.3 patient-years [PY] of TV-46000 treatment. Treatment-emergent adverse events (AEs) reported for ≥5% of patients were: overall–injection site pain (event rate/100 PY, n [%]; 23.23, 16 [5%]); de novo (n=109)–injection site pain (56.10, 11 [10%]), injection site nodule (16.03, 6 [6%]), blood creatine phosphokinase increased (16.03, 8 [7%]), urinary tract infection (10.69, 7 [6%]); placebo rollover (n=53)–tremor (18.50, 5 [9%]); TV46000 rollover (n=172)–headache (7.97, n=8 [5%]). Serious AEs reported for ≥2 patients were worsening schizophrenia and hyperglycemia. Kaplan– Meier estimates for remaining relapse-free at week 56 were 0.98 (2% risk; q1m) and 0.88 (12%; q2m). SQLS improved for q1m (least-squares mean change [SE], − 2.16 [0.98]) and q2m (− 0.43 [0.98]); other PCOs (5Level EuroQoL 5Dimensions Questionnaire, Personal and Social Performance Scale, Drug Attitudes Inventory 10-item version) remained stable. Conclusions: TV-46000 had a favorable long-term benefit–risk profile in patients with schizophrenia. Funding: Teva Branded Pharmaceutical Products R&D Inc. Study Registration Number: NCT03893825 [ABSTRACT FROM AUTHOR]

As of March 2018, rasagiline is approved for the treatment of Parkinson disease in 55 countries including Japan. The present study evaluated the pharmacokinetics (PK) and safety of rasagiline in healthy Japanese and Caucasian subjects following single and multiple administrations of three rasagiline doses. In this double‐blind, placebo‐controlled study, 64 healthy subjects (32 Japanese and 32 Caucasian) received either rasagiline (0.5, 1.0, or 2.0 mg) or placebo for 10 days with PK sampling for single‐dose administration on day 1 and for multiple administration on day 10. Regardless of administration schedule, rasagiline plasma concentrations and dose‐related increases in exposure parameters were similar between Japanese and Caucasians. Rasagiline accumulation (2‐fold for 0.5 mg and 3‐fold for 1.0 mg and 2.0 mg doses) following multiple administration was similar across the ethnic groups. Geometric mean ratios (GMR) comparing Japanese to Caucasians for AUC0‐24, Cmax and AUCinf following single administration were 1.38, 1.17 and 1.38 for 0.5 mg; 1.22, 1.20 and 1.22 at 1.0 mg; and 1.02, 1.00 and 1.02 at for 2.0 mg. GMR for AUCtau and Cmax,ss following multiple administration were 1.43 and 1.06 at 0.5 mg, 1.06 and 1.00 at 1.0 mg, and 1.09 and 1.07 at 2.0 mg. Safety measures were unremarkable and similar between Caucasian and Japanese subjects. Comparable systemic exposure and safety parameters were demonstrated for rasagiline administered to healthy Japanese and Caucasian subjects. [ABSTRACT FROM AUTHOR]

In this randomized double‐blind study, 4 groups of healthy subjects (50 per arm) participated to evaluate the effect of laquinimod, an oral treatment in development for multiple sclerosis and Huntington disease, on the QTc interval. Subjects received a dose of either 0.6 or 1.2 mg/day laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a dose of 400 mg moxifloxacin on day 14. Continuous 12‐lead electrocardiograms were recorded on day –1 (baseline) and days 14 to 17,  and quadruplicate electrocardiograms were extracted at predefined time points. The primary measure was time‐matched change from baseline in individual QTc (QTcI), and an analysis of variance was conducted on the placebo‐corrected change from baseline data (ddQTcI). Pharmacokinetic‐pharmacodynamic and safety assessments were included. Results showed that the upper limits of the 2‐sided 90%CI for ddQTcI for both laquinimod doses were below 10 millisconds at all time points, whereas lower limits for moxifloxacin were above 5 milliseconds. No notable changes in ECG parameters were observed. Pharmacokinetic/pharmacodynamic analysis showed no positive correlation between laquinimod plasma levels and QTcI. In conclusion, laquinimod was not found to affect cardiac repolarization or to cause prolongation of QTcI at doses of 0.6 and 1.2 mg/day. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that D-xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myotubes in vitro. Due to the unfavorable pharmacokinetic properties of D-xylose we aimed at synthesizing active derivatives with improved parameters. Quantitative structure-activity relationship analysis identified critical hydroxyl groups in D-xylose. These data were used to synthesize various hydrophobic derivatives of D-xylose of which compound 19 the was most potent compound in stimulating the rate of hexose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of myotubes. This effect resulted from the activation of AMP-activated protein kinase without recruiting the insulin transduction mechanism. These results show that lipophilic D-xylose derivatives may serve as prototype molecules for the development of novel antihyperglycemic drugs for the treatment of diabetes.