A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia.

AIMS: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694). METHODS: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia. RESULTS: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia. CONCLUSION: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.

Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease.

OBJECTIVE: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements. METHODS: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1 second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years. RESULTS: No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1andA2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS. CONCLUSIONS: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects.

This open-label, single-sequence study in healthy subjects investigated the effects of steady-state carbamazepine on the pharmacokinetic (PK) profile of a single 2-mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up-titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady-state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod-P. Models linking fingolimod-P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.

Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial.

INTRODUCTION: AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability. RESULTS: Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile. CONCLUSIONS: Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

Cardiac Effects of Siponimod (BAF312) Re-initiation After Variable Periods of Drug Discontinuation in Healthy Subjects.

PURPOSE: The goal of this study was to investigate the effect of siponimod treatment re-initiation on the initial negative chronotropic effects and cardiac rhythm after variable drug discontinuation periods. METHODS: This partially double-blind, randomized, placebo-controlled study was conducted in healthy subjects. Siponimod doses (0.5-4.0 mg) and placebo were evaluated in combination with drug discontinuation periods ranging from 48 to 192 hours. Twelve-lead Holter ECGs were performed from 1.5 hours before until 24 hours after single-dose re-initiation. Atrioventricular blocks (AVBs) and sinus pauses (RR >2 seconds) were categorized according to dose level, discontinuation period, and resting and nonresting hours. FINDINGS: Of the enrolled 138 subjects, 117 were evaluated. Demographic and baseline characteristics were comparable between the treatment groups. Subjects rechallenged at the combination of 4 mg/192 hours (highest investigated dose and longest discontinuation period [7 missed doses]) exhibited the highest decrease in pooled, placebo-adjusted heart rate (HR) of 14.53 beats/min. The magnitude of the negative chronotropic effect of siponimod re-initiation was dependent on both dose and duration of treatment discontinuation. Regardless of the dose, the placebo-adjusted HR reduction at re-initiation of drug treatment after up to 96 hours of drug discontinuation remained <10 beats/min. Except for 1 outlier for HR decrease under the 96-hour/placebo combination, no outliers were observed for any combination up to and including the 96-hour discontinuation periods. Most of the AVBs and sinus pauses were observed during nocturnal hours concurrent with increased vagal tone. All detected AVBs and sinus pauses were asymptomatic and not considered clinically relevant. IMPLICATIONS: Siponimod could be safely re-initiated without retitration after drug discontinuation periods up to 96 hours. Retitration is required if patients miss ≥ 4 consecutive doses.