Naohisa Uchimura’s research while affiliated with Kurume University and other places

Background Effective alternative therapies are needed to improve outcomes in the treatment of insomnia disorder due to concerns regarding the risks of tolerance, dependence, falls and withdrawal syndrome with the use of pharmacological treatments such as benzodiazepine-receptor agonists (BZRA). Lemborexant (LEM), a competitive dual orexin-receptor antagonist approved in Japan and other countries to treat adults with insomnia, has shown superior therapeutic efficacy to zolpidem extended-release 6.25 mg in a phase 3 clinical trial; therefore, LEM may be a potential alternative candidate. Aims & Objectives To evaluate whether the approach of a direct transition to LEM either from a Z-drug (zolpidem, zopiclone, or eszopiclone) or suvorexant (SUV) monotherapy or from SUV or BZRA and ramelteon (RMT) combination therapy can be supported for patients with insomnia. Methods A prospective, nonrandomized, open-label, multicenter study conducted in Japan with 90 subjects with chronic insomnia dissatisfied with current treatment was designed to investigate whether direct transition to LEM improved patient satisfaction. The study was comprised of four cohorts: (1) nonbenzodiazepine sedative-hypnotic (Z-drug) monotherapy, (2) orexin receptor antagonist (SUV) monotherapy, (3) SUV plus BZRA combination therapy, and (4) melatonin receptor agonist (RMT) plus BZRA combination therapy. The primary outcomes were continuation of treatment after 2 weeks (end of titration phase) and 14 weeks (titration phase and maintenance phase), as well as responses on the Patient Global Impression – Insomnia version (PGI-I) and Insomnia Severity Index (ISI) scales. Subjects in the BZRA combination therapy groups could attempt, but were not required, to decrease BZRA use during the maintenance phase. This study was approved by the Certified Clinical Research Review Board, and informed consent was obtained. Results In all, 95.6% (n=86/90) successfully transitioned to LEM after 2 weeks, and LEM continuation rates were 97.8% (n=88/90) at the completion of the titration phase and 82.2% (n=74/90) at the completion of the maintenance phases. At 14 weeks, dose reduction and interruption of BZRA occurred in 12.5% (n=4/32) of the combined cohort. In the entire cohort, PGI-I scores showed a greater percentage of positive responses than negative responses. ISI total scores also improved over time after the transition to LEM. The overall incidence of adverse events was 47.8% (n=43/90) and none were serious. Discussion & Conclusion These findings suggest that direct transition to LEM is a valid treatment option for insomnia in patients who are dissatisfied with their current treatment. Support Eisai, Ltd.

Background While switching of medications for insomnia occurs frequently in clinical practice, few clinical studies have examined the impact of transitioning patients between different insomnia medications, especially between different classes of drugs (eg, GABA-ergic agonists versus dual-orexin- receptor-antagonists [DORA]). Lemborexant (LEM) is a DORA approved in the United States and Japan with the same dosing instructions to treat adults with insomnia. Two studies (United States: E2006- A001-312, Study 312, NCT04009577; Japan: E2006-M081-401, Study 401, NCT04742699) evaluated the success rate of transitioning to LEM in subjects with insomnia who were dissatisfied with their previous insomnia medications in terms of efficacy or tolerability. In Japan, the focus was particularly on those who wished to switch from all or some of their previous insomnia medications to LEM. Aims & Objectives Evaluate the success rate of direct transitioning from non-benzodiazepine GABA- ergic agonist Z-drugs to LEM in subjects with insomnia who were dissatisfied with their current treatment in terms of effectiveness and/or tolerability. Methods Both studies employed an open-label design that examined prespecified dosing paradigms for directly transitioning subjects from a Z-drug to LEM without a down-titration of the Z-drug. Study 312 included a 3-week Screening Period (subjects continued zolpidem [ZOL]), 2-week Titration Period (TITR), 12-week Extension Period (EXT; not reported here), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3-4 nights/week) or frequent (at least 5 nights/week) ZOL users were assigned to 1 of 2 cohorts. Cohort 1: Intermittent ZOL users and subjects with 1 week each of intermittent and frequent ZOL usage began TITR with LEM 5 mg (LEM5). Cohort 2: Frequent ZOL users were randomized 1:1 to LEM5 or LEM 10 mg (LEM10). Subjects who successfully transitioned (elected to continue LEM in EXT or to discontinue for reasons other than AE or lack of efficacy) to LEM had the option to enter the EXT. Study 401 was of similar design, with the exception of a 2-week Screening Period during which subjects continued their current Z-drug (ZOL, zopiclone, or eszopiclone); all subjects started with LEM5. The primary endpoint in both studies was the proportion of subjects who successfully transitioned to LEM at the end of TITR. Routine safety evaluations were conducted. Results In Study 312, the Full Analysis Set comprised 53 subjects (Cohort 1, n=10; Cohort 2, n=43). Following 2 weeks of LEM treatment, the majority of subjects (overall, n=43/53; 81.1%) transitioned from ZOL to LEM, regardless of prior intermittent or frequent use of ZOL determined during the Screening Period. In Study 401, 25 subjects were taking Z-drugs (n=6 ZOL, n=1 zopiclone, n=18 eszopiclone) during TITR. The proportion of subjects with successful LEM treatment in the Z-drug group was 92.0% (n=23/25). No new safety signals emerged during transitioning, and the safety profile was similar to pivotal trials. Discussion & Conclusion Results from both studies indicate that adults can successfully transition directly from a Z-drug to LEM. LEM was generally well tolerated. Support Eisai Inc; Eisai Co., Ltd.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without changing the saturation of percutaneous oxygen. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptive area of respiration (the postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores.

Introduction: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. Methods: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). Results: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. Conclusions: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. Trial registration: ClinicalTrials.gov identifier, NCT04742699.