Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years. LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia. Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

Gotfried MH ，Auerbach SH ，Dang-Vu TT ，Mishima K ，Kumar D ，Moline M ，Malhotra M ... -  《-》

Effect of lemborexant on sleep architecture in participants with insomnia disorder and mild obstructive sleep apnea.

Comorbid insomnia with obstructive sleep apnea (COMISA) is associated with worse daytime function and more medical/psychiatric comorbidities vs either condition alone. COMISA may negatively impact sleep duration and reduce rapid eye movement (REM) sleep, thereby impairing cognition. These post-hoc analyses evaluated the effect of lemborexant (LEM), a dual-orexin-receptor antagonist approved for adults with insomnia, on sleep architecture in participants with COMISA. E2006-G000-304 was a phase 3, one-month polysomnography trial in adults aged ≥55 years with insomnia receiving LEM 5 mg (LEM5) or 10 mg (LEM10), placebo (PBO), or zolpidem-tartrate-extended-release 6.25 mg (ZOL). Sleep architecture was determined from 2 nights during placebo run-in (baseline), nights 1 and 2 (NT1/2), and nights 29 and 30 (NT29/30) of treatment. In the Full Analysis Set, 40.8 % (410/1006) had mild obstructive sleep apnea (OSA; apnea-hypopnea-index ≥5 and <15 events/hour of sleep). Mean change from baseline (CFB) in total sleep time (TST) was significantly greater at NT1/2 and NT29/30 with LEM5 and LEM10 vs ZOL (NT1/2, LEM5, P ≥ 0.05; LEM10, P < 0.0001; NT29/30, both P < 0.0001) and PBO (NT1/2 and NT29/30, all P < 0.0001). REM sleep and REM latency CFB were significantly greater (P < 0.0001 and P < 0.01, respectively) for LEM5 and LEM10 vs PBO/ZOL at NT1/2 and NT29/30. LEM significantly increased TST in participants with insomnia and mild OSA. Importantly, REM sleep, associated with cognitive performance, increased. These data support the use of LEM in patients with insomnia and mild OSA. NCT02783729.

Kushida CA ，Zammit GK ，Cheng JY ，Kumar D ，Moline M ... -  《-》

Effect of Lemborexant on Daytime Functioning in Adults With Insomnia: Patient-Reported Outcomes From a Phase 3 Clinical Trial.

Objective: Insomnia and some insomnia treatments can impact an individual's daytime functioning. Here, we performed post hoc analyses of patient-reported outcomes from a phase 3 clinical trial to assess the impact of lemborexant (LEM), a dual orexin receptor antagonist, on daytime functioning. Methods: Adults with insomnia were randomized 1:1:1 to receive placebo, LEM 5 mg (LEM5) or LEM 10 mg (LEM10) for 6 months. Treatment impact on subjects' perceptions of their insomnia symptoms and daytime functioning was assessed by the Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS) questionnaires. Safety assessments included monitoring of treatment emergent adverse events. Results: Compared with placebo, LEM5 and LEM10 treatment significantly improved ISI Total Score (ISI-TS) (LEM5, P < .01; LEM10, P < .0001) and ISI Daytime Functioning Score (ISI-DFS) (LEM5, P < .05; LEM10, P < .01) at 1 month; these improvements were maintained at the end of 6 months (P < .0001 for LEM5 and LEM10, both scores). In separate analyses, baseline ISI-TS or ISI-DFS was used to classify subjects' symptom severity into 1 of 4 categories. At 1 and 6 months, greater proportions of subjects treated with LEM5 and LEM10 shifted to a category associated with less severe symptoms (P < .01 for all comparisons vs placebo). FSS score also improved with LEM treatment vs placebo as assessed at month 3; improvements were maintained at month 6 (P < .05). LEM5 and LEM10 treatment was well tolerated. Conclusion: Improved insomnia symptoms with LEM treatment may translate into improved daytime functioning, suggesting LEM may be appropriate for adults experiencing daytime impairment with their nighttime symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT02952820. Prim Care Companion CNS Disord 2025;27(1):24m03810. Author affiliations are listed at the end of this article.

Chepke C ，Cote KA ，Pinner K ，Yardley J ，Lundwall C ，Moline M ... -  《-》

A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea.

Cheng JY ，Lorch D ，Lowe AD ，Uchimura N ，Hall N ，Shah D ，Moline M ... -  《-》

Efficacy and safety of lemborexant in subjects with insomnia disorder receiving medications for depression or anxiety symptoms.

Individuals with insomnia frequently have comorbid depression or anxiety. This study sought to provide a preliminary indication of the effects of lemborexant (LEM) in subjects treated for mild depression/anxiety symptoms. E2006-G000-303 (NCT02952820; EudraCT 2015-001463-39; SUNRISE-2) was a 12-month, phase 3, randomized, placebo-controlled, double-blind study where subjects with insomnia disorder were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10) for 6 months. During the second 6 months (not reported), placebo-treated subjects were re-randomized to LEM5 or LEM10. In this post hoc analysis, changes from baseline (CFB) in subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Fatigue Severity Scale, and Insomnia Severity Index were evaluated in subjects treated with medications for symptoms of depression/anxiety (subpopulation). Of 949 randomized subjects, 61 treated with medications for symptoms of depression/anxiety were included. In the subpopulation, CFB comparing LEM with placebo were generally smaller than the overall population due to a larger placebo response in the subpopulation. However, the magnitudes of CFB within the active treatment groups for sSOL, sWASO, sTST, and sSE were similar between the subpopulation and the overall population. No new safety signals were observed in the subpopulation. LEM treatment benefited subjects with insomnia treated with medications for depression/anxiety symptoms, with no new safety signals. A greater placebo response in the subpopulation than in the overall population decreased the drug versus placebo effect size for LEM, as has been reported for other insomnia medications.

Krystal A ，Blier P ，Culpepper L ，Nierenberg AA ，Takaesu Y ，Kubota N ，Moline M ，Malhotra M ，Pinner K ，Yardley J ... -  《-》