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.

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.

Abstract Aim 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. Methods 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). Results 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. Conclusion 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.

Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5 mg (LEM5) and 10 mg (LEM10) in the subgroup age ≥ 65 years with insomnia. Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18 years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression–Insomnia [PGI-I] questionnaire), and safety were also evaluated. In this subgroup of older adults (≥ 65 years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65 years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016). Insomnia is a common sleep disorder associated with significant difficulties, particularly in older adults. Although there are many drug treatments available, some are associated with the important risk of side effects and may not adequately treat sleep maintenance (ability to stay asleep), which is a frequent sleep complaint in older people. Lemborexant has been approved in multiple countries for the treatment of adults with insomnia based on studies that show lemborexant improved adults’ ability to fall asleep and stay asleep and is well tolerated. To examine the long-term benefit of lemborexant, we investigated subject-reported benefits and safety of lemborexant in older (≥ 65 years) adults who participated in a 1-year study. The results showed that within the first few days of taking lemborexant, and lasting through 12 months of treatment, nightly lemborexant improved nighttime sleep (that is, it reduced the time it took to fall asleep, reduced the time awake during the night, and increased total sleep time) more than placebo. Morning alertness improved more in older adults who took lemborexant compared with placebo. In addition, those who took lemborexant also reported that their insomnia symptoms were less severe and they had less fatigue compared with placebo. Lemborexant was well tolerated in older adults. These results suggest that lemborexant may be a good option for older adults with insomnia disorder.

Abstract Discontinuing long‐term pharmacotherapy for insomnia can result in rebound insomnia or withdrawal symptoms and suboptimal treatment. Post hoc analyses evaluated rebound insomnia and withdrawal symptoms among the subset of subjects from a phase III, 12‐month, global, multicenter, randomized, double‐blind, parallel‐group study who completed 12 or 6 months of active treatment and follow‐up period. Study E2006‐G000‐303 (Study 303) included adults (N = 655) with subjective sleep‐onset latency ≥30 min and/or subjective wake‐after‐sleep onset ≥60 min at least three times weekly during the 4 weeks before enrollment. Subjects were randomized 1:1:1 to lemborexant 5 mg (LEM5) or 10 mg (LEM10) or placebo for 6 months. Thereafter, for an additional 6 months, LEM5‐ and LEM10‐treated subjects continued lemborexant and the placebo group was rerandomized 1:1 to LEM5 or LEM10. Month 12 was followed by abrupt discontinuation and a 2‐week end‐of‐study follow‐up. Using daily electronic sleep diaries, patients reported (subjective) sleep end points (sleep‐onset latency, wake‐after‐sleep onset, sleep efficiency, and total sleep time). Withdrawal symptoms were assessed using the Tyrer Benzodiazepine Withdrawal Symptoms Questionnaire (T‐BWSQ). Sleep outcome improvements with lemborexant at month 12 were generally maintained throughout the 2‐week off‐treatment period wherein <20% of subjects experienced significant worsening of insomnia symptoms versus screening. There was no evidence of withdrawal symptoms by T‐BWSQ following lemborexant discontinuation. This analysis demonstrates rebound insomnia is unlikely to occur with lemborexant, and its effectiveness is maintained after abrupt discontinuation without placebo replacement following 6–12 months of treatment.

What is this summary about? This is a summary of an article originally published in the journal Postgraduate Medicine. Lemborexant is a type of medication called a dual orexin receptor antagonist (often abbreviated to DORA) that is approved for treating people with insomnia, a sleep disorder in which people have trouble falling asleep, staying asleep or both. Two studies, one called SUNRISE-1 (Study 304), which lasted one month, and SUNRISE-2 (Study 303), which lasted 12 months, looked at the effects of lemborexant on sleep compared to placebo in people with insomnia. People with insomnia often experience fatigue (or tiredness) during the daytime, which affects their daily lives and health, and often have other conditions which can also cause fatigue. This summary reports an analysis that looked at whether lemborexant improves fatigue during the daytime as well as nighttime symptoms of insomnia in all participants and in participants with clinically significant fatigue before treatment. What were the results? In both studies, participants completed a questionnaire, called the Fatigue Severity Scale, that measured how significant their fatigue was. The researchers looked at the change in fatigue over time in participants treated with lemborexant compared with those given placebo. They also looked at the change in a group of participants who reported clinically important levels of fatigue at the beginning of the study. People in these studies also completed diaries about how long it took them to fall asleep and how long they slept. The researchers compared improvements in fatigue with changes in how participants slept over time. Overall, lemborexant reduced daytime fatigue compared with placebo in all study participants. It also reduced daytime fatigue in the smaller group of participants who had clinically significant fatigue at the beginning of the study. The reductions in fatigue seen with lemborexant remained during 1 year of treatment. There was also a relationship between reduced fatigue, falling asleep faster and not waking up as much. What do the results mean? Researchers concluded that in addition to improving sleep in people with insomnia, lemborexant can reduce daytime fatigue.

ObjectiveInsomnia is common in midlife women. The efficacy and safety of lemborexant (LEM), a competitive dual orexin receptor antagonist, was assessed for 12 months in a subgroup of midlife women (age, 40-58 y) from Study E2006-G000-303 (Study 303; SUNRISE-2).MethodsThis was a randomized, double-blind, placebo (PBO)-controlled (first 6 mo) study of adults with insomnia disorder (N = 949). During treatment period 1 (TP1), participants received PBO or LEM 5 mg (LEM5) or 10 mg (LEM10). During TP2 (second 6 mo), LEM participants continued their assigned dose; PBO participants were rerandomized to LEM5 or LEM10. Assessments included patient-reported sleep- and fatigue-related measures and treatment-emergent adverse events.ResultsThe midlife female subgroup comprised 280 of 949 participants (TP1: PBO, n = 90 of 318 [28.3%]; LEM5, n = 82 of 316 [25.9%]; LEM10, n = 108 of 315 [34.3%]). At 6 months, median changes from baseline in subjective sleep-onset latency (in minutes) were -17.9, -20.7, and - 30.4 for PBO, LEM5, and LEM10 (vs PBO: LEM5, P = not significant; LEM10, P = 0.0310). At 6 months, mean changes from baseline in subjective wake after sleep onset (in minutes) were -37.0 (59.6), -50.1 (74.5), and -54.5 (65.4) for PBO, LEM5, and LEM10 (vs PBO: LEM5 and LEM10, P = not significant), with benefits sustained through 12 months. Greater decreases from baseline (improvement) in Insomnia Severity Index total score and Fatigue Severity Scale total score were seen with LEM versus PBO at 6 months; benefits continued through 12 months. Most treatment-emergent adverse events were mild to moderate in severity.ConclusionsConsistent with the total population, subjective sleep parameters improved, and improvement was sustained over time in midlife women. LEM was well tolerated, suggesting that LEM may be a potential treatment option for midlife women with insomnia.

Abstract Introduction The Insomnia Severity Index (ISI) is a 7-item self-reported questionnaire evaluating perception of symptom severity included in Phase 3 studies of lemborexant (LEM), a competitive dual orexin receptor antagonist approved in several countries to treat adults with insomnia. The ISI total score, and items 4-7 for daytime function (DF), improved significantly with LEM treatment compared to placebo (PBO) as assessed at 1, 3 and 6 months. Here we report shifts in DF scores at 6 months depending on baseline severity. Methods Study 303 was a 12-month, randomized, double-blind PBO-controlled (first 6months; Treatment Period 1 [TP1]) phase 3 study in subjects (age ≥18y) with insomnia disorder. Subjects were randomized to PBO, LEM 5mg (LEM5) or 10mg (LEM10) for 6 months. ISI items are rated on a 5-point Likert scale from 0 (no problem) to 4 (very severe problem). Daytime-related items include ratings on sleep satisfaction, extent symptoms are noticeable to others, cause worry/distress, or interferes with daily function. Data were analyzed by Cochran-Mantel-Haenszel test of general association vs placebo. Results Of the 949 subjects, 749 (78.9%) completed the ISI at baseline and end of TP1: PBO (258/318 [81.1%]; LEM5, 257/316 [81.3%]; LEM10, 234/315 [74.3%]). Baseline daytime ISI-total-score distribution was similar between groups; most had scores of 9-12 (66.7-68.6%). At the end of TP1, more subjects with baseline scores of 9-12 shifted to 0-4 with LEM5 (49.7%) and LEM10 (46.2%) than with PBO (26.6%). Similarly, more subjects with baseline scores of 13-16 shifted to 0-4 with LEM5 (39.1%) and LEM10 (46.3%) than with PBO (29.6%). An additional 28.1% and 25.9% of subjects with LEM5 or LEM10, respectively, with baseline scores of 13-16 shifted to scores of 9-12, compared with 31.5% of PBO. The overall shift distributions were significantly different, favoring both LEM groups (p< 0.01). Conclusion More LEM-treated subjects improved in daytime functioning as evidenced by the significantly large number of subjects whose scores moved into the lower categories (i.e., better sleep) compared with PBO subjects. These data support important improvements in daytime function that are evident even after 6 months of continuous LEM treatment. Support (if any) Eisai Inc.

Objective/Background: To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial. Patients/Methods: The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study. Results: Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (similar to 20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%-15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups. Conclusions: These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant.

Objective: Investigate the impact of lemborexant (LEM), a competitive dual orexin receptor antagonist approved in multiple countries for the treatment of adults with insomnia, on the Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS), and on correlation between the 2 measures. Background: An effective insomnia treatment should both improve sleep and reduce daytime impairments and fatigue in patients reporting these symptoms. Study E2006-G000–303 (Study 303; NCT02952820) showed LEM provided significant benefit versus placebo (PBO) on patient-reported sleep outcomes based on the ISI and on fatigue assessed by FSS. Design/Methods: Study 303 was a 12mo, randomized, double-blind PBO-controlled (first 6mo) phase 3 study in subjects (age ≥18y) with insomnia disorder and baseline (BL) ISI Total Score (TS) ≥15. There was no fatigue criterion for study eligibility. Subjects were randomized to PBO or LEM 5mg (LEM5) or 10mg (LEM10) for 6mo. ISI and FSS were administered at BL and Months 1, 3, and 6. Mean changes from BL in ISI daytime functioning score (ISI-DFS; items 4–7) and FSS-TS were assessed. Results: Mean (SD) ISI-DFS and FSS-TS at BL were similar between groups (PBO, n=318; LEM5, n=316; LEM10, n=315). At 6mo, mean (SD) ISI-DFS decreased (improved) from BL (PBO, −4.3 [3.66]; LEM5, −6.0 [3.76] and LEM10, −5.7 [4.00], both P<0.0001 versus PBO) and mean FSS-TS decreased (improved) (PBO, −6.3 [12.07]; LEM5, −10.1 [13.56], P=0.0134 versus PBO; LEM10, −8.9 [14.91], P=0.0128 versus PBO) for both LEM groups. Pearson analysis showed a positive correlation over time between reductions in ISI-DFS and FSS-TS (correlation: PBO, 0.513; LEM5, 0.553; LEM10, 0.539; all P<0.0001). Most adverse events were mild/moderate in severity. Conclusions: Compared with PBO, in these post-hoc analyses, LEM significantly improved daytime functioning and fatigue in subjects with insomnia, and improvements in both measures were correlated. Disclosure: Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Janssen. Craig Chepke has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Otsuka. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Craig Chepke has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Neurocrine. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for AbbVie. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Acadia. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Otsuka. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Takeda. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Janssen. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Ironshore. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Teva. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Intracellular. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Eisai. Craig Chepke has received research support from Acadia. Craig Chepke has received research support from Harmony. Craig Chepke has received research support from Neurocrine. Jane Yardley has received personal compensation for serving as an employee of Eisai Ltd. Kate Pinner has received personal compensation for serving as an employee of Eisai Ltd. Dr. Lundwall has received personal compensation for serving as an employee of Eisai. Margaret Moline has received personal compensation for serving as an employee of EISAI, INC.. Margaret Moline has received intellectual property interests from a discovery or technology relating to health care. Margaret Moline has received personal compensation in the range of $0-$499 for serving as a review, loan repayment program with NIH.

Abstract Introduction Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries for the treatment of adults with insomnia. In Study 303 (NCT02952820), LEM provided significant benefit on subject-reported sleep measures versus placebo (PBO). This post hoc analysis investigated whether changes from baseline in sleep parameters with LEM are correlated with insomnia disorder severity. Methods Study 303 was a randomized, double-blind, PBO-controlled (first 6mo [Period 1]), phase 3 study. During Period 1, subjects received LEM 5mg (LEM5), LEM 10mg (LEM10), or PBO. During Period 2 (second 6mo), LEM subjects continued their assigned dose and PBO subjects were rerandomized to LEM5 or LEM10 (rerandomized subjects not reported here). The correlation between changes in subject-reported sleep parameters (sleep onset latency [sSOL], wake after sleep onset [sWASO], sleep efficiency [sSE], total sleep time [sTST]) and insomnia disorder severity, as assessed by the Insomnia Severity Index total score (ISI-TS) were evaluated in the Full Analysis Set (FAS; ISI-TS ≥15) and in a subgroup of subjects with severe (ISI-TS ≥22 at baseline) insomnia over 12mo for LEM and over 6mo for PBO. Results Among 949 (PBO=318; LEM5=316; LEM10=315) subjects, 223 (PBO=65; LEM5=84; LEM10=74) had severe insomnia at baseline. Within each sleep parameter and severity group, baseline values were similar across treatments. Overall, strong to very strong correlations were observed between changes from baseline in sleep parameters and decrease in ISI-TS, regardless of treatment, as determined by correlation coefficients for sSOL (LEM5=0.973 [P=0.0053]; LEM10=0.997 [P=0.0002]; PBO=0.844 [P=0.361]), sSE (LEM5=–0.937 [P=0.0188]; LEM10=–0.992 [P=0.0008]; PBO=–0.950 [P=0.2018]), sWASO (LEM5=0.937 [P=0.0187]; LEM10=0.996 [P=0.0003]; PBO=0.979 [P=0.1299]), and sTST (LEM5=–0.876 [P=0.0515]; LEM10=–0.974 [P=0.0050]; PBO=–0.933 [P=0.2346]). Strong to very strong correlations were also observed in subjects with severe insomnia: sSOL (LEM5=0.818 [P=0.0904]; LEM10=0.823 [P=0.0868]; PBO=0.828 [P=0.3788]), sSE (LEM5=–0.860 [P=0.0616]; LEM10=–0.975 [P=0.0048]; PBO=–0.961 [P=0.1792]), sWASO (LEM5=0.871 [P=0.0544]; LEM10=0.936 [P=0.0194]; PBO=0.875 [P=0.3213]), and sTST (LEM5=–0.843 [P=0.0729]; LEM10=–0.969 [P=0.0095]; PBO=–0.974 [P=0.1449]). Conclusion Across the study period, changes from baseline in reported nocturnal sleep parameters correlated with reductions in severity of insomnia disorder regardless of insomnia severity at baseline. Support (If Any) Eisai Inc.

AbstractIntroductionThe dual orexin receptor antagonist lemborexant (LEM) is approved in multiple countries including the United States, Japan, Canada, and Australia for insomnia treatment in adults. In phase 3 study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), LEM provided significant benefit vs placebo (PBO) on subjective sleep outcomes over 6 months and was well tolerated. This post hoc analysis evaluated the effect of LEM on sleep outcome measures and insomnia severity as assessed by the Insomnia Severity Index (ISI) over 6 months in subjects with a lifetime history of depression (DepHx subgroup). We performed this analysis as insomnia in DepHx subjects could be a residual symptom of unresolved depression, and therefore, these subjects may respond differently to insomnia treatment.MethodsStudy 303 was a randomized, double-blind, 12 months global study in adults (≥18 years) with DSM-5 insomnia disorder. For 6 months (Treatment Period 1), subjects were randomized to PBO or LEM (5 mg [LEM5]; 10 mg [LEM10]). For the next 6 months (Treatment Period 2; not reported), PBO subjects were rerandomized to LEM and LEM subjects continued their original dose. The inclusion criteria allowed for participation of subjects with a lifetime DepHx, concomitant antidepressant medication use and/or mild depression (maximum Beck Depression Inventory II score of 19). Subjects had a baseline ISI total score (ISI-ts) ≥15.ResultsThe Full Analysis Set comprised 949 subjects, including 112 subjects in the DepHx subgroup (PBO, n = 34; LEM5, n = 39; LEM10, n = 39). Baseline median subjective sleep onset latency (sSOL; minutes) was 52.9, 57.1, and 70.7 for PBO, LEM5, and LEM10, respectively. At 6 months, greater median decreases from baseline in sSOL were observed with LEM5 (−21.7) and LEM10 (−40.1) vs PBO (−12.9). Baseline mean subjective sleep efficiency (sSE; %) was 62.2, 59.2, and 62.4 for PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) increases from baseline in sSE were observed with LEM5 (17.2 [18.3]) and LEM10 (20.9 [19.0]) vs PBO (14.9 [15.4]). Baseline mean subjective wake after sleep onset (sWASO; minutes) was 123.7, 151.0, and 132.6 for PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) decreases from baseline in sWASO were observed with LEM5 (−52.7 [69.2]) and LEM10 (−68.8 [81.9]) vs PBO (−46.7 [69.4]). Mean baseline ISI-ts were 18.6, 19.9, and 19.0 PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) decreases from baseline in ISI-ts were observed with LEM5 (−9.1 [6.8]) and LEM10 (−10.0 [5.9]) vs PBO (−7.9 [5.6]). Treatment-emergent adverse event rates in the DepHx subgroup were similar to those in the overall study population.DiscussionAt 6 months, LEM improved patient-reported sleep outcomes and reduced patient-reported insomnia severity in subjects with DepHx. These results suggest that LEM may be a therapeutic option for patients with insomnia and DepHx.FundingEisai, Inc.

Introduction Amongelderly persons (age ≥65 years), insomnia is a prevalent sleep disorder. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries, including the United States, Japan, Canada, Hong Kong, Australia, and India, for the treatment of insomnia in adults (age ≥18 years). Clinical trials for insomnia therapies include data from daily sleep diaries to assess the magnitude of change quantitatively in subjective sleep outcomes, including sleep onset and maintenance. Additionally, there are instruments that assess patient estimates of time to sleep onset and duration of nighttime awakenings. Assessment of symptom improvement provides critical information on treatment effectiveness. The demonstration of improvement in sleep from the patient's perspective is important in the assessment of the effectiveness of an insomnia therapy, as insomnia is a symptom-based disorder. The Patient Global Impression–Insomnia version (PGI-I) is a self-report instrument used to evaluate a patient's perception (qualitative) of the effects of their insomnia medication on their sleep relative to their sleep before starting their treatment. The PGI-I includes 3 items related to medication effects (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep; choices for patient responses include: 1=positive, 2=neutral, 3=negative). The PGI-I also includes 1 item related to perceived appropriateness of study medication strength with a different set of possible responses (choices for patient responses include: 1=too strong, 2=just right, 3=too weak). In Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), significantly greater percentages of subjects in the age ≥65 years subgroup reported a positive impact of LEM versus placebo (PBO) at 1, 3 and 6 months for each of the PGI-I items related to medication effects. The majority of subjects also reported medication strength as “just right” at 1, 3 and 6 months. PGI-I results at 9 and 12 months for subjects age ≥65 years are presented here for subjects that received continuous treatment with LEM for up to 12 months in Study 303. Methods Study303 was a Phase 3, 12-month, double-blind, global study in adults age ≥18 years with insomnia disorder that included a 6-month PBO-controlled period (Treatment Period 1) followed by a 6-month active-only (Treatment Period 2) period. Subjects received PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for the first 6 months. For Treatment Period 2, PBO-treated subjects were rerandomized to LEM (not reported here), while LEM-treated subjects continued their original dose. Titration to higher or lower doses was not permitted. The PGI-I was administered at Months 1, 3, 6, 9, and 12. Results for the PGI-I were analyzed by age (age ≥65 years). Results TheFull Analysis Set comprised 949 subjects, of which 262 (27.6%;[PBO, n=89; LEM5, n=87; LEM10, n=86]) were age ≥65y. At 9 and 12 months, the majority of elderly LEM5-treated (total treated up to 9 months, n=68; total treated up to 12 months, n=61) and LEM10-treated (total treated up to 9 months, n=61; total treated up to 12 months, n=56) subjects reported that their study medication “helped” sleep at night (9 months: LEM5=51 [75.0%], LEM10=45 [73.8%]; 12 months: LEM5=47 [77.0%], LEM10=42 [75.0%]), reduced time to fall asleep (9 months: LEM5=59 [86.8%], LEM10=47 [77.0%]; 12 months: LEM5=53 [86.9%], LEM10=44 [78.6%]), and increased total sleep time (9 months: LEM5=43 [63.2%], LEM10=45 [73.8%]; 12 months: LEM5=38 [62.3%], LEM10=33 [58.9%]). Also, at both 9 and 12 months, the majority of subjects in the LEM5 and LEM10 groups responded that their medication strength was “just right” (9 months: LEM5=46 [67.6%], LEM10=37 [60.7%]; 12 months: LEM5=43 [70.5%], LEM10=37 [66.1%]). LEM was well tolerated. Most adverse events were mild or moderate. Conclusions Themajority of elderly subjects receiving LEM5 or LEM10 for up to 12 months reported a positive medication effect and perceived their medication strength as “just right” at both 9 and 12 months. These results demonstrate that the similar positive perceptions of the effects of LEM achieved during Treatment Period 1 in the elderly subgroup were sustained through Treatment Period 2. This research was funded by Supported by Eisai Inc.

Objective: Fatigue is a common symptom in patients with insomnia. This analysis evaluated whether treatment of nighttime symptoms of insomnia with a dual orexin receptor antagonist, lemborexant, might also reduce fatigue. Methods: Analyses were conducted of two phase 3 studies of subjects with insomnia disorder. Subjects received placebo, lemborexant 5 mg, or lemborexant 10 mg in the 12-month (6 months placebo-controlled) Study E2006-G000-303 (Study 303: SUNRISE-2) of adults (N = 949; full analysis set [FAS]), and the 1-month, placebo- and active-controlled Study E2006-G000-304 (Study 304; SUNRISE-1) of older adults (females >= 55 years, males >= 65 years) (N = 1006; FAS). Fatigue was assessed using the Fatigue Severity Scale (FSS). Patient-reported sleep onset and maintenance endpoints were analyzed using data from electronic sleep diaries. Results: Lemborexant significantly reduced subject-reported fatigue versus placebo over a 6-month treatment period (FSS total score least-squares mean treatment difference of -2.50 for 5 mg and -2.56 for 10 mg of lemborexant; p < 0.05 for both). This reduction was sustained over 12 months of lemborexant in both the overall population and in subjects with clinically meaningful fatigue (FSS total score >= 36) at baseline. Improvements in fatigue over time positively correlated with improvements in sleep onset and maintenance parameters. Improvements in sleep quality were evident as early as 1 week after lemborexant treatment, whereas longer-term treatment (>1 month) may be needed for improvements in insomnia-related fatigue. Conclusions: In addition to improving sleep onset and sleep maintenance in subjects with insomnia disorder, lemborexant provides further benefit by reducing daytime fatigue.

Objective/background: Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score >= 15) treated for 12 months nightly with lemborexant. Patients/methods: This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores. Results: Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (-7.1, -7.2, -5.2, respectively), 3 (-8.6, -8.9, -6.1, respectively), and 6 (-9.9, -9.8, -7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (-11.1 and -11.2, respectively) and 12 (-11.5 and -11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (>= 7-point ISI score decrease from baseline) were observed with LEM5 (44%-57%) and LEM10 (44%-52%) versus placebo (30%-41%). At months 1, 3, and 6, more remitters (ISI total score <10 and < 8) were observed with LEM5 (30%-44% and 22%-34%, respectively) and LEM10 (31%-41% and 22%-31%, respectively) versus placebo (18%-28% and 11%-21%, respectively). Conclusions: Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo. (C) 2022 The Author(s). Published by Elsevier B.V.

Study objectivesLemborexant (LEM) is a dual orexin receptor antagonist approved for treating adults with insomnia. We analyzed the efficacy (subjective sleep outcomes) and safety of LEM over 12 months in the subgroup of Asian subjects from Study E2006-G000-303 (Study 303).MethodsStudy 303 was a 12-month, randomized, placebo-controlled (first 6 months), double-blind, parallel-group, phase 3 study of adults with insomnia disorder. During the 6-month Period 1, subjects were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10); LEM subjects continued treatment in the following 6-month Period 2. Outcome measures included subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Insomnia Severity Index (ISI), and Patient Global Impression–Insomnia version (PGI-I). Treatment-emergent adverse events (TEAEs) were assessed.ResultsOverall, 178 Asian subjects (Japanese, n = 161; Chinese, n = 4; other Asian, n = 13) were included. Greater decreases in sSOL and sWASO and increases in sSE and sTST from baseline were observed with LEM vs placebo at 6 months; LEM benefits were sustained through 12 months. Greater decreases in ISI total score were seen with LEM vs placebo at 6 months; improvements from baseline with LEM continued through 12 months. For each PGI-I item, LEM-treated subjects had more positive medication effects than placebo-treated subjects at 6 months; these effects were maintained with LEM in Period 2. TEAEs were generally mild to moderate.ConclusionsLEM improved subjective sleep parameters and was well-tolerated in Asian subjects with insomnia disorder over 12 months.Clinical trial registrationClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Abstract Introduction Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adults with insomnia. In Study 303 (NCT02952820), LEM provided significant benefit on sleep outcomes including patient-reported (subjective) sleep onset latency (sSOL) and wake after sleep onset (sWASO) versus placebo (PBO). This post-hoc analysis assessed these measures in Insomnia Severity Index (ISI) responders, defined as subjects with clinically meaningful reductions (≥7 points) in ISI total scores (ISI-TS). Methods Study 303 was a 12-month, PBO-controlled (first 6mo), randomized, double-blind, phase 3 study in subjects with ISI-TS ≥15 (moderate to severe insomnia). Subjects (n=949; Full Analysis Set [FAS]) received LEM (5mg [LEM5]; 10mg [LEM10]) or PBO for 6mo. Changes from baseline (CFB) in sSOL (min) and sWASO (min) at 6mo were analyzed in ISI responders from the FAS and in subjects with severe insomnia (baseline ISI-TS ≥22), using mixed-effect model repeated measurement analysis. Results At 6mo, 175 (LEM5), 151 (LEM10), and 124 (PBO) subjects were ISI responders; of these, 46 (LEM5), 48 (LEM10) and 29 (PBO) had severe insomnia. CFB in the FAS in median sSOL was significantly greater with LEM5 (−21.8) and LEM10 (−28.2) versus PBO (−11.4; both P<0.001). ISI responders also had significantly greater decreases in sSOL with LEM (LEM5: −26.7, P<0.01; LEM10: −32.6, P<0.001) than PBO (−18.0). In ISI responders from the severe insomnia subgroup, greater CFB in median sSOL was observed with LEM10 (−41.4) than with PBO (−32.1; P>0.05), but not with LEM5 (−32.9, P>0.05).Least-squares mean (standard error) CFB in sWASO in the FAS was −46.8(3.7) with LEM5 (P<0.001), −42.0(3.7) with LEM10 (P<0.05), versus −29.3(3.6) with PBO. In ISI responders, CFB in sWASO was greater with LEM10 (−52.7[4.0], P>0.05) and significantly greater with LEM5 (−58.9[3.8], P<0.01) versus PBO (−43.6[4.4]). In ISI responders from the severe insomnia subgroup, greater CFB was observed with LEM5 (−91.6[9.5]) versus PBO (−70.2[11.1]); P>0.05); CFB with LEM10 (−71.4[9.0]) was similar to PBO. Conclusion ISI responders including those from the severe insomnia subgroup reported greater CFB in sSOL and sWASO than the FAS that was somewhat dose dependent. LEM generally showed benefit versus PBO. Support (If Any) Eisai Inc.

Introduction Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries including the United States, Japan, Canada, Hong Kong, Australia, and India, for the treatment of adults with insomnia. Patient-reported perceptions of medication effectiveness and strength, and perceptions of insomnia severity can be assessed by the Patient Global Impression–Insomnia (PGI-I) and Insomnia Severity Index (ISI) questionnaires, respectively. PGI-I items 1-3 assess perceived effects (positive, neutral, or negative) of the study medication on sleep (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep). PGI-I item 4 assesses the perceived appropriateness of study medication strength ("too strong," "just right," or "too weak"). In Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), significantly greater percentages of subjects with insomnia disorder age ≥65y (elderly) treated with LEM indicated a positive effect of their medication compared with placebo (PBO), as assessed by items 1-3 of the PGI-I at 1, 3, and 6 months. A significantly greater percentage of these elderly subjects also indicated on PGI-I item 4 that their medication strength was "just right" at these time points. Additionally, significantly greater decreases from baseline in ISI total score were also observed with LEM vs PBO in elderly subjects, as assessed at 1, 3, and 6 months. In this post hoc analysis, potential tolerance to LEM was evaluated in the elderly subgroup by analyzing ratings of medication strength on PGI-I item 4 in the subsets of elderly subjects who had moderate (ISI total score 15-21) or severe (ISI total score 22-28) insomnia at baseline. Methods Study 303 was a 12-month, double-blind, PBO-controlled (first 6 months [Treatment Period 1]), phase 3 study in subjects ≥18y with insomnia disorder and baseline ISI total score ≥15. Subjects were randomized to PBO, LEM 5mg (LEM5), or LEM 10mg (LEM10). During the second 6 months (Treatment Period 2, not reported here), PBO-treated subjects were rerandomized to LEM, while LEM-treated subjects continued their originally assigned dose. During Treatment Period 1, the PGI-I and ISI were administered at 1, 3, and 6 months; the ISI was also administered at baseline. Titration to higher or lower doses was not permitted during the study. Results Of 949 subjects in the Full Analysis Set, 262 (27.6%; [PBO, n=89; LEM5, n=87; LEM10, n=86]) were age ≥65y. Among these subjects, 193 (73.7% [PBO, n=66; LEM5, n=63; LEM10, n=64]) had moderate insomnia, and 61 (23.3%; [PBO, n=20; LEM5, n=21; LEM10, n=20]) had severe insomnia at baseline, respectively. In both insomnia severity groups, greater percentages of LEM-treated than PBO-treated subjects rated their medication strength as "just right" at 1 month (moderate: LEM5=47.4%; LEM10=46.4%; PBO=21.3%; severe: LEM5=47.6%; LEM10=44.4%; PBO=5.3%), at 3 months (moderate: LEM5=60.4%; LEM10=53.8%; PBO=34.4%; severe: LEM5=47.4%; LEM10=64.7%; PBO=22.2%) and at 6 months (moderate: LEM5=59.6%; LEM10=51.0%; PBO=34.4%; severe: LEM5=76.5%; LEM10=68.8%; PBO=25.0%). The majority of LEM-treated subjects who rated their medication strength as "just right" had an ISI total score ≤14 (ie, subthreshold insomnia) at each of the time points. Ratings of "too weak" were greater with PBO than with LEM and did not increase over time (Months 1, 3, and 6) in subjects with moderate (LEM10: 42.9%; 34.6%; 38.8%; LEM5: 50.9%; 39.6%, 40.4%; PBO: 75.4%, 65.6%, 65.6%) or severe (LEM10: 55.6%, 35.3%, 31.3%; LEM5: 52.4%, 52.6%, 23.5%; PBO: 89.5%, 77.8%, 75.0%) insomnia at baseline. In subjects with moderate insomnia, ratings of "too strong" at 1, 3, and 6 months were higher with LEM10 (10.7%, 11.5%, 10.2%) than with LEM5 (1.8%, 0%, 0%) or PBO (3.3%, 0%, 0%). However, no LEM5- or LEM10-treated subjects with severe insomnia at baseline rated their medication as "too strong" at any time point. LEM was well tolerated with adverse events being mild or moderate in severity. Conclusions These analyses suggest that tolerance to LEM5 and LEM10 does not develop over time, as ratings of "too weak" did not increase across the study period. In both insomnia severity groups, ratings of "just right" were more common in subjects treated with LEM5 or LEM10 than PBO. These data support LEM as a long-term treatment option in adults ≥65y with insomnia. This research was funded by Supported by Eisai Inc.