
==== Front
Drugs Aging
Drugs Aging
Drugs & Aging
1170-229X
1179-1969
Springer International Publishing Cham

39120786
1135
10.1007/s40266-024-01135-8
Original Research Article
Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials
http://orcid.org/0000-0001-7279-8101
Gotfried Mark H. 1
http://orcid.org/0000-0003-2962-6405
Auerbach Sanford H. 2
http://orcid.org/0000-0002-7235-2721
Dang-Vu Thien Thanh 34
http://orcid.org/0000-0003-1182-1181
Mishima Kazuo 5
http://orcid.org/0000-0001-5880-4237
Kumar Dinesh 6
http://orcid.org/0000-0003-0807-2167
Moline Margaret margaret_moline@eisai.com

6
http://orcid.org/0000-0002-4315-8284
Malhotra Manoj 6
1 https://ror.org/048qnxy85 grid.477708.b 0000 0004 0633 0705 Pulmonary Associates, Phoenix, AZ USA
2 grid.189504.1 0000 0004 1936 7558 Department of Neurology, Boston University School of Medicine, Boston, MA USA
3 https://ror.org/0420zvk78 grid.410319.e 0000 0004 1936 8630 Department of Health, Kinesiology and Applied Physiology, Concordia University, Montreal, QC Canada
4 https://ror.org/041c8tt83 grid.459225.d Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM), Le Centre integre universitaire de sante et de services sociaux (CIUSSS), Centre-Sud-de-l’île-de-Montréal, Montreal, QC Canada
5 https://ror.org/03hv1ad10 grid.251924.9 0000 0001 0725 8504 Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Akita Japan
6 grid.418767.b 0000 0004 0599 8842 Eisai Inc., 200 Metro Blvd, Nutley, NJ 07110 USA
9 8 2024
9 8 2024
2024
41 9 741752
15 7 2024
© The Author(s) 2024
2024
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Background

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.

Methods

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.

Results

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.

Conclusions

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.

Trial Registration Numbers and Dates of Registration

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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40266-024-01135-8.

Plain Language Summary

The prevalence of insomnia increases with age; however, some hypnotics used for treating insomnia do not adequately resolve sleep problems in older adults and may be associated with adverse residual effects. Specifically, some hypnotics pose safety concerns in this population of patients who are generally more vulnerable to treatment-related effects, including increasing the risk of falls, risks of cognitive impairment, automobile accidents, and unresponsiveness to auditory stimuli. Safer and more effective insomnia medications are needed to reduce sleep problems with improved side-effect profiles. This analysis of lemborexant clinical studies conducted in adult subjects at least 65 years old found the drug to be effective without impairing memory, attention or balance the following day compared with placebo. These subjects were normal sleepers (for age) or had insomnia disorder. Furthermore, lemborexant was not associated with impaired ability to drive the next morning or awaken to loud middle-of-the-night sounds. Lemborexant was well tolerated in these older adults, similar to findings for adults aged at least 18 years. These findings indicate that lemborexant may be an appropriate treatment option for insomnia in older adults.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40266-024-01135-8.

http://dx.doi.org/10.13039/501100004896 Eisai Incorporated issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

In older adults (aged ≥ 65 years) with insomnia, lemborexant 5 mg and 10 mg provided significant, rapid, and sustained benefits on sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended-release 6.25 mg.	
Bedtime administration of lemborexant did not result in significant next-morning residual effects with regard to postural stability upon getting out of bed or affect performance on memory in older adults with or without insomnia. It also did not impair the ability to awaken in the middle of the night to an external stimulus in older adults without insomnia.	
Lemborexant was well tolerated in older adults.	

Introduction

The prevalence of insomnia increases with age, with sleep difficulties affecting up to half of older adults [1, 2]. In particular, difficulty initiating and maintaining sleep are some of the more common sleep symptoms associated with increasing age [3–6]. For example, in a survey of predominantly (76% of the study population) older (aged ≥ 65 years) adult inpatients, 60.1% complained of difficulty maintaining sleep [7].

Although insomnia is often treated with cognitive behavioral therapy, some patients benefit from pharmacotherapy alone or combined with cognitive behavioral therapy [8]. As older adults may be more susceptible to daytime residual effects of insomnia pharmacotherapy, ideal pharmacologic treatments in this population should effectively improve sleep without next-day residual adverse effects [5]. However, currently available and often-prescribed insomnia medications with short half-lives, including zolpidem, for example, may not adequately treat older adults who have difficulty maintaining sleep during the second half of the night [2, 3]. In addition, many benzodiazepine and nonbenzodiazepine hypnotics pose safety concerns for older adults, including impaired cognitive and psychomotor function, postural instability, and increased risk of falls and motor vehicle accidents [3, 9–11] and are not recommended for insomnia therapy on the Beers list [11].

Lemborexant (LEM) is a competitive dual orexin-receptor antagonist approved in multiple countries, including the USA, Japan, Canada, Australia, and several Asian countries, for the treatment of adults with insomnia. In two pivotal phase 3 studies in subjects with insomnia disorder, E2006-G000-304 (Study 304; SUNRISE 1; NCT02783729) and E2006-G000-303 (Study 303; SUNRISE 2; NCT02952820), LEM provided significant benefit versus placebo (PBO) on sleep onset and sleep maintenance that persisted at 12 months (in Study 303) and had a favorable safety profile [12–14]. Analyses from these and other studies, including Study E2006-E044-106 (Study 106; NCT02583451) and Study E2006-A001-108 (Study 108; NCT03008447), showed that LEM did not substantially impair measures of next-day functioning, including postural stability, cognitive performance, and driving ability, in healthy adults and adults with insomnia disorder [15–17].

Given the prevalence of insomnia in older adults, defined as those aged ≥ 65 years, and the special concerns about the use of insomnia medications in this population, we evaluated the effects of LEM in those subjects on objectively measured sleep parameters in Study 304 and on next-day functioning in Study 304, Study 106, and Study 108.

Methods

Post hoc analyses were performed in the subgroup of subjects aged ≥ 65 years from Study 304, Study 106, and Study 108 [13, 16, 17]. Each study was conducted in accordance with the principles of the International Conference on Harmonization guidelines for Good Clinical Practice and the Declaration of Helsinki. Trial protocols were approved by the appropriate institutional review boards. All subjects provided written informed consent prior to participation. Detailed study methodologies were previously published [13, 16, 17].

Study Design

Study 304

Study 304 was a 1-month, global, multicenter, randomized, double-blind, PBO-controlled, active-comparator, parallel-group, fixed-dose, phase 3 study in females aged ≥ 55 years and males aged ≥ 65 years who met the criteria for insomnia disorder as defined in Diagnostic and Statistical Manual of Mental Disorders, 5th edition [18] and had evidence of sleep maintenance insomnia. The study was previously reported by Rosenberg et al. [13].

Study 304 included a 2-week PBO run-in period, followed by a 5:5:5:4 randomization to LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days (Online Resource 1A).

Study 106

Study 106 was a single-center, randomized, double-blind, PBO-controlled, active‑comparator, four-period, incomplete crossover study in healthy subjects aged ≥ 21 years as reported previously [16].

Subjects were randomized to four eight-night treatment periods (separated by a washout of ≥ 14 days) (Online Resource 1B). On days 1 and 8 of each treatment period, subjects were administered a bedtime dose of LEM 2.5 mg (not reported here), LEM5, or LEM10. On days 2–7, subjects were instructed to take the study drug before bedtime at home. Zopiclone 7.5 mg, an active control, was taken at bedtime on days 1 and 8 only (with PBO administered on the days in between). In the PBO period, PBO was taken for 8 days. All subjects received PBO and zopiclone and two of the three doses of LEM.

Study 108

Study 108 was a multicenter, single-dose, randomized, double-blind, PBO-controlled, active-comparator, four-period, crossover, phase 1 study in healthy female subjects aged ≥ 55 years and healthy male subjects aged ≥ 65 years. This age range matched that of Study 304. Subjects had regular sleep timing and duration and no insomnia, as previously reported [17].

The randomization phase comprised four 1-day treatment periods with a minimum 14-day washout interval between each (Online Resource 1C). Subjects were randomized to one of four sequences to receive LEM5, LEM10, ZOL, and PBO administered as a single dose within 5 min before bedtime.

Assessments

Sleep Parameters

In Study 304, polysomnograms (PSGs) were performed at baseline (two consecutive PSGs during the single-blind run-in period), after the first two nights (nights 1 and 2), and the last two nights (nights 29 and 30) of treatment to assess latency to persistent sleep (LPS), determined as minutes from lights-off to the first epoch of 20 consecutive epochs of non-wakefulness; wake after sleep onset (WASO), measured as minutes of wake from LPS until lights-on; WASO in the second half of the night (WASO2H), defined as minutes of wake during the interval from 240 min after lights-off until lights-on; and sleep efficiency (SE), defined as the proportion of minutes spent asleep per total time in bed. For the indicated time points, each sleep outcome measure was determined from the average of the paired PSGs during the baseline and treatment period.

Postural Stability

In Studies 304 and 108, postural stability was assessed using an ataxiameter to measure body sway during 60 s in units of 1/3° angle of arc, with higher values indicating more body sway. For the outcome of postural stability, the effect of alcohol on body sway was used as a threshold for indicating impairment [19]. A 7-unit difference between treatments in the change from time-matched baseline was considered clinically meaningful [17]. In Study 304, postural stability was assessed at baseline (mornings after the pair of PSGs) and at the beginning (days 2 and 3) and end (days 30 and 31) of treatment within 5 min of morning awakening (approximately 8 h post dose). In Study 108, postural stability was assessed at baseline and after each treatment, within 5 min of middle-of-the-night awakening (approximately 4 h post dose) and within 5 min of morning awakening (approximately 8 h post dose).

Driving Performance

In Study 106, next-morning driving tests were assessed on days 2 and 9 post treatment using a standardized on-the-road driving test, as described previously [16]. Subjects were asked to drive 100 km for 1 h on a highway. They were instructed to drive with a steady position between the delineated boundaries of the slower (right) traffic lane while maintaining a constant speed of 95 km/h (59 mph). The primary outcome variable was standard deviation of lateral position (SDLP) in centimeters. A clinically meaningful effect was defined as mean change from PBO in SDLP ≥ 2.4 cm [16].

Cognitive Performance

In Studies 304 and 108, cognitive performance was assessed using a computerized cognitive performance assessment battery (CPAB), which comprised nine tasks assessing various aspects of memory and attention. Output variables from the nine tasks were combined to derive scores for four cognitive domains: power of attention (ability to focus and process information), continuity of attention (ability to maintain attention), quality of memory (ability to store and retrieve information), and speed of memory retrieval (time to retrieve stored information). Higher values indicate better continuity of attention and quality of memory (measured in units); lower values indicate better power of attention and speed of memory retrieval (measured in ms). In Study 304, the CPAB was administered at baseline (following the two PSGs after having taken PBO) and at the beginning (days 2 and 3) and end (days 30 and 31) of randomized treatment in the morning, following the postural stability assessment. In Study 108, the CPAB was administered after the postural stability test (starting within 15 min of middle-of-the-night awakening) and within 15 min of morning awakening.

Auditory Awakening Threshold

In Study 108, subjects were awakened via the auditory awakening threshold (AAT) ≥ 4 h after bedtime and (preferably) after 5 consecutive minutes of nonrapid eye movement stage 2 (N2) sleep. AAT was assessed using an audiometer that delivered tones at increasing volumes, from 15 dB up to a maximum of 105 dB [17]. The tones increased until the subject said, “I’m awake.” The decibel level on this response was scored as the AAT. Subjects who did not awaken to the maximum tone were awakened by the technician [17].

Return-to-Sleep Latency

In Study 108, return-to-sleep latency (RSL) was measured after participants completed the middle-of-the-night assessments. Overhead lights were turned off, and the time to return to sleep was measured by PSG. The RSL was defined as the duration in minutes from lights-off after middle-of-the-night assessments to the first epoch of N2, nonrapid eye movement stage 3 (N3), or rapid eye movement sleep.

Safety

The incidence and severity of adverse events (AEs) and their relatedness to treatment were recorded. Vital signs, electrocardiograms, and laboratory parameters were also evaluated.

Statistical Analysis

For Study 304, PSG, body sway, and CPAB findings were analyzed for the elderly subgroup, i.e., randomized subjects who were ≥ 65 years of age (received at least one dose of study drug and had at least one post dose primary efficacy measurement). For Study 106, driving performance was analyzed for the subgroup of subjects ≥ 65 years of age who received at least one dose of study drug and who had sufficient pharmacodynamic data to derive at least one SDLP measure. For Study 108, body sway, CPAB, and AAT findings were analyzed for the subgroup of subjects ≥ 65 years of age who had sufficient pharmacodynamic data to derive at least one outcome variable. For all studies, AEs were similarly analyzed for subjects ≥ 65 years of age in the safety analysis set (randomized subjects who received at least one dose of study drug and had at least one post dose safety assessment).

For Study 304, PSG and body sway measures and CPAB findings were analyzed using the mixed-effect model for repeated measurements, with factors for age group (65–75 years and > 75 years), region, treatment, visit (time point), and treatment-by-visit interaction as fixed effects and baseline value as a covariate, and with log transformation for LPS only. For all measures, missing values were not imputed and assumed to be missing at random. For body sway, subjects with extreme values (values outside of the physiological range, n = 2) were excluded.

For Study 106, SDLP (primary outcome) was analyzed using repeated-measures analyses of variance. Secondary endpoints included symmetry analysis of individual changes from PBO in SDLP. McNemar test was used to compare the subjects with a mean difference in SDLP > 2.4 cm (reflecting impairment) to those subjects with a mean difference in SDLP < − 2.4 cm (reflecting improvement).

For Study 108, statistical analyses for RSL included a repeated mixed-effects model, as described previously [17], for the subgroup of subjects ≥ 65 years of age. Mean change from baseline and associated 95% confidence intervals (CIs) were calculated for body sway, AAT, and CPAB domains for 4 h post dose (middle of the night) and 8 h post dose (morning). Statistical significance was taken to be indicated by nonoverlapping 95% CIs. No adjustments were made for multiple comparisons.

Results

Baseline Characteristics

Of 1006 subjects in Study 304, 453 (45.0%) were ≥ 65 years of age. Among this cohort, subjects had a median age of 69 years (range 65–88), 316 (69.8%) were female, 338 (74.6%) were white, and 103 (22.7%) were Black or African American (Table 1). Baseline characteristics were generally well balanced among the four treatment arms (Table 2).Table 1 Demographics in subjects aged ≥ 65 years from Study 304 (subjects with insomnia disorder), Study 106 (healthy subjects), and Study 108 (healthy subjects)

Characteristic	Study 304	Study 106	Study 108	
PBO (n = 93)	ZOL (n = 120)	LEM5 (n = 118)	LEM10 (n = 122)	Total (n = 24)	Total (n = 28)	
Age, years	
 Mean (SD)	69.4 (4.3)	70.9 (4.8)	69.8 (5.0)	70.4 (4.9)	68.8 (4.0)	69.1 (4.4)	
 Median (range)	68.0 (65–82)	70.0 (65–83)	69.0 (65–88)	69.0 (65–85)	67.0 (65–78)	68.0 (65–80)	
Female, n (%)	69 (74.2)	83 (69.2)	81 (68.6)	83 (68.0)	10 (41.7)	14 (50.0)	
Race, n (%)	
 White	68 (73.1)	78 (65.0)	93 (78.8)	99 (81.1)	24 (100)	18 (64.3)	
 Black or African American	22 (23.7)	36 (30.0)	23 (19.5)	22 (18.0)	0	7 (25.0)	
 Chinese	1 (1.1)	0	0	0	0	0	
 Other Asian	0	3 (2.5)	1 (0.8)	1 (0.8)	0	2 (7.1)	
 Native Hawaiian or other Pacific Islander	0	2 (1.7)	0	0	0	0	
 Other	2 (2.2)	1 (0.8)	1 (0.8)	0	0	1 (3.6)	
LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, PBO placebo, SD standard deviation, ZOL zolpidem tartrate extended-release 6.25 mg

Table 2 Baseline sleep characteristics in subjects aged ≥ 65 years from Study 304 (subjects with insomnia disorder)

Characteristic	Study 304	
PBO	ZOL	LEM5	LEM10	
PSG sleep variables, mean (SD)	
 n	93	120	118	122	
 LPS, min	47.0 (39.0)	40.9 (34.7)	44.0 (33.3)	43.3 (33.5)	
 WASO, min	120.7 (43.6)	124.4 (38.6)	119.0 (43.3)	123.1 (38.6)	
 WASO2H, min	81.6 (32.1)	83.0 (35.3)	83.0 (36.7)	83.0 (31.2)	
 SE, %	66.5 (10.7)	66.8 (10.9)	67.4 (11.4)	66.3 (9.8)	
Body swaya	
 n	90	107	109	108	
 Mean (SD)	22.9 (16.8)	28.2 (25.8)	27.7 (22.6)	23.5 (17.3)	
Power of attention, mean (SD), ms	
 n	86	108	113	110	
 Mean (SD)	1400.6 (178.3)	1436.5 (170.7)	1475.9 (273.8)	1392.7 (215.4)	
Continuity of attention, mean (SD), units	
 n	86	108	113	110	
 Mean (SD)	90.5 (4.5)	90.3 (7.4)	90.4 (6.5)	91.3 (3.1)	
Quality of memory, mean (SD), units	
 n	86	108	112	110	
 Mean (SD)	333.2 (63.4)	337.6 (67.6)	332.0 (70.3)	322.6 (68.8)	
Speed of memory retrieval, mean (SD), ms	
 n	86	107	111	110	
 Mean (SD)	4639.3 (920.3)	4776.7 (1184.9)	4836.2 (1150.4)	4663.6 (1036.4)	
LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, LPS latency to persistent sleep, PBO placebo, PSG polysomnogram, SD standard deviation, SE sleep efficiency, WASO wake after sleep onset, WASO2H wake after sleep onset in the second half of the night, ZOL zolpidem tartrate extended-release 6.25 mg

aUnit of body sway is defined as 1/3° angle of arc movement of the ataxiameter. A higher value represents more body sway and less postural stability.

Forty-eight subjects were randomized in Study 106. All the randomized subjects completed the study, 24 (50.0%) subjects were ≥ 65 years of age. Of those 24 subjects, the median age was 67 years (range 65–78), 10 (41.7%) were female, and all were white (Table 1). All were good sleepers per sleep diary entries.

Sixty-three subjects were randomized in Study 108. A total of 56 subjects completed the study, of whom 28 (50.0%) were ≥ 65 years of age (safety analysis set). Of those 28 subjects, the median age was 68 years (range 65–80), 14 (50.0%) were female, 18 (64.3%) were white, and 7 (25.0%) were Black or African American (Table 1). The pharmacodynamic analysis subset of older adults from Study 108 comprised 27 subjects. All were good sleepers per sleep diary entries (Table 3).Table 3 Baseline sleep characteristics in subjects aged ≥ 65 years from Study 108 (healthy subjects)

Characteristic	Study 108	
Total (n = 28)	
Body sway,a mean (SD)	
 4 h after lights off	22.3 (19.1)	
 8 h after lights off	26.1 (19.7)	
Power of attention, mean (SD), ms	
 4 h after lights off	1380.9 (179.2)	
 8 h after lights off	1437.7 (293.1)	
Continuity of attention, mean (SD), units	
 4 h after lights off	92.2 (1.93)	
 8 h after lights off	91.6 (2.8)	
Quality of memory, mean (SD), units	
 4 h after lights off	345.8 (69.4)	
 8 h after lights off	331.3 (68.0)	
Speed of memory retrieval, mean (SD), ms	
 4 h after lights off	4637.3 (863.6)	
 8 h after lights off	4594.8 (858.9)	
SD standard deviation

aUnit of body sway is defined as 1/3° angle of arc movement of the ataxiameter. A higher value represents more body sway and less postural stability.

Sleep parameters

In Study 304, significantly greater decreases from baseline in LPS were observed with LEM5 and LEM10 versus PBO and ZOL at nights 1 and 2 (all p < 0.05; Fig. 1A). The decreases in LPS were sustained at nights 29 and 30 for both LEM doses versus ZOL and for LEM10 versus PBO (all p < 0.01). The decrease from baseline in WASO was significantly greater for each LEM dose versus ZOL and PBO at nights 1 and 2 (all p < 0.01; Fig. 1B) and was sustained at nights 29 and 30 (all p < 0.05). LEM also improved sleep maintenance in the second half of the night versus ZOL and PBO, as demonstrated by significantly larger decreases from baseline in WASO2H at the beginning (nights 1 and 2) and end of treatment (nights 29 and 30; all p < 0.05; Fig. 1C). Significant, rapid, and larger increases from baseline in SE were also observed with each LEM dose versus PBO and ZOL at both assessment time points (all p < 0.0001; Fig. 1D).Fig. 1 Sleep onset and maintenance in patients aged ≥ 65 years from Study 304: a LPS, b WASO, c WASO2H, and d SE. Estimates based on a repeated mixed-effects model with factors for region, treatment, visit (nights 1 and 2 and nights 29 and 30), and treatment-by-visit interaction as fixed effects, and baseline LPS, WASO, WASO2H, or SE as a covariate. Missing values were not imputed and assumed to be missing at random. The repeated mixed-effects model for LPS used log transformation of LPS. *p < 0.0001, †p < 0.001, ‡p < 0.01, §p < 0.05 versus PBO, ‖p < 0.0001, ¶p < .001, #p < 0.01, ¶¶p < 0.05 versus ZOL. BL baseline, LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, LPS latency to persistent sleep, LSM least squares mean, PBO placebo, SD standard deviation, SE standard error, WASO wake after sleep onset, WASO2H wake after sleep onset in the second half of the night, ZOL zolpidem tartrate extended-release 6.25 mg

Postural Stability

In Study 304, when postural stability was assessed immediately upon awakening, there was no significant treatment difference in body sway for either LEM treatment group compared with PBO at either the beginning (days 2 and 3) or the end (days 30 and 31) of treatment. In contrast, after the first two doses of ZOL on days 2 and 3, the increase from baseline in body sway was larger and differed significantly from PBO (p < 0.01). Changes from baseline for subjects taking LEM5 (p < 0.01) and LEM10 (p < 0.05) were significantly smaller compared with ZOL. At days 30 and 31, the difference from baseline in body sway for ZOL remained higher compared with PBO but was not significant (Fig. 2A).Fig. 2 Postural stability, as measured by body sway, in subjects aged ≥ 65 years: a Study 304 at days 2 and 3 and days 30 and 31 of treatment and b Study 108 4 h and 8 h post dose. For Study 304, changes from baseline were assessed using a repeated mixed-effects model analysis with factors for region, visit (time point), and treatment-by-visit interaction as fixed effects, and baseline body sway as a covariate. For Study 108, mean change from baseline and associated 95% CIs were calculated for body sway and CPAB domains for 4 h post dose (middle of the night) and 8 h post dose (morning). aA unit of body sway is defined as 1/3° angle of arc movement of the ataxiameter. A higher value represents more body sway and less postural stability. ‡p < 0.01 versus PBO; #p < 0.01, ¶¶p < 0.05 versus ZOL. BL baseline, CI confidence interval, CPAB cognitive performance assessment battery, LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, LSM least squares mean, PBO placebo, ZOL zolpidem tartrate extended-release 6.25 mg

In Study 108, although the mean change from time-matched baseline in body sway was significantly higher (worse) for all active treatments compared with PBO when subjects were awakened in the middle of the night (4 h post dose), these changes were significantly less for LEM5 and LEM10 compared with ZOL, indicating a clinically significant greater impairment of postural stability in the middle-of-the-night with ZOL than with LEM (Fig. 2B). A 7-unit difference from time-matched baseline between active treatments and zolpidem was proposed to be a minimally clinically meaningful effect based on prospective studies, predictive of the risk of falling [20–22]. There were no significant differences compared with PBO for any of the active treatments upon morning awakening.

Driving Performance

LEM did not impair driving performance at days 2 or 9 post treatment based on least squares mean estimates of SDLP and ΔSDLP (mean drug–PBO changes) (Online Resource 2). The upper limit of the 95% CI of the mean treatment difference from PBO in SDLP was < 2.4 cm, indicating that LEM did not exceed the clinically important threshold. Individual subject differences from PBO in SDLP are shown in Online Resource 3. Symmetry analysis showed that, as expected, following treatment with zopiclone, a significantly greater proportion of subjects had an increase in SDLP > 2.4 cm (driving impairment) than a decrease of the same magnitude on both days 2 (p < 0.001) and 9 (p < 0.05). In contrast, the symmetry analyses were not significant for either LEM dose on day 2 or day 9.

Cognitive Performance

In Study 304, neither LEM dose significantly impacted any CPAB domain compared with PBO at days 2 and 3 (Fig. 3). In contrast, ZOL resulted in significantly poorer performance in the domains of continuity of attention, quality of memory, and speed of memory retrieval versus PBO. The least squares mean change from baseline for LEM5 in the domains of continuity of attention, quality of memory, and speed of memory retrieval was significantly different compared with ZOL (all p < 0.05), indicating improvement. At days 30 and 31, there were no significant differences from baseline in the CPAB domains for any treatment condition (Fig. 3) except for LEM10, which was the only treatment condition that showed a mean increase from baseline (improvement) in the speed of memory retrieval domain compared with ZOL (p < 0.05).Fig. 3 Change from baseline in cognitive performance as measured by CPAB in subjects aged ≥ 65 years from Study 304 for the domains a power of attention, b continuity of attention, c quality of memory, and d speed of memory retrieval. For power of attention and speed of memory retrieval, lower values reflect better performance; for continuity of attention and quality of memory, higher values reflect better performance. ‡p < 0.01, §p < 0.05 versus PBO; ¶p < 0.001, #p < 0.01, ¶¶p < 0.05 versus ZOL. Changes from baseline were analyzed using a repeated mixed-effects model with factors for region, visit (days 2 and 3 and days 30 and 31), and treatment-by-visit interactions as fixed effects, and baseline CPAB domain as a covariate. Missing values were not imputed and assumed to be missing at random. BL baseline, CPAB cognitive performance assessment battery, LEM5, lemborexant 5 mg, LEM10 lemborexant 10 mg, LSM least squares mean, PBO placebo, SE standard error, ZOL zolpidem tartrate extended-release 6.25 mg

In Study 108, there were no significant differences in the CPAB domains of power of attention, continuity of attention, quality of memory, and speed of memory between LEM doses and PBO on waking in the middle of the night (Online Resource 4). In contrast, based on nonoverlapping 95% CIs, the continuity of attention and quality of memory domains were both significantly poorer with ZOL versus PBO. On morning awakening (8 h post dose), there were no significant differences in any CPAB domain among treatment groups (Online Resource 4).

Auditory Awakening Threshold

In Study 108, the time to awaken to an auditory stimulus during the LEM and ZOL treatment condition did not differ from PBO (Online Resource 5). However, there were differences in the proportion of subjects who did not awaken to the maximum tone of 105 dB: 11.1% (n = 3/27) with LEM5, 3.7% (n = 1/27) with LEM10, 3.7% (n = 1/27) with PBO, and 18.5% (n = 5/27) with ZOL.

Return-to-Sleep Latency

In Study 108, there were significant differences in RSL following the middle-of-the-night awakening for LEM5 (p < 0.01), LEM10 (p < 0.001), and ZOL (p < 0.05) compared with PBO (Fig. 4). Notably, RSL was shortest for subjects who received LEM10 (10.6 min), followed by LEM5 (21.1 min) and ZOL (22.5 min) compared with those who received PBO (41.3 min). There was a significant difference in RSL for LEM10 (p < 0.05) compared with ZOL.Fig. 4 Mean (SD) RSL in subjects aged ≥ 65 years from Study 108. * p < 0.05, †p < 0.01 versus PBO; ‡p < 0.05 versus ZOL. ER extended release, PBO placebo, RSL return-to-sleep latency, SD standard deviation, ZOL zolpidem tartrate extended-release 6.25 mg

Safety

LEM was well tolerated in subjects aged ≥ 65 years across Studies 304, 106, and 108 (Online Resources 6–8). No serious treatment-emergent AEs (TEAEs), falls, or deaths were reported with LEM5 or LEM10 across the studies. In Study 304, one subject in the ZOL group experienced three serious TEAEs and two subjects also in the ZOL group experienced one serious TEAE each. Most TEAEs across the studies and treatment groups were mild to moderate in severity. The most common TEAE with LEM in Study 304 was somnolence, which appeared to be dose dependent (Online Resource 6).

Discussion

These post hoc analyses of older adults (aged ≥ 65 years) from three clinical studies revealed significant benefits of LEM on aspects of sleep and morning functioning versus PBO. Notably, LEM improved sleep maintenance during the second half of the night. Further, after middle-of-the-night awakening, subjects taking LEM10 returned to sleep significantly faster than those taking ZOL. Potential residual effects of LEM were also evaluated and found to be similar to PBO. Specifically, postural stability, next-day driving performance, and cognition were generally better or associated with less impairment with LEM versus ZOL. LEM also did not impair the ability to awaken to auditory signals and was well tolerated in these older adult populations. These analyses provided preliminary evidence of benefit from the use of lemborexant in older patients with insomnia. Nonetheless, in the future, confirmatory studies that can definitively establish the safety and efficacy of lemborexant in this patient population (aged ≥ 65 years) would be desirable.

The increase from baseline in body sway was significantly larger for ZOL versus PBO on days 2/3, whereas there were no significant treatment differences in body sway for either LEM treatment group versus PBO. Habitual physical activity in older adults has been reported to reduce insomnia [23], and muscle strength has been associated with improved physical and mental health-related quality of life in older adults (> 90 years of age) [24]. These factors may be of interest in future studies examining insomnia in older adults.

Even though the studies were not powered to detect treatment differences in the subgroups of older adults, the findings of these post hoc analyses are consistent with results from the overall Study 304, Study 106, and Study 108 populations [13, 16, 17]. Trends in postural stability, cognitive performance, and awakening to auditory signals in subjects aged ≥ 65 years were similar to those in the overall Study 108 population [17]. Further, consistent with observations in adults aged ≥ 21 years, LEM showed no clinically meaningful effects on next-day driving performance in healthy subjects aged ≥ 65 years [16]. Safety signals reported in subjects aged ≥ 65 years in all three studies were consistent with those in the overall study populations [13, 16, 17]. In contrast, in healthy subjects 55–65 years of age, a bedtime dose of ZOL was found to impair next-day driving performance [25, 26]. These studies corroborate the findings presented here, where ZOL but not LEM was associated with impaired next-day functioning in older adults.

As a potential limitation, it should be noted that the studies from which these data were derived were not powered to detect treatment differences in the subgroup of adults ≥ 65 years of age.

Conclusion

These additional analyses from three clinical studies used a variety of methodologies that demonstrate that LEM appears safe and effective in this important subpopulation of older adults. Real-world and controlled studies could be considered to definitively characterize the safety and efficacy in this population.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 880 KB)

Medical writing assistance from outline to final draft was provided by Lisa Baker, PhD, CMPP, Samantha Forster, PhD, CMPP, and Rency Mathew, PhD of Envision Pharma Group, and editorial support was provided by Carla Resvanis of OPEN Health Group. Both were funded by Eisai. Envision Pharma Group services complied with the International Society for Medical Publication Professionals guidelines for Good Publication Practice (GPP3).

Declarations

Funding

This work was supported by Eisai Inc., which is the manufacturer/licensee of lemborexant. Eisai was involved in the study design, data collection, data analysis, and preparation of the manuscript.

Conflicts of interests

Dr. Gotfried has received research support and/or speaker fees from Eisai Inc., Idorsia, Jazz Pharmaceuticals, and Merck. Dr. Auerbach declares he has no conflicts of interest. Dr. Dang-Vu has been a consultant and/or speaker for and/or has received research support from Eisai Inc., Jazz Pharmaceuticals, and Paladin Labs. Dr. Mishima has been a consultant and/or speaker for and/or has received research support from Eisai Co., Ltd., MSD, Nobelpharma, and Takeda Pharmaceutical Limited. Drs Kumar and Moline are employees of Eisai Inc. Dr. Malhotra is a former employee of Eisai Inc.

Availability of data

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics Approval

The study protocols were approved by relevant institutional review boards and independent ethics committees. The studies adhered to Good Clinical Practice guidelines, the Declaration of Helsinki and local regulations.

Consent to participate

All study participants provided written informed consent prior to participation.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author contributions

Study concept and design: Margaret Moline. Acquisition of subjects and/or data: Mark H. Gotfried. Analysis and interpretation of data: all authors. Preparation of manuscript: all authors. All authors have read and approved the final submitted manuscript and agree to be held accountable for the work.

Manoj Malhotra: Formerly at Eisai Inc.
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