pii: jc-17-00052
`
`http://dx.doi.org/10.5664/jcsm.6800
`
`SCIENTIFIC INVESTIGATIONS
`Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of
`Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-
`Blind, Placebo-Controlled Study
`Patricia Murphy, PhD1; Margaret Moline, PhD1; David Mayleben, PhD2; Russell Rosenberg, PhD3; Gary Zammit, PhD4; Kate Pinner, MSc5;
`Shobha Dhadda, PhD1; Quan Hong, PhD1; Luigi Giorgi, MD5; Andrew Satlin, MD1
`1Eisai Inc, Woodcliff Lake, New Jersey; 2Community Research Inc, Cincinnati, Ohio; 3NeuroTrials Research Inc, Atlanta, Georgia; 4CLINILABS, Inc, New York, New York; 5Eisai Ltd,
`Hatfield, United Kingdom
`
`Study Objectives: To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and
`evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset
`[WASO]) at the beginning and end of treatment.
`Methods: Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in
`a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or
`placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured
`by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized
`reaction time tests, and adverse events (AEs).
`Results: A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (~63%
`female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria
`for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective
`sleep onset latency at the beginning and end of treatment for lemborexant doses ≥ 5 mg (P < .05). WASO and subjective WASO showed numerically greater
`improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence.
`Conclusions: Lemborexant doses ranging from 2.5–10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.
`Clinical Trial Registration: Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design,
`Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838;
`Identifier: NCT01995838
`Keywords: Bayesian method, insomnia, orexin receptor antagonists
`Citation: Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, a dual orexin receptor
`antagonist (DORA) for the treatment of insomnia disorder: results from a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin
`Sleep Med. 2017;13(11):1289–1299.
`
`INTRODUCTION
`
`Insomnia is highly prevalent, with approximately 30% of
`the general population reporting symptoms of insomnia1 and
`6.6% satisfying the Diagnostic and Statistical Manual of Men-
`tal Disorders, Fourth Edition2 criteria for insomnia disorder.3
`Non-depressed individuals with insomnia are twice as likely
`to develop depression compared with individuals not suffer-
`ing from insomnia.4 Insomnia results in lost work performance
`amounting to an estimated $63 billion annually.5
`Benzodiazepines, nonbenzodiazepine hypnotics (“z-drugs”
`such as zolpidem, zolpidem CR, and eszopiclone), and sedat-
`ing antidepressants are the primary prescription medications
`currently used to treat insomnia in the United States, but there
`is need for agents that more effectively reduce wakefulness
`throughout the night without safety issues such as complex
`sleep-related behaviors and cognitive/psychomotor impair-
`ments.6–11 Impairment of driving abilities the day following
`
`BRIEF SUMMARY
`Current Knowledge/Study Rationale: There is a need for improved
`efficacy and safety of prescription medications used for treating
`insomnia. In particular, patients would benefit if treatments showed
`greater efficacy in reducing wakefulness throughout the night without
`producing important residual morning sleepiness.
`Study Impact: This study of lemborexant, a dual orexin receptor
`antagonist in clinical development, identified doses that showed
`promising activity for treatment of insomnia, while not substantially
`affecting either subjective or objective measures of residual morning
`sleepiness. These lemborexant doses will be evaluated in additional
`clinical trials.
`
`therapy and falls by the elderly are also key safety issues
`that have come to the forefront with benzodiazepines and z-
`drugs.10–13 These agents also may lose efficacy over time.9,14
`These issues with currently available therapies have driven in-
`terest in the orexin system as a different target for developing
`
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`EISAI EXHIBIT 1032
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`insomnia drugs. Orexins are neuropeptides involved with
`regulating the sleep-wake cycle15; they help promote wakeful-
`ness by binding to the G-protein–coupled receptors, OX1R
`and OX2R.9,16 The dual orexin receptor antagonist (DORA) su-
`vorexant (approved in the United States and Japan17) has been
`shown to treat insomnia disorder and is thought to block the
`wakefulness that is interfering with sleep.16 However, higher
`doses have been associated with residual daytime sleepiness,
`which is a safety concern.18
`Lemborexant (E2006) is an orally active investigational
`DORA in clinical development. Presented here are the results
`from a phase 2 study of the efficacy and safety of lemborexant
`in the treatment of subjects with insomnia disorder. The study
`used a Bayesian adaptive design to permit more efficient use
`of the data. Frequent interim analyses (IAs) utilized emerg-
`ing on-treatment outcomes to adjust randomization ratios to
`assign more subjects to the most successful doses and to test
`for early signals of success or futility. Both approaches im-
`proved the efficiency of the study design for dose selection and
`decision-making.
`
`METHODS
`Objectives
`The primary study objective was to identify the dose or doses
`of lemborexant that maximized efficacy for the treatment of
`insomnia while minimizing next-morning residual sleepiness.
`This objective was evaluated using a utility function of ef-
`ficacy and safety that combined sleep efficiency (SE) ([total
`sleep time / time in bed] × 100%) as measured by polysom-
`nography (PSG) with residual morning sleepiness as rated on
`the Karolinska Sleepiness Scale (KSS). Because the primary
`objective focused on identifying a dose or doses that balanced
`efficacy and safety, it was necessary to find a means of jointly
`assessing both factors. To do this, a utility function integrating
`SE and KSS was developed. SE was used in the utility function
`because it takes into account both sleep onset and sleep main-
`tenance in one parsimonious measure. The KSS was included
`as a validated measure of subjective sleepiness that has been
`found to be sensitive to sleepiness in other studies of treat-
`ments for insomnia.19 Utility indices combining efficacy and
`safety variables have also been developed and used effectively
`in studying treatments in other disease areas.20
`Clinically significant differences from placebo were defined
`in advance as superiority by ≥ 6% (equivalent to > 30 minutes
`increase in time spent asleep, which is a clinically significant
`difference) on change from baseline of SE at days 1 and 2 and
`no change of > 4 units from baseline on the KSS at 1 hour af-
`ter morning waketime on days 2 and 3. Using this definition,
`a score of zero on the utility function corresponded to either
`insufficient efficacy or unacceptable next-day sleepiness. A
`utility function score > 1 represented a sufficiently positive
`benefit:risk ratio to warrant the selection of doses for further
`study. This utility function was the first primary endpoint of the
`study. A second primary endpoint was a change of > 4 units
`relative to placebo on the KSS at 1 hour after waketime on days
`15 and 16, included as a measure of unacceptable safety after
`
`15 days of treatment. Thus, at any IA, randomization could be
`stopped for an early signal of success if the Bayesian analysis
`indicated there was at least 1 dose with at least an 85% probabil-
`ity of having a utility function > 1, and if that dose did not meet
`the operational definition of unacceptable safety at days 15 and
`16. If randomization was not stopped early, success at study
`completion was defined similarly, except that the probability of
`the utility function > 1 was only required to be at least 80%.
`Secondary objectives were evaluated by additional PSG
`measures of sleep improvement comparing each dose of lem-
`borexant with placebo. Efficacy at the beginning of treatment
`was measured as change from mean at baseline to mean after
`dosing on day 1 and day 2 for SE (overall efficacy), latency
`to persistent sleep (LPS; sleep onset, defined as minutes from
`“lights off” to the first epoch of 20 consecutive epochs of non-
`wakefulness), and wake after sleep onset (WASO; sleep main-
`tenance, defined as minutes of wakefulness from the onset of
`persistent sleep until “lights on”). Efficacy at the end of treat-
`ment was measured as change in SE, LPS, and WASO from
`mean baseline to mean after dosing on days 14 and 15. Poten-
`tial durability of effect from the beginning to end of treatment
`was evaluated as change from baseline in mean SE, LPS, and
`WASO after the first 2 doses compared with change from base-
`line in mean SE, LPS, and WASO after the last 2 doses. Poten-
`tial for rebound insomnia was measured as change from mean
`SE at baseline to mean SE after dosing (with placebo washout)
`on days 16 and 17.
`Exploratory efficacy objectives included subject-reported
`outcomes on the sleep diary. Subjects completed sleep dia-
`ries on each morning of the study, providing self-reported as-
`sessments of sleep including subjective sleep efficiency (sSE;
`[subjective total sleep time / subjective time in bed] × 100%),
`subjective sleep onset latency (sSOL; estimated minutes from
`lights off to sleep onset), and subjective wakefulness after
`sleep onset (sWASO; estimated minutes of wakefulness during
`the night after initial sleep onset).
`
`Study Population
`Study participants were men and women 19 to 80 years of age
`who met Diagnostic and Statistical Manual of Mental Disor-
`ders, Fifth Edition21 criteria for insomnia disorder. Subjects
`were also required to meet the following objective inclusion
`criteria on 2 consecutive screening/baseline PSGs: LPS aver-
`age of ≥ 30 minutes with neither night < 15 minutes; and/or
`WASO average of ≥ 30 minutes with neither night < 20 minutes;
`and an SE average of ≤ 85% with neither night > 87.5%. At the
`first screening visit, an in-depth interview with the investigator
`visit included self-reported sleep, medical, and psychiatric his-
`tory. In addition, medical records were reviewed if available.
`Questionnaires were administered to rule out subjects with life-
`time suicidal behavior, suicidality within the past 6 months, or
`threshold levels of self-reported depression and anxiety symp-
`toms. Urine samples were tested for common drugs of use/
`abuse (eg, cocaine, cannabinoids, phencyclidine, nicotine/coti-
`nine, opioids [as a group], benzodiazepines, barbiturates, am-
`phetamines, and methamphetamine). Subjects with diagnosis
`of a sleep disorder other than insomnia were excluded. Use of
`sleep medication or concomitant medications to treat insomnia
`
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`Figure 1—Study design.
`
`Randomization
`
`Screening
`
`Baseline
`
`Treatment
`
`Rebound
`insomnia
`
`Follow-up
`
`EOS
`
`−21
`
`Study
`day
`
`−9
`to
`−4
`
`−8
`
`−3
`
`−1
`
`1
`
`2
`
`3
`
`14 15 16 17 18
`
`30
`
`Placebo, LEM 1, 2.5,
`5, 10, 15, 25 mg
`
`All placebo
`
`= 8 h PSG
`
`=KSS, DSST, RTT*
`
`* = assessed within 15 minutes, and at 1 hour and 2 hours after morning waketime. DSST = Digit Symbol Substitution Test, EOS = end of study,
`KSS = Karolinska Sleepiness Scale, LEM = lemborexant, PSG = polysomnography, RTT = Reaction Time Task.
`
`symptoms within 2 weeks of first screening/baseline PSG, or
`having a current diagnosis or being treated for major medical or
`psychiatric disorders excluded subjects from this study.
`Written informed consent was obtained from all subjects
`after they received an explanation of study procedures, risks,
`and benefits. The study protocol was approved by the relevant
`institutional review board and was conducted in accordance
`with principles of Good Clinical Practice and any applicable
`local regulations.
`
`Study Design and Procedure
`The study was conducted at 22 investigational sites in the
`United States from November 13, 2013 to April 29, 2014 (Clin-
`icalTrials.gov NCT01995838). Study treatment was adminis-
`tered for 15 days, followed by a single-blind placebo washout
`for 2 days (Figure 1). The study drug was taken 30 minutes
`before a subject’s median habitual bedtime when in clinic and
`30 minutes before self-selected bedtime when at home. Sub-
`jects continued to complete the sleep diary for 12 additional
`days after the treatment period.
`A Bayesian dose-response adaptive design with response
`adaptive randomization (RAR) was used to fully explore the
`dose-response curve of lemborexant. The RAR utilized results
`from frequent IAs to update randomization ratios and random-
`ize subjects to placebo or to 1 of 6 active lemborexant doses
`(1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, or 25 mg per day) by
`weighting the allocation toward the doses most likely to meet
`prespecified efficacy and safety criteria according to the util-
`ity function that combined the evaluation of efficacy as mea-
`sured by SE and next-morning residual sleepiness as measured
`by the KSS. The first 105 subjects were randomized at a fixed
`1:1:1:1:1:1:1 ratio to placebo or to 1 of the active lemborexant
`dose arms. After 15 subjects were allocated to each group,
`the first IA was conducted, and RAR was started. A maxi-
`mum sample size of 300 subjects was set. An independent data
`monitoring committee conducted the IA every 2 weeks. After
`
`each IA, the study could be stopped for success or futility, or
`continued with updated randomization allocations.
`
`Safety Assessments
`Safety and tolerability were assessed by adverse event (AE)
`reports and changes in vital signs, electrocardiograms (ECGs),
`clinical laboratory reports, and physical examinations. Poten-
`tial for residual morning sleepiness was assessed using sub-
`jective (sleep diary and KSS) and objective measures (Digit
`Symbol Substitution Test [DSST] and a Reaction Time Task
`[RTT; simple reaction time and 5-choice reaction time]). On
`each morning in the clinic following a PSG recording, within
`15 minutes, and at 1 hour and 2 hours after morning waketime,
`the KSS, a DSST, and a RTT were administered (Figure 1).
`AEs related to the mechanism of action of lemborexant that
`are associated with the sleep disorder narcolepsy (eg, sleep pa-
`ralysis) were reported as designated compound-specific AEs of
`special interest and were documented in depth. Suicidality was
`assessed using the Columbia-Suicide Severity Rating Scale22 at
`several time points throughout the study.
`Analyses of relationships of pharmacokinetic parameters
`with pharmacodynamic markers and safety variables will be
`reported separately.
`
`Statistical Analyses
`Efficacy analyses were based on the full analysis set, defined
`as subjects who received ≥ 1 dose of study drug and had ≥ 1
`postdose primary efficacy measurement. At each IA and at fi-
`nal analysis, the SE and KSS data were analyzed according to
`independent dose-response models. The active treatment arms
`for each endpoint were modeled with a normal dynamic lin-
`ear model. Endpoints were then jointly assessed using utility
`functions. The adaptive aspects of the trial were based on the
`utility function. The utility was a function of the 2 endpoints,
`constructed by specifying the 1-dimensional component for
`each endpoint and then combining them multiplicatively.
`
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`Figure 2—Subject disposition.
`
`Subjects consented
`n = 616
`
`Subjects randomized
`n = 291 (47.2%)
`
`Screen failures
`n = 325 (52.8%)
`
`Inclusion/exclusion criteria
`Adverse event
`Lost to follow-up
`Withdrawn consent
`Other
`
`259
`2
`8
`23
`33
`
`Placebo
`n = 56
`
`Lemborexant (all doses)
`n = 235
`
`Completed
`Discontinuation: AE
`Discontinued: all other
`AE = adverse event.
`
`51 (91.1%)
`0 (0%)
`5 (8.9%)
`
`Completed
`Discontinuation: AE
`Discontinued: all other
`
`222 (94.5%)
`1 (0.4%)
`12 (5.1%)
`
`Adaptations as well as decisions regarding success and futility
`were based on the maximum utility dose, defined as the dose
`with highest mean utility. At each IA, the probability that the
`utility exceeded 1 at the maximum utility dose was computed
`and compared with prespecified early stopping criteria. The
`utility function had been constructed so that a utility above 1
`corresponded to regions where efficacy and safety were both
`acceptable. The endpoint of KSS at days 15 and 16 was ana-
`lyzed using a 90% confidence interval (CI) as described in the
`definition of acceptable KSS.
`In addition to the Bayesian analysis, SE change from base-
`line to the mean of days 1 and 2 was analyzed using analysis
`of covariance, with treatment and baseline as fixed effects on
`the full analysis set. Analysis of KSS change from baseline
`to the mean of days 2 and 3 and to the mean of days 15 and
`16 also used analysis of covariance, with treatment and base-
`line as fixed effects on the pharmacodynamics (PD) analysis
`set, defined as subjects who had sufficient PD data to derive
`at least 1 PD parameter. SE or KSS distributions were normal-
`ized by log-transformation before analysis and nonparametric
`methods were used for non-normally distributed data. Least
`squares mean (LSM) change from baseline, standard errors,
`differences between LSMs of placebo and each lemborexant
`dose (LSM difference from placebo), 95% CIs, and P values
`comparing LSM changes from baseline for placebo and each
`lemborexant dose were summarized.
`Secondary efficacy and safety endpoints—SE, LPS, and
`WASO from the beginning of treatment and at end of treatment,
`and rebound insomnia—were analyzed using the same method
`as the SE component of the primary endpoint. Sleep diary pa-
`rameters (sSE, sSOL, and sWASO) were similarly analyzed.
`Incidence of AEs and change from baseline in laboratory
`values, ECG findings, vital signs, weight, and suicidality were
`
`summarized by treatment group using descriptive statistics on
`the safety analysis set, defined as subjects who received ≥ 1
`dose of study drug and had ≥ 1 postdose safety assessment.
`Endpoints for residual morning sleepiness (KSS, DSST, and
`RTT) were analyzed using the same method as the KSS com-
`ponent of the primary endpoint.
`Simulations showed that a maximum sample size of 300
`subjects was sufficient to achieve a desirable chance of suc-
`cess for a wide range of different efficacy and residual morning
`sleepiness scenarios with an overall type I error rate of 2%. All
`statistical tests were based on the 5% level of significance, ex-
`cept for the Bayesian methods used for the primary endpoint.
`
`RESULTS
`Subject Disposition, Baseline Demographics, and
`Characteristics
`A total of 616 subjects were screened, and 291 were random-
`ized into the study (Figure 2). A total of 325 failed screen-
`ing. Screen failures were mostly due to subjects not meeting
`inclusion/exclusion criteria (79.7%). The main reasons for
`screen failures included: not meeting PSG evidence of insom-
`nia (27%), use of prohibited concomitant medications during
`the screening/baseline period prior to randomization (4.6%),
`or testing positive for use of illegal (or legalized) recreational
`drugs (3.9%). Baseline characteristics were similar between
`lemborexant groups and placebo (Table 1). Slightly more than
`60% of subjects were female; the majority were white. Median
`age was 49.0 years (range: 19–80 years) in the lemborexant
`group and 46.5 years (range: 20–79 years) in the placebo group;
`14.4% of all subjects were age 65 years or older. The most com-
`mon subtype of insomnia, determined based on PSG findings,
`
`Journal of Clinical Sleep Medicine, Vol. 13, No. 11, 2017
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`Table 1—Baseline demographics and characteristics.
`
`Category
`Demographics
`Age, y*
`Age, ≥ 65 y, %
`Female, %
`White, %
`Black/
`African American, %
`American Indian/
`Alaskan Native, %
`Other race, %
`BMI, kg/m2 *
`PSG sleep*
`SE, %
`LPS, min
`WASO, min
`Subjective sleep*
`sSE, %
`sSOL, min
`sWASO, min
`
`Placebo
`(n = 56)
`
`1 mg
`(n = 32)
`
`2.5 mg
`(n = 27)
`
`5 mg
`(n = 38)
`
`Lemborexant
`10 mg
`(n = 32)
`
`15 mg
`(n = 56)
`
`25 mg
`(n = 50)
`
`Total
`(n = 235)
`
`47.1 (15.6)
`16.1
`64.3
`69.6
`26.8
`
`53.3 (13.0)
`21.9
`71.9
`78.1
`21.9
`
`49.7 (14.3)
`14.8
`63.0
`77.8
`18.5
`
`51.1 (14.3)
`21.1
`60.5
`84.2
`7.9
`
`47.1 (13.7)
`15.6
`62.5
`65.6
`21.9
`
`44.0 (14.6)
`7.1
`57.1
`69.6
`26.8
`
`48.9 (13.4)
`10.0
`62.0
`78.0
`16.0
`
`48.5 (14.2)
`14.0
`62.1
`75.3
`19.1
`
`Combined
`Total
`(n = 291)
`
`48.3 (14.4)
`14.4
`62.5
`74.2
`20.6
`
`0.0
`
`0.0
`
`0.0
`
`2.6
`
`3.1
`
`0.0
`
`2.0
`
`1.3
`
`1.0
`
`3.6
`26.8 (5.1)
`
`0.0
`26.9 (4.2)
`
`3.7
`26.3 (4.2)
`
`5.3
`26.6 (4.1)
`
`9.4
`26.3 (4.4)
`
`3.6
`27.0 (5.1)
`
`4.0
`26.6 (4.9)
`
`4.3
`26.7 (4.6)
`
`4.1
`26.7 (4.7)
`
`66.6 (9.2)
`58.8 (30.6)
`108.9 (37.5)
`
`61.7 (12.3)
`69.9 (39.1)
`121.2 (49.6)
`
`61.3 (14.7)
`73.0 (50.9)
`119.8 (51.2)
`
`63.1 (12.5)
`70.4 (42.7)
`113.7 (48.0)
`
`65.1 (12.2)
`65.1 (11.7)†
`72.5 (36.1)
`67.9 (52.4)†
`103.5 (34.4)† 103.3 (42.9)
`
`66.6 (10.9)
`64.3 (45.9)
`103.9 (40.5)
`
`64.7 (11.8)§
`64.2 (12.3)‡
`67.4 (41.6)§
`69.5 (43.6)‡
`109.3 (44.4)‡ 109.2 (43.1)§
`
`62.8 (13.0)
`61.0 (32.0)
`118.4 (56.4)
`
`63.4 (10.8)
`57.0 (27.1)
`115.8 (43.1)
`
`65.8 (8.5)
`51.2 (15.0)
`113.1 (49.9)
`
`66.0 (11.6)
`61.9 (36.7)
`102.7 (50.9)
`
`65.5 (11.3)
`66.4 (11.8)†
`63.6 (46.8)
`48.2 (27.9)†
`108.7 (37.9)† 100.9 (38.9)
`
`63.9 (11.3)
`62.4 (27.5)
`110.4 (50.2)
`
`64.6 (11.4)§
`65.1 (11.0)‡
`59.1 (33.4)§
`58.7 (33.8)‡
`107.7 (45.2)‡ 109.8 (47.6)§
`
`* = data are presented as mean (standard deviation). † = n = 31. ‡ = n = 234. § = n = 290. BMI = body mass index, LPS = latency to persistent sleep,
`PSG = polysomnography, SE = sleep efficiency, sSE = subjective sleep efficiency, sSOL = subjective sleep onset latency, sWASO = subjective wakefulness
`after sleep onset, WASO = wake after sleep onset.
`
`was mixed insomnia (ie, subjects exhibiting both sleep onset
`and sleep maintenance insomnia) (59.8%), followed by sleep
`maintenance insomnia only (29.2%), sleep onset insomnia only
`(9.6%), and other (1.4%). Baseline sleep parameters, including
`SE, LPS, WASO, sSE, sSOL, and sWASO, were similar among
`lemborexant dose groups and placebo (Table 1). The majority
`of subjects (lemborexant: 94.5%; placebo: 91.1%) completed
`the planned 15-day treatment regimen.
`
`Primary Analysis—Utility Index
`The study was stopped for early success after the fifth IA,
`which included data from 262 of the planned 300 subjects. At
`that analysis, 4 of the 6 doses (5, 10, 15, and 25 mg) met the util-
`ity index and KSS criteria for success, with 15 mg identified
`as the maximum utility dose; that is, this dose had the high-
`est probability (93.5%) of having a utility index > 1, without
`unacceptable KSS at days 15 and 16. By the time this analysis
`was completed, an additional 29 subjects had been random-
`ized, for a total n value of 291. At study completion, analysis of
`data from all 291 subjects showed that all 6 lemborexant doses
`met criteria for success (> 80% probability of having a utility
`index > 1, with acceptable KSS at days 15 and 16), with 15 mg
`again identified as the maximum utility dose.
`
`Efficacy on Secondary Endpoints
`Sleep Efficiency
`After the first 2 doses, all dose groups of lemborexant showed
`significantly greater improvement from baseline in LSM SE
`
`compared with placebo (Figure 3A; P < .05 for all doses;
`P ≤ .0001 for doses ≥ 10 mg), with generally higher SE at
`higher lemborexant doses. The improvements in SE with lem-
`borexant ranged from 4.4% (2.5 mg dose) to 10.1% (15 and 25
`mg doses) above the placebo percentage. Findings were similar
`after the last 2 doses on days 14 and 15, with statistically sig-
`nificant improvement from baseline compared with placebo for
`all lemborexant dose groups ≥ 2.5 mg (P < .05 for doses ≥ 2.5
`mg; P < .0001 for doses ≥ 10 mg). The improvements in SE
`with lemborexant ranged from 0.3% (1 mg) to 8.9% (25 mg)
`above the placebo percentage.
`Similar to these PSG results, there was generally substan-
`tially greater improvement from baseline in LSM sSE on lem-
`borexant compared with placebo (Figure 3B). Statistically
`significant improvements in mean sSE compared with placebo
`were observed at lemborexant doses of ≥ 5 mg on days 1 to 7
`(P < .01), with differences ranging from 6.0% (5 mg) to 9.4%
`(10 mg) higher than placebo. On days 8 to 15, significant im-
`provement in LSM sSE compared with placebo was observed
`at doses of ≥ 2.5 mg (P < .05 for doses ≥ 2.5 mg; P < .01 for
`doses ≥ 10 mg), with differences ranging from 4.9% (2.5 mg)
`to 9.5% (10 mg) higher than placebo.
`Sleep Onset
`After the first 2 doses, all dose groups of lemborexant ex-
`perienced greater decreases from baseline in LSM LPS
`compared with placebo (Figure 4A). Because LPS was not
`normally distributed, comparisons were conducted using the
`geometric mean ratio (active dose/placebo), which showed
`
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`Days 1–7
`
`Days 8–15
`§
`
`§
`
`*
`
`†
`
`*
`
`‡
`
`‡
`
`† †
`
`25
`
`20
`
`15
`
`10
`
`5
`
`B
`
`LSM change from baseline (%)
`
`Figure 3—Sleep efficiency.
`A
`
`Days 1/2
`
`Days 14/15
`
`§ §
`
`§
`
`§
`
`§
`
`§
`
`†
`
`* *
`
`‡
`
`‡
`
`30
`
`25
`
`20
`
`15
`
`10
`
`LSM change from baseline (%)
`
`5 0
`
`PBO
`
`1
`
`10
`
`15
`
`25
`
`0
`
`PBO
`
`1
`
`10
`
`15
`
`25
`
`5
`2.5
`5
`2.5
`Dose (mg)
`Dose (mg)
`Sleep efficiency as measured by (A) polysomnography and (B) sleep diary. * = P < .05. † = P < .01. ‡ = P < .001. § = P ≤ .0001. P values calculated based on
`differences in least squares mean (LSM) changes from baseline between lemborexant and placebo (PBO). Error bars represent upper confidence interval.
`
`B
`
`10
`
`15
`
`25
`
`Figure 4—Latency to persistent sleep and sleep onset latency.
`Dose (mg)
`A
`2.5
`5
`
`10
`
`15
`
`25
`
`PBO
`
`1
`
`0
`
`PBO
`
`1
`
`Dose (mg)
`2.5
`5
`
`†
`
`†
`
`†
`
`‡
`
`§
`
`§
`
`§
`
`§
`
`†
`
`§
`
`0
`
`–5
`
`–10
`
`–15
`
`–20
`
`–25
`
`–30
`
`–35
`
`–40
`
`LSM change from baseline (min)
`
`†
`
`§
`
`‡
`
`†
`
`‡
`
`§ §
`
`§ §
`
`§
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`–60
`
`–70
`
`LSM change from baseline (min)
`
`Days 1/2
`Days 14/15
`Days 1–7
`Days 8–15
`(A) Latency to persistent sleep as measured by polysomnography and (B) sleep onset latency as measured by sleep diary. † = P < .01. ‡ = P ≤ .001.
`§ = P ≤ .0001. P values calculated based on differences in geometric mean ratio between lemborexant and placebo (PBO). Error bars represent lower
`confidence interval (CI). LPS/sSOL are not considered normally distributed, but for ease of presentation of data, adjusted LSMs and 95% CIs are shown
`here. LPS = latency to persistent sleep, LSM = least squares mean, sSOL = subjective sleep onset latency.
`
`a statistically significant decrease in mean LPS compared
`with placebo in lemborexant dose groups ≥ 2.5 mg (P < .01
`for doses ≥ 2.5 mg; P < .001 for doses ≥ 10 mg). A generally
`shorter LPS was seen as lemborexant dose increased. The
`decreases in median LPS with lemborexant ranged from 1.5
`
`(1 mg) to 13.8 (25 mg) minutes greater than with placebo.
`Similarly, following the last 2 doses, decreases from base-
`line in LSM LPS were significantly greater than placebo at
`lemborexant doses of ≥ 2.5 mg (P < .01 for doses ≥ 2.5 mg;
`P < .001 for doses ≥ 10 mg). The decreases in median LPS
`
`Journal of Clinical Sleep Medicine, Vol. 13, No. 11, 2017
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`P Murphy, M Moline, D Mayleben, et al. Lemborexant, a Dual Orexin Receptor Antagonist for Treatment of Insomnia
`
`PBO
`
`1
`
`Dose (mg)
`2.5
`5
`
`10
`
`15
`
`25
`
`† †
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`–60
`
`–70
`
`–80
`
`B
`
`LSM change from baseline (min)
`
`10
`
`15
`
`25
`
`†
`
`†
`
`§
`
`†
`
`§
`
`Figure 5—Wake after sleep onset.
`Dose (mg)
`A
`2.5
`5
`
`PBO
`
`1
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`–60
`
`–70
`
`–80
`
`LSM change from baseline (min)
`
`Days 8–15
`Days 1–7
`Days 14/15
`Days 1/2
`Wake after sleep onset as measured by (A) polysomnography and (B) sleep diary. † = P < .01. § = P ≤ .0001. P values calculated based on differences in
`least squares mean (LSM) changes between lemborexant and placebo (PBO). Error bars represent lower confidence interval.
`
`with lemborexant ranged from 7.0 (1 mg) to 17.3 (25 mg)
`minutes greater than with placebo.
`Sleep diary results were similar; all dose groups of lembo-
`rexant experienced greater decreases from baseline in LSM
`sSOL compared with placebo (Figure 4B). These changes
`were statistically significant at lemborexant doses ≥ 2.5 mg
`(P < .01) on days 1 to 7. The decreases in median sSOL with
`lemborexant ranged from 3.2 (1 mg) to 18.5 (10 mg) minutes
`greater than with placebo. On days 8 to 15, statistical improve-
`ments in LSM sSOL compared with placebo were observed for
`lemborexant doses ≥ 2.5 mg (P < .01). The decreases in median
`sSOL with lemborexant ranged from 7.1 (1 mg) to 20.9 (10 mg)
`minutes greater than with placebo.
`Sleep Maintenance
`After the first 2 doses, all dose groups of lemborexant showed
`greater decreases from baseline in LSM WASO compared with
`placebo (Figure 5A), and these decreases were significantly
`greater for lemborexant dose groups of ≥ 10 mg (P < .01). The
`decreases in WASO with lemborexant ranged from 2.3 (2.5
`mg) to 29.3 (15 mg) minutes greater than with placebo. After
`the last 2 doses, decrease from baseline in LSM WASO was
`significantly greater compared with placebo for lemborexant
`doses of ≥ 15 mg (P < .01). The differences in WASO with
`lemborexant ranged from an increase of 5.7 minutes (1 mg)
`to a decrease of 21.5 minutes (25 mg) compared with placebo.
`Sleep diary results showed a similar trend (Figure 5B).
`For days 1 to 7, subjects treated with lemborexant reported
`numerically greater decreases from baseline in LSM sWASO
`than did subjects treated with placebo for all dose groups of
`lemborexant, despite a relatively large improvement in LSM
`sWASO in the placebo group. This decrease from baseline in
`
`LSM sWASO was significantly greater than that for placebo
`at the 10-mg dose (P < .01), but the observed trends did not
`reach statistical significance at the other doses of lemborexant.
`Treatment with lemborexant resulted in decreases in sWASO
`with differences ranging from 0.1 (1 mg) to 28.6 (10 mg) min-
`utes. Results were similar for days 8 to 15. Subjects treated
`with all doses of lemborexant except 1 mg reported numeri-
`cally greater decreases from baseline in LSM sWASO, with the
`10-mg dose reaching statistical significance (P < .01). The dif-
`ferences in sWASO with lemborexant ranged from an increase
`of 0.7 (1 mg) to a decrease of 26.6 (10 mg) minutes compared
`with placebo.
`Durability of Effect
`Lemborexant demonstrated a durability of effect from the be-
`ginning to the end of treatment. Based on placebo-corrected
`comparisons, the improvements from baseline in LSM SE after
`administration of lemborexant on days 14 and 15 did not dif-
`fer significantly from those after lemborexant on days 1 and
`2. Similarly, changes in LSM WASO did not differ over this
`treatment interval. In fact, mean LPS was numerically shorter
`on days 14 and 15 for all doses except for 1 mg and 25 mg,
`as compared with days 1 and 2; at the 10-mg dose, this com-
`parison reached statistical significance (P < .05), suggesting an
`increase in efficacy from beginning to end of treatment.
`The increases from b