Lemborexant for use in a method for treating irregular sleep-wake rhythm disorders and circadian rhythm sleep disorders associated with neurodegenerative diseases

Abstract

Methods for treating sleep-wake rhythm disorders associated with neurodegenerative diseases and related circadian rhythm sleep disorders are disclosed.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 203,512, filed July 26, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] Novel methods and compositions using lemborexant for use in treating irregular sleep-wake rhythm disorders and related circadian rhythm sleep disorders associated with neurodegenerative diseases are disclosed. [Background technology]

[0003] Irregular Sleep-Wake Rhythm Disorder ("ISWRD") is an internationally recognized and accepted disorder. The sleep-wake pattern exhibited by subjects with ISWRD is diagnostically distinct from insomnia. Unlike insomnia disorder, in ISWRD, sleep is fragmented throughout the entire 24-hour day. In contrast, subjects with insomnia experience either increased sleep latency or decreased sleep maintenance during the night or both, but tend not to sleep during the day. ISWRD is a disruption of the normal circadian, or 24-hour, diurnal pattern of sleep and wakefulness.

[0004] ISWRD is identified and coded as different disorders in several international classification systems, e.g., Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type G47.23 (ICD-10); Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type 307.45-3 (DSM-5); and Circadian Rhythm Sleep-Wake Disorder, Irregular Sleep-Wake Rhythm Disorder 307.45-3 (ICSD-3). Summary of the Invention

[0005] There is an unmet medical need for safe and effective treatments that can be administered conveniently to address the irregular sleep and wake patterns and then assist with the problematic behaviors (e.g., nightfall, restlessness, agitation, and / or wandering) and cognitive difficulties (e.g., with memory and / or attention) associated with ISWRD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The orexin neurotransmitter pathway is directly involved in the regulation of circadian sleep-wake rhythms, and orexins promote wakefulness. Orexin receptors are G protein-coupled receptors found primarily in the brain. Their endogenous ligands, orexin A and orexin B, are expressed by neurons localized in the hypothalamus. Orexin A is a 33 amino acid peptide, and orexin B is a 28 amino acid peptide. Sakurai, T., et al., Cell, 1998, 92, 573-85. There are two subtypes of orexin receptors: orexin receptor 1 and orexin receptor 2. Orexin receptor 1 preferentially binds to orexin A, while orexin receptor 2 binds to both orexin A and orexin B. Orexins have been shown to control wakefulness and sleep states. Chemelli, RM, et al., Cell, 1999, 98, 437-51. Lemborexant is being investigated for the treatment of insomnia disorders and at least one circadian rhythm sleep disorder in subjects suffering from dementia and / or related disorders due to Alzheimer's disease ("AD") and / or mild cognitive impairment due to Alzheimer's disease. See, e.g., U.S. Patent Application Publication No. 2012 / 0095031 and U.S. Provisional Patent Application No. 62 / 335,599 and U.S. Provisional Patent Application No. 62 / 335,611, the contents of which are incorporated herein by reference.

[0007] In some embodiments, methods of treating irregular sleep-wake rhythm disorders associated with neurodegenerative diseases and associated circadian rhythm sleep disorders are provided, comprising administering an effective amount of lemborexant to a subject in need thereof. In some embodiments, prior to administration of an effective amount of lemborexant, the subject in need thereof achieves a score of 46 or greater on the ISWRD ObsRO Questionnaire Daytime Component. In some embodiments, prior to administration of an effective amount of lemborexant, the subject achieves a score of 8 or greater on the ISWRD ObsRO Questionnaire Nighttime Component. In some embodiments, the associated circadian rhythm sleep disorder is selected from insomnia, sleep-wake fragmentation, and circadian rhythm sleep disorder. In some embodiments, the ISWRD is due to at least one neurological disorder.

[0008] In some embodiments, the subject is being treated for ISWRD. In some embodiments, the subject is being treated for ISWRD with an effective amount of lemborexant. In some embodiments, the subject is being treated for an associated circadian rhythm sleep disorder associated with a neurological disorder. In some embodiments, the subject is being treated for an associated circadian rhythm sleep disorder associated with a neurological disorder with an effective amount of said lemborexant. In some embodiments, the subject experiences at least one symptom selected from confusion, anxiety, agitation, pacing, wandering, mental fatigue, physical fatigue, and nightfall symptoms.

[0009] In some embodiments, the neurological disorder may include a neurodegenerative and / or neurodevelopmental disease.

[0010] In some embodiments, neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, synucleinopathies, prion diseases, motor neuron diseases (MND), Huntington's disease (HD), spinocerebellar ataxias (SCA), and spinal muscular atrophy (SMA).

[0011] As the elderly population increases globally, neurological disorders are of great and growing public health concern. Among the many symptoms associated with dementia, sleep and wakefulness disorders are both common and are themselves risk factors that contribute to the development and worsening of neuropathology and symptoms, including cognitive and behavioral impairments, collectively commonly referred to as behavioral and psychological symptoms of dementia (BPSD) based on animal models and human studies.

[0012] Sleep and wake disorders appear early in the course of diseases, e.g., Alzheimer's disease and other dementias, and are commonly associated with a loss of circadian periodicity. Dementia subjects often have a marked decrease in sleep maintenance when attempting to sleep at night, which can consume a significant portion of daily sleep. This pattern is referred to as sleep-wake fragmentation and is characterized by reduced amplitude of the sleep-wake rhythm with reduced predictability of daily sleep-wake patterns.

[0013] As dementia progresses, subjects often exhibit behavioral disorders such as agitation and night wandering. They often exhibit anxiety behaviors that may worsen before and during the evening, where they are described as "nightfall symptoms." Sleep disorders may also increase the risk of falls, due in part to disorientation after waking from sleep. Subjects with the most severe sleep disorders at night have been shown to have more problematic behaviors during the day, such as restlessness, agitation, and wandering. These behaviors, which also disrupt the sleep of caregivers, are the reason that underpins some decisions to hospitalize dementia subjects.

[0014] There is an unmet medical need for safe and effective treatments administered conveniently to address sleep-wake fragmentation in subjects with ISWRD, which would then assist with behavioral problems (e.g., nightfall, restlessness, agitation, and / or wandering) and cognitive difficulties (e.g., with memory and / or attention) associated with dementia due to Alzheimer's disease and / or other neurodegenerative disorders, and / or mild cognitive impairment due to Alzheimer's disease, and may also help slow the brain degeneration that occurs in AD. In particular, increased sleep duration in certain sleep stages, such as slow-wave sleep and REM sleep, may improve cognition. These stages are associated with performance on working memory tasks and memory consolidation, respectively. Targeting sleep may also improve behavioral deficits in AD.

[0015] In some embodiments, a method of continuing treatment of irregular sleep-wake rhythm disorder associated with neurodegenerative disease and associated circadian rhythm sleep disorders is provided, comprising administering an effective amount of lemborexant to a subject in need thereof. In some embodiments, the subject in need thereof achieves a score of 46 or greater on the ISWRD ObsRO Questionnaire Daytime Component. In some embodiments, the subject in need thereof achieves a score of 8 or greater on the ISWRD ObsRO Questionnaire Nighttime Component. In some embodiments, the associated circadian rhythm sleep disorder is selected from insomnia and sleep-wake fragmentation. In some embodiments, the ISWRD is due to at least one neurodevelopmental disorder, at least one neurodegenerative disorder, or a combination thereof.

[0016] In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an increase in sleep efficiency. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences a decrease in daytime sleepiness and / or daytime dozing. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an increase in wakefulness efficiency. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an increase in daytime wakefulness. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences a decrease in behavioral disturbance. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences a decrease in concentration problems. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an increase in performing personal care. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an improvement in emotional stability. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences an increase in participation in leisure time activities. In some embodiments, after administration of an effective amount of lemborexant, the subject experiences increased participation in social and occupational activities.

[0017] In some embodiments, methods are provided for determining therapeutic benefit in treating irregular sleep-wake rhythm disorders associated with neurodegenerative diseases and related circadian rhythm sleep disorders, comprising administering to a subject the ISWRD ObsRO Questionnaire Daytime Component and / or the ISWRD ObsRO Questionnaire Nighttime Component prior to treatment for irregular sleep-wake rhythm disorder and at least one day after treatment for irregular sleep-wake rhythm disorder, and comprising administering an effective amount of lemborexant.

[0018] In some embodiments, subjects to whom lemborexant is administered achieve a pre-treatment score on the ISWRD ObsRO Questionnaire Daytime Component of less than 46. In some embodiments, subjects to whom lemborexant is administered achieve a post-treatment score on the ISWRD ObsRO Questionnaire Daytime Component of 46 or greater.

[0019] In some embodiments, subjects to whom lemborexant is administered achieve a pre-treatment score of less than 8 on the ISWRD ObsRO Questionnaire Nighttime Component. In some embodiments, subjects to whom lemborexant is administered achieve a post-treatment score of 8 or greater on the ISWRD ObsRO Questionnaire Nighttime Component.

[0020] In some embodiments, the methods described herein enhance sleep during nighttime hours. In some embodiments, the methods described herein enhance wakefulness during daytime hours in the treated subject. In some embodiments, after treatment, the subject has increased wakefulness efficiency. In some embodiments, after treatment, the subject has increased sleep efficiency. In some embodiments, the methods described herein reduce daytime sleepiness in the treated subject. In some embodiments, after treatment, the subject has reduced daytime sleepiness and / or daytime dozing. In some embodiments, after treatment, the subject has improved daytime wakefulness. In some embodiments, after treatment, the subject experiences stabilization of one or more circadian rhythms. In some embodiments, after treatment, the subject has improved circadian rhythms.

[0021] In some embodiments, after treatment, the subject experiences clinical stabilization in cognitive impairment. In some embodiments, after treatment, the subject experiences clinical stabilization in cognitive impairment due to neurological disorders. In some embodiments, after treatment, the subject experiences a clinical benefit in cognitive impairment due to Alzheimer's disease and / or other neurodegenerative disorders. In some embodiments, after treatment, the subject experiences a clinical reduction in the rate of decline in cognitive impairment due to Alzheimer's disease. In some embodiments, after treatment, the subject experiences clinical stabilization in subjects with dementia due to Alzheimer's disease and / or other neurodegenerative disorders. In some embodiments, after treatment, the subject experiences a clinical benefit in subjects with dementia due to Alzheimer's disease and / or other neurodegenerative disorders. In some embodiments, after treatment, the subject with dementia due to Alzheimer's disease and / or other neurodegenerative disorders experiences a clinical reduction in the rate of decline. In some embodiments, the methods described herein reduce behavioral impairment in the subject.

[0022] As used herein, the following definitions shall apply unless otherwise indicated.

[0023] As used herein, the term “lemborexant” refers to the compound also known as (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide or (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide, having the structure: [ka] As used herein, the term "effective amount" refers to an amount sufficient to effect an intended result, including, but not limited to, treatment of at least one symptom associated with a disorder or condition, such as ISWRD and / or Alzheimer's disease, as exemplified below. As discussed below, in some embodiments, the effective amount in the dosage form is between 0.5 mg and 100 mg of lemborexant.

[0024] As used herein, the term "subject" refers to an animal subject, e.g., a mammalian subject, e.g., a human. As used herein, a subject may be of any age. In some embodiments, the age of the subject may range from less than 1 year to more than 95 years. In some embodiments, the age of the subject may range from less than 1 year to 15 years. In some embodiments, the age of the subject may range from 10 years to 30 years. In some embodiments, the age of the subject may range from 25 years to 45 years. In some embodiments, the age of the subject may range from 40 years to 60 years. In some embodiments, the age of the subject may range from 55 years to 75 years. In some embodiments, the age of the subject may range from 70 years to 95 years. In some embodiments, the age of the subject may range from 60 years to 95 years.

[0025] As used herein, the terms "treatment" and "treating" refer to an approach for obtaining beneficial or desired results, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit.

[0026] As used herein, the term "ISWRD", also known as "irregular sleep-wake pattern disorder" and "irregular sleep-wake rhythm disorder", refers to a sleep cycle characterized by having a sleep-wake pattern, potentially with a rhythm, where the amplitude of the rhythm may be decreased, or the phase of the pattern may be delayed or advanced, or the duration of the pattern may be shortened or lengthened, or fragmentation of the pattern may occur.

[0027] In ISWRD, the main sleep period is not very clear, and in some embodiments, sleep is fragmented into at least three or four periods, for example, in a 24-hour day. In some embodiments, sleep is fragmented into at least three periods, for example, in a 24-hour day. In some embodiments, sleep is fragmented into at least four periods, for example, in a 24-hour day. The number of sleep fragments can vary from day to day. For example, see Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 394-95. This disorder is a circadian rhythm sleep disorder and is different from general insomnia disorder.

[0028] In some embodiments, the ISWRD may be due to at least one neurological disorder. In some embodiments, the ISWRD may be due to traumatic brain injury. See, e.g., Viola-Saltzman, M. and Watson, NF, Neurol. Clin., 2012, 30, 1299-1312 (describing a potential association between traumatic brain injury and irregular sleep-wake rhythm disorder). In some embodiments, the ISWRD may be due to at least one neurodevelopmental disorder. See, e.g., Abbott, SM and Zee, PC, Sleep Med. Clin., 2015, 10, 517-22. In some embodiments, the at least one neurodevelopmental disorder may be selected from Angelman syndrome, autism, mental retardation, and Down syndrome. See supra. In some embodiments, the at least one neurodevelopmental disorder may be Angelman syndrome. In some embodiments, the at least one neurodevelopmental disorder may be autism. In some embodiments, the at least one neurodevelopmental disorder may be mental retardation. In some embodiments, the at least one neurodevelopmental disorder may be Down's syndrome.

[0029] In some embodiments, ISWRD may be caused by dementia. In some embodiments, ISWRD may be caused by Parkinson's disease. In some embodiments, ISWRD may be caused by dementia caused by Alzheimer's disease. See, e.g., Vitiello, MV and Zee, PC, Sleep Med. Clin., 2009, 4, 213-18. In some embodiments, ISWRD may be caused by dementia caused by related disorders. See, e.g., supra. In some embodiments, ISWRD may be caused by mild cognitive impairment, e.g., dementia caused by traumatic brain injury. See, e.g., supra.

[0030] According to the DSM-V, circadian rhythm sleep-wake disorder, irregular sleep-wake type, is described as “[a] temporally disrupted sleep-wake pattern in which the timing of sleep and wake periods is not consistent across a 24-hour period.” See, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 390.

[0031] As used herein, the term "at least one circadian rhythm sleep disorder" means at least one condition selected from insomnia, sleep-wake fragmentation, and circadian rhythm sleep disorder.

[0032] As used herein, the term "insomnia," also known as "disrupted sleep," "dissociated sleep," "fragmented sleep," and "segmented sleep," among other terms, refers to a sleep pattern in which nighttime sleep is interrupted by one or more awake periods and daytime sleep is interrupted by one or more sleep periods. Insomnia can be assessed, for example, by wake time after sleep onset (WASO), sleep efficiency, duration of awakenings, and / or number of awakenings (NAW) and sleep fragmentation index (SFI).

[0033] As used herein, the term "nightfall symptoms" refers to disorientation that begins at dusk and persists throughout the night.

[0034] As used herein, the term "wake efficiency" refers to the amount of time awake / out of bed, including the number and duration of planned and spontaneous sleep episodes.

[0035] As used herein, the term "sleep-wake fragmentation", also known as "fragmented sleep and wakefulness", is a disorder characterized by nocturnal sleep periods that are interrupted by one or more wakefulness periods and that may be shorter in duration than subjects who slept before the onset of any of the sleep disturbing factors. The time spent asleep during the nocturnal sleep periods is less continuous than normal in any sleep stage. Daytime wakefulness is interrupted by irregular dozing.

[0036] As used herein, the term "circadian rhythm sleep disorder" refers to a family of disorders that affect the timing of sleep, among other bodily processes. Circadian rhythm sleep disorders can be characterized by a disruption or interruption in at least one selected from the following: A. A persistent or recurrent pattern of insomnia primarily due to alterations in the circadian system or an imbalance between endogenous circadian rhythms and the sleep-wake schedule dictated by the individual's physical environment or social or professional schedule; B. insomnia causes excessive sleepiness or insomnia, or both; and C. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. See, for example, 390-98 above.

[0037] As used herein, the terms "stabilization of one or more circadian rhythms," "stabilizing one or more circadian rhythms," and "stabilizing circadian rhythms" refer to the absence of an increase in one or more impairments and / or disruptions associated with a circadian rhythm sleep disorder.

[0038] As used herein, the terms "improving one or more circadian rhythms," "improving one or more circadian rhythms," and "improving circadian rhythm" refer to a reduction in one or more impairments and / or disruptions associated with a circadian rhythm sleep disorder.

[0039] As used herein, the term "dementia" refers to neurocognitive disorder.See, for example, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 602-14; Albert, MS et al., Alzheimer's & Dementia, 2011, 7, 271-72; McKhann, GM, et al., Alzheimer's & Dementia, 2011, 7, 265; Dubois, B., et al., Lancet Neurol., 2014, 13, 614-29.

[0040] As used herein, the term "mild cognitive impairment due to Alzheimer's disease" means a subtle but noticeable and measurable decline in cognitive abilities, such as memory and thinking skills, due to Alzheimer's disease, and is discussed, for example, in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 602-14; Albert, MS et al., Alzheimer's & Dementia, 2011, 7, 271-72; McKhann, GM, et al., Alzheimer's & Dementia, 2011, 7, 265; Dubois, B., et al., Lancet Neurol., 2014, 13, 614-29.

[0041] As used herein, the terms "clinical stabilization in mild cognitive impairment due to Alzheimer's disease" and "clinical stabilization in dementia due to Alzheimer's disease and / or other neurodegenerative disorders" refer to stabilization or no decline or no treatment-unnecessary decline in at least one domain selected from cognitive, functional, and behavioral, such as, but not limited to, mood, activities of daily living, agitation, restlessness, etc.

[0042] As used herein, the term "clinical stabilization" in the context of ISWRD means stabilization or no decline or no decline requiring treatment in at least one domain selected from sleep-wake fragmentation, sleep-wake and wakefulness amplitude, daily sleep-wake patterns, sleep efficiency, wakefulness efficiency, etc.

[0043] As used herein, the term "clinical benefit" in ISWRD refers to improvement in at least one domain selected from sleep-wake fragmentation, sleep-wake and wakefulness amplitude, daily sleep-wake patterns, sleep efficiency, wakefulness efficiency, etc.

[0044] As used herein, the term "clinical reduction in rate of decline" in ISWRD refers to a reduction in the rate of decline in at least one domain selected from at least one domain of sleep-wake fragmentation, sleep-wake and wakefulness amplitude, daily sleep-wake patterns, sleep efficiency, and wakefulness efficiency.

[0045] As used herein, the term "sleep time" refers to the amount of time a subject spends sleeping. Sleep time can be continuous or discontinuous.

[0046] As used herein, the term "sleep efficiency" refers to the total amount of sleep time a subject gets during his or her time in bed. Sleep efficiency is calculated according to the formula: sleep efficiency = 100% * It is measured by (total sleep time / total time in bed).

[0047] As used herein, "reducing daytime sleepiness" means an increase and / or stabilization in the percentage of time spent wakeful during the day.

[0048] As used herein, "reduced daytime sleepiness" means a reduction in the number and duration of daytime sleepiness (planned and unplanned).

[0049] As used herein, "improvement in daytime alertness" means stabilization, improvement, and / or a slower rate of decline in ratings of alertness.

[0050] As used herein, "reduction in behavioral disturbance" refers to stabilization, improvement, and / or a slower rate of reduction in ratings of agitation and / or behavioral disturbance.

[0051] The subjective and objective assessment of the above circadian rhythm sleep disorders and quality, such as actigraphy, are known in the art. In some embodiments, at least one circadian rhythm sleep disorder is assessed by subjective measurement, such as, for example, questioning the subject, keeping a sleep diary, or assessing through a standardized questionnaire how restorative and undisturbed the sleep is (e.g., Pittsburgh Sleep Quality Index (Buysse et al., Psychiatry Research, 1989, 28, 193-213)). In some embodiments, at least one circadian rhythm sleep disorder is assessed by observing the subject, such as, for example, observing how long it takes the subject to fall asleep, how many times the subject wakes up during the night, how agitated the subject is (e.g., physical or verbal agitation), how aggressive the subject's behavior is, how confused the subject is when awake, etc. In some embodiments, at least one circadian rhythm sleep disorder is assessed using polysomnography. Polysomnography is the monitoring of multiple electrophysiological parameters during sleep, and generally includes measurements of EEG activity, electrooculographic activity, and electromyographic activity, as well as other measurements. These results, in conjunction with observations, can assess sleep latency (the period required to fall asleep) as well as sleep continuity (the overall balance of sleep and wakefulness, or the percentage of time spent asleep or the time spent awake after sleep onset), which can be an indicator of sleep quality. Similarly, actigraphy measurement techniques can be used. Actigraphy is an objective measurement of motor activity in a subject using a device worn on the body, typically the non-dominant wrist.

[0052] The dosage forms of the present disclosure contain a therapeutically effective amount of lemborexant, for example for the treatment of ISWRD, when administered according to the teachings of the present disclosure. The effective amount unit dose in the dosage form is 0.5 mg to 100 mg, 2 mg to 75 mg, 2 mg to 70 mg, 2 mg to 65 mg, 2 mg to 60 mg, 2 mg to 55 mg, 2 mg to 50 mg, 2 mg to 45 mg, 2 mg to 40 mg, 2 mg to 35 mg, 2 mg to 30 mg, 2 mg to 25 mg, 2 mg to 20 mg, 1 mg to 15 mg, 2 mg to 15 mg, or selected from 2 mg, 2.5 mg, 4 mg, 5 mg, 8 mg, 10 mg, or 15 mg. The unit dose is not limited by the type of dosage form or the number of dosage forms for a single dose. In some embodiments, the unit dose may be 2.5 mg. In some embodiments, the unit dose may be 5 mg. In some embodiments, the unit dose may be 10 mg. In some embodiments, the unit dose may be 15 mg.

[0053] In some embodiments, dosage forms of the present disclosure may comprise one or more pharmaceutical compositions comprising lemborexant together with a pharma- ceutically acceptable excipient.

[0054] As used herein, the term "composition" includes any product that contains a specific component in a specific amount and any product that is produced directly or indirectly by combining specific components in a specific amount. Such terms relating to pharmaceutical compositions are intended to include products that contain active components and inactive components that constitute a carrier, and also include any product that is produced directly or indirectly by the combination, complexation or aggregation of any two or more components, or the dissociation of one or more components, or any other type of reaction or interaction. Thus, the pharmaceutical compositions of the present disclosure include any composition prepared by mixing the compounds of the present disclosure with a pharma-ceutically acceptable carrier.

[0055] As used herein, the term "pharmaceutical acceptable" means the carrier, diluent, excipient, or vehicle is compatible with the other ingredients of the formulation and non-toxic to the subject.

[0056] Solid dosage forms of the present disclosure include capsules, granules, lozenges, pellets, pills, powders, suspensions, and tablets.

[0057] The pharmaceutical compositions of the present disclosure can be prepared using standard techniques and manufacturing processes generally known in the art. For example, see the monograph of Japanese Pharmacopoeia, 16 th Edition; and Pharmaceutical Dosage Forms of US Pharmacopoeia-NF, Chapter 1151.

[0058] In some embodiments, the pharmaceutical composition comprises lemborexant. In some embodiments, the pharmaceutical composition further comprises at least one additional component selected from a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable vehicle, and a pharma- ceutically acceptable excipient.

[0059] In some embodiments, at least one additional component in the pharmaceutical composition is selected according to the intended route of administration of the pharmaceutical composition. Non-limiting examples of suitable routes of administration for which the pharmaceutical composition can be used include parenteral, oral, inhalation aerosol, topical, rectal, nasal, buccal, vaginal and implanted reservoir administration. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intracisternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the mode of administration is selected from intravenous, oral, subcutaneous and intramuscular administration. Sterile injectable forms of the compositions of the present disclosure may be, for example, aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art and with suitable dispersing or wetting agents and suspending agents known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Non-limiting examples of acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils can be used as a solvent and / or suspending medium.

[0060] For this purpose, any brand of fixed oil can be used, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, that are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, and / or other dosage forms, can also be used for formulation purposes.

[0061] For oral administration, lemborexant can be provided in any acceptable oral dosage form, including, but not limited to, capsules, tablets, orally disintegrating tablets, sprinkles, and other oral formulations that will be easy to swallow. In some embodiments, lemborexant is provided in the form of a tablet or capsule. In some embodiments, lemborexant is provided in the form of a crushable tablet. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricating agents, such as magnesium stearate, can also be added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0062] In some embodiments, the methods disclosed herein comprise orally administering to a subject a dosage form comprising lemborexant. In some embodiments, the methods disclosed herein comprise orally administering to a subject a dosage form comprising 5 mg of lemborexant. In some embodiments, the methods disclosed herein comprise orally administering to a subject a dosage form comprising 10 mg of lemborexant.

[0063] In some embodiments, the methods disclosed herein involve orally administering to a subject a dosage form containing 2.5 mg to 15 mg of lemborexant no more than once per night immediately prior to bedtime (leaving at least 7 hours before planned awakening time), where the dose can be increased based on clinical response and tolerability up to a maximum of 15 mg, e.g., up to 5 mg or 10 mg of lemborexant, or an equivalent dose of a pharma- ceutically acceptable salt thereof.

[0064] In some embodiments, the methods disclosed herein involve orally administering to a subject a dosage form containing 5 mg to 10 mg of lemborexant no more than once per night immediately prior to bedtime (leaving at least 7 hours before planned awakening time), where the dose can be increased based on clinical response and tolerability up to a maximum of 15 mg of lemborexant, or an equivalent dose of a pharma- ceutically acceptable salt thereof.

[0065] In some embodiments, the methods disclosed herein comprise orally administering to a subject a dosage form containing 5 mg of lemborexant no more than once per night, immediately prior to going to bed (remaining at least 7 hours before planned awakening time), where the dose can be escalated based on clinical response and tolerability up to a maximum of 10 mg of lemborexant, or an equivalent dose of a pharma- ceutically acceptable salt thereof. In some embodiments, the 5 mg dose can be escalated based on clinical response and tolerability up to a maximum of 10 mg or up to a maximum of 15 mg of lemborexant, or an equivalent dose of a pharma-ceutically acceptable salt thereof. In some embodiments, the 10 mg dose can be escalated based on clinical response and tolerability up to a maximum of 15 mg of lemborexant, or an equivalent dose of a pharma-ceutically acceptable salt thereof.

[0066] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner. EXAMPLES

[0067] Example 1 The recommended dose of lemborexant is 5 mg taken not more than once per night just prior to bedtime (leaving at least 7 hours before planned awakening time). The dose may be increased to 10 mg based on clinical response and tolerability.

[0068] Example 2. Treatment of subjects with ISWRD Subjects, both male and female, ranging in age from 60 to 90 years, who complain of sleep disturbances or multiple awakenings at night along with frequent daytime sleep onset periods, can be asked to complete the following questionnaire.

[0069] During screening, a clinician will verify that the subject has been diagnosed with ISWRD and / or a related circadian rhythm sleep disorder. This is accomplished by evaluation of the subject's electrocardiogram, clinical examination, vital signs, height and weight, as well as medical, psychiatric, and sleep history, and the subject's participation in the Mini-Mental State Examination ("MMSE").

[0070] The clinician will determine whether the subject is currently taking any medications, such as lemborexant, any other medications used to treat ISWRD that are suitable for treatment, or any other medications for any other disease or condition.

[0071] The clinician will administer the following questionnaire to the subject and / or the subject's caregiver / nurse to determine whether the lemborexant regimen is appropriate or whether a change (e.g., increase or decrease) in the subject's lemborexant dose is necessary.

[0072] The questionnaire is divided into a daytime portion and an evening portion. The questions in each portion are multiple choice questions. The caregiver selects the best answer to each question from a list of multiple choice answers. For each answer, the subject is given a score from 1 to 5 depending on the type of question.

[0073] Questionnaire Nighttime Questions Question 1: How many times have you noticed him / her waking up during the night? Multiple Choice Answers: I wasn't able to observe him / her last night. Never 1 time 2-3 times 4-6 times 7 or more times

[0074] Alternative answer options: I wasn't able to observe him / her last night. 0-25 times (varies)

[0075] Question 2: How many times have you allowed him / her to get out of bed during the night? Multiple Choice Answers: I wasn't able to observe him / her last night. Never 1 time 2-3 times 4-6 times 7 or more times

[0076] Alternative answer options: I wasn't able to observe him / her last night. 0-25 times (varies)

[0077] Question 3: How many times have you noticed him / her wandering at night? Wandering could mean walking around the perimeter of the house or going from room to room aimlessly. Multiple Choice Answers: I wasn't able to observe him / her last night. Never 1 time 2-3 times 4-6 times 7 or more times

[0078] Alternative question: Have you noticed that he / she wanders at night? Wandering could be walking around the house or heading to a room aimlessly. I wasn't able to observe him / her last night. No, he / she didn't wander around last night Yes, he / she wandered around last night

[0079] Question 4: How many times have you observed him / her refusing to go back to sleep at night, for example starting to watch TV, read, or just sitting in another room aimlessly? Multiple Choice Answers: I wasn't able to observe him / her last night. Never 1 time 2-3 times 4-6 times 7 or more times

[0080] Daytime Questions Question 5: How many times have you allowed him / her to nap or "doze off" during the day? Multiple Choice Answers: I was not able to observe him / her today. Never 1 time 2-3 times 4-6 times 7 or more times

[0081] Alternative answer options: I was not able to observe him / her today. 0-25 times (varies)

[0082] Question 6: To what extent did he / she fall asleep when he / she should not, e.g., in the waiting room, during meals, in the car? Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0083] Alternative question: Have you observed him / her falling asleep when he / she should not have, for example, in the waiting room, during meals, in the car? Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not show inappropriate sleepiness or fall asleep when he / she should not have done so Yes, he / she exhibited inappropriate sleepiness or fell asleep when he / she should not have

[0084] Alternative question: How disruptive was his / her sleep today? Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0085] Question 7: To what extent did he / she exhibit drowsiness or fatigue, e.g., yawning, droopy eyes, change in voice, slow speech, bloodshot eyes? Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit In moderation Very Extremely

[0086] Alternative questions: Did you notice his / her physical signs of sleepiness or fatigue, such as yawning, droopy eyes, a change in voice, slow speech, bloodshot eyes? Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not have any physical symptoms of fatigue today Yes, he / she had physical symptoms of fatigue today

[0087] Alternative question: How many times did you notice his / her physical signs of sleepiness or fatigue, such as yawning, droopy eyes, change in voice, slow speech, bloodshot eyes? Multiple Choice Answers: I was not able to observe him / her today. Never 1 time 2-3 times 4-6 times 7 or more times

[0088] Question 8: To what extent does he / she seem to lose concentration because of excessive sleepiness or fatigue? For example, forgetting to be in the middle of an activity in the yard or around the house, taking breaks or taking breaks for too long, stopping an activity too early to rest, not moving throughout an activity, not talking, etc. Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit In moderation Very Extremely

[0089] Alternative question: Did you notice that he / she was losing concentration because of excessive sleepiness or fatigue? For example, forgetting to be in the middle of an activity in the yard or around the house, taking breaks or taking breaks for too long, stopping an activity too early to rest, not moving throughout an activity, not talking. Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not stop working because of fatigue Yes, he / she had to stop the activity due to fatigue

[0090] Question 9: To what extent did sleepiness interfere with his / her ability to carry out personal care activities? For example, not taking a shower because of being too tired, not getting changed because of being too tired. Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0091] Alternative question: Did you notice that he / she does not perform personal care activities because of drowsiness? For example, not taking a shower because of excessive fatigue, not getting dressed because of excessive fatigue. Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not have fatigue affecting his / her personal care today Yes, he / she had fatigue affecting his / her personal care today

[0092] Question 10: To what extent did he / she seem to not do leisure activities because of excessive sleepiness or fatigue? For example, not finishing a TV show, not finishing a game, or not completing a hobby activity because of excessive fatigue. Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0093] Alternative question: Did you notice that he / she does not engage in leisure activities because of excessive sleepiness or fatigue? For example, not finishing a TV show, not finishing a game, or not completing a hobby activity because of excessive fatigue. Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not stop working due to fatigue Yes, he / she had to stop working due to fatigue

[0094] Question 11: To what extent did he / she seem to put off activities because of excessive sleepiness or fatigue? For example, putting off going to bed, washing clothes, or cooking for the day? Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0095] Alternative question: Have you noticed that he / she postpones activities because of excessive sleepiness or fatigue? For example, putting off going to bed, washing clothes, or cooking for the day. Multiple Choice Answers: I was not able to observe him / her today. No, he / she did not postpone activities due to excessive fatigue Yes, he / she postponed the activity due to excessive fatigue

[0096] Question 12: To what extent have plans been altered because of his / her excessive sleepiness? For example, starting or committing to a social activity. Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0097] Question 13: To what extent has he / she verbalized or expressed avoiding activities so that he / she could sleep instead? For example, avoiding talking to people on the phone or in person, not participating in leisure activities such as games or walking. Multiple Choice Answers: I was not able to observe him / her today. None at all · a bit · pretty Very Much more

[0098] Substitute question: Have you observed him / her verbalize or express avoidance of activities so that he / she can sleep instead? For example, avoiding talking to people on the phone or in person, not participating in leisure activities such as games or walking. Multiple Choice Answers: I was not able to observe him / her today. No, he / she could not avoid the activity and use sleep instead Yes, he / she could sleep instead of avoiding the activity

[0099] Question 14: To what extent do you acknowledge that he / she exhibits any effect on his / her emotions due to sleepiness today? Multiple Choice Answers:

[0100] [Table 1]

[0101] Question 15: Did his / her behavior or emotions start to worsen before or during the evening? Multiple Choice Answers: · no Yes (if yes, continue)

[0102] Question 16: How much worse was his / her behavior or emotions in the evening before or after? Multiple Choice Answers:

[0103] [Table 2]

Claims

**Claim 1** A pharmaceutical composition comprising lenvorexant for treating irregular sleep-wake rhythm disorder associated with neurodegenerative diseases and related circadian rhythm sleep disorders, which is used for administration to subjects who achieve a score of 46 or more for the ISWRD ObsRO Questionnaire Daytime Component. **Claim 2** A pharmaceutical composition comprising lenvorexant for treating irregular sleep-wake rhythm disorder associated with neurodegenerative diseases and related circadian rhythm sleep disorders, which is used for administration to subjects who achieve a score of 8 or more for the ISWRD ObsRO Questionnaire Nighttime Component. **Claim 3** The pharmaceutical composition according to claim 1 or 2, wherein the subject experiences at least one symptom selected from confusion, anxiety, agitation, pacing, wandering, mental fatigue, physical fatigue, and sundowning. **Claim 4** The pharmaceutical composition according to claim 1 or 2, wherein the irregular sleep-wake rhythm disorder is caused by at least one neurodevelopmental disorder, at least one neurodegenerative disorder, or a combination thereof. **Claim 5** The pharmaceutical composition according to claim 1 or 2, wherein the subject suffers from at least one circadian rhythm sleep disorder in addition to the irregular sleep-wake rhythm disorder. **Claim 6** A pharmaceutical composition comprising lenvorexant for continuing the treatment of irregular sleep-wake rhythm disorder associated with neurodegenerative diseases and related circadian rhythm sleep disorders, which is used for administration to subjects who achieve a score of 46 or more for the ISWRD ObsRO Questionnaire Daytime Component. **Claim 7** A pharmaceutical composition comprising lenvorexant for continuing the treatment of irregular sleep-wake rhythm disorder associated with neurodegenerative diseases and related circadian rhythm sleep disorders, which is used for administration to subjects who achieve a score of 8 or more for the ISWRD ObsRO Questionnaire Nighttime Component. **Claim 8** The pharmaceutical composition according to claim 6 or 7, wherein the subject experiences an increase in sleep efficiency. **Claim 9** The pharmaceutical composition according to claim 6 or 7, wherein the subject experiences a decrease in daytime sleepiness and / or daytime dozing. **Claim 10** The subject is the pharmaceutical composition according to claim 6 or 7 that experiences an increase in wakefulness efficiency.

11. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences an increase in daytime wakefulness.

12. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences a decrease in motor impairment.

13. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences a reduction in decreased concentration.

14. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences an increase in performing personal care.

15. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences an improvement in emotional stability.

16. The subject is the pharmaceutical composition according to claim 6 or 7 that experiences an increase in participation in leisure activities.

17. A method for determining a therapeutic benefit in the treatment of irregular sleep-wake rhythm disorder associated with neurodegenerative diseases and related circadian rhythm sleep disorders, comprising administering the ISWRD ObsRO Questionnaire Daytime Component and / or the ISWRD ObsRO Questionnaire Nighttime Component to the subject before treatment of the irregular sleep-wake rhythm disorder and at least one day after treatment of the irregular sleep-wake rhythm disorder.

18. The treatment of the subject comprises administration of lenvorexant, the method according to claim 17.

19. The subject achieves a score of less than 46 for the ISWRD ObsRO Questionnaire Daytime Component after treatment, the method according to claim 17 or 18.

20. The subject achieves a score of 46 or more for the ISWRD ObsRO Questionnaire Daytime Component before treatment, the method according to claim 17 or 18.

21. The subject achieves a score of less than 8 for the ISWRD ObsRO Questionnaire Nighttime Component after treatment, the method according to claim 17 or 18.

22. The subject achieves a score of 8 or more for the ISWRD ObsRO Questionnaire Nighttime Component before treatment, the method according to claim 17 or 18.

23. The pharmaceutical composition or method according to any one of claims 1, 2, 6, 7, 17 and 18, wherein 5 mg or 10 mg of lenvoxant is administered to the subject once per night, immediately before going to bed.

24. The pharmaceutical composition or method according to any one of claims 1, 2, 6, 7, 17 and 18, wherein 5 mg or 10 mg of lenvoxant is administered to the subject once per night, immediately before going to bed (remaining at least 7 hours before the planned wake-up time).

25. The pharmaceutical composition or method according to any one of claims 1, 2, 6, 7, 17 and 18, wherein 5 mg of lenvoxant is administered to the subject once per night.