METHOD FOR TREATING SLEEP FRAGMENTATION DISORDERS USING NEUROSTEROID

POSITIVE ALLOSTERIC MODULATORS OF THE GABAA RECEPTOR

RELATED APPLICATION

[0001] This application claims priority to, and the benefit of U.S. Provisional Application No. 62/815,566, filed on March 8, 2019, the entire contents of which are incorporated by reference.

FIELD OF THE APPLICATION

[0002] The present disclosure relates to methods of alleviating a symptom of, treating, or preventing a sleep disorder (e.g., increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold) by administering a neurosteroid GABAA positive allosteric modulator or pharmaceutically acceptable salt thereof.

BACKGROUND

[0003] Breakthroughs in the field of sleep disorder research has brought about widespread scientific and popular appreciation for the health benefits of restful and restorative sleep. Sleep is now recognized, along with diet and exercise, as one of the three pillars of good health. The overall prevalence of current or previous sleep disorders in adults is estimated at 52.4% of the population. Almost two-thirds (64%) of the population report sleep difficulties at least a few times a week (National Sleep Foundation,“2012 Sleep in America” Poll). The International Classification of Sleep Disorders distinguishes over 80 different disorders and each can have profound health and economic implications. Whilst the daytime impairment caused by poor sleep has long been appreciated, poor sleep also has cascading negative impact upon alertness, cognition, learning and memory, vigilance, performance, and a broad range of co-morbid health conditions including, but not limited to, acute and chronic pain and pain disorders, psychiatric conditions, neurodegenerative disease, developmental disorders, metabolic disease and diabetes, obesity, cardiovascular disease, immunological disorders, and many other medical conditions.

[0004] Sleep disorder patients are now readily segmented into a broader range of sleep disorder categories and conditions that are more amenable to new and tailored therapies that hold promise for delivering better patient outcomes. Objective measures of sleep can play a vital role toward understanding poor sleep and its amelioration. Despite sleeping 7-8 hours or more, patients, wherein the sleep is frequently interrupted or“fragmented” suffer all the consequences of sleep deprivation. Indeed sleep consolidation is necessary for the restorative physiological benefits of sleep to be realized and comorbid conditions to be managed.

[0005] Pharmacological options are limited for the treatment of sleep fragmentation. In response to the lack of pharmacological options, there exists an unmet clinical need to develop new methods of treating sleep fragmentation, including pharmacological methods of treatment.

SUMMARY

[0006] In one aspect, the present disclosure provides compounds for alleviating a symptom of, treating, or preventing a sleep disorder.

[0007] In some embodiments, the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold. In some embodiments, the sleep disorder is increased disturbed sleep. In some embodiments, the sleep disorder is increased sleep fragmentation. In some embodiments, the sleep disorder is increased arousals. In some embodiments, the sleep disorder is decreased arousal threshold.

[0008] In one aspect, the present disclosure provides the identification of a pharmacological compound class having positive allosteric modulatory activity at Gamma Amino Butyric Acid (GABA) receptor subtype A (GABAA) to alleviate the symptom of, treat, or prevent a sleep disorder. In some embodiments, the sleep disorder is characterized in whole or in part by sleep fragmentation. Molecules with the requisite GABAA positive allosteric modulator pharmacology were studied for their effects on EEG sleep-wakefulness, locomotor activity, drink- and food- related activity and body temperature in laboratory rats using an enhanced and expanded version of SCORE-2000 ^® , a sleep-wake bioassay and analysis system known as“SCORE™”.

[0009] In some embodiments, a compound of the present disclosure is a neurosteroid GABAA positive allosteric modulator. In some embodiments, the neurosteroid GABAA positive allosteric modulator is selected from: CCD-3693 (l-((3R,5R,10S,13S,17S)-3-hydroxy-13-methyl-3- (trifluoromethyl)hexadecahydro-lH-cyclopenta[a]phenanthren-1 7-yl)ethan-l -one), Co- 13-4444 (1 -((3R,5S, 1 OS, 13 S, 17S)-3-hydroxy-3-(methoxymethy 1)-10, 13 -dimethylhexadecahydro- 1 H- cyclopenta[a]phenanthren-17-yl)-2-(lH-imidazol-l-yl)ethan-l- one), ganaxolone (1- ((3R, 1 OS, 13 S, 17S)-3-hydroxy-3, 10, 13-trimethylhexadecahydro-l H-cyclopenta[a]phenanthren- 17-yl)ethan-l-one), pregnenolone (l-((3R,5R,10S,13S,17S)-3-hydroxy-10,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren- 17-y l)ethan- 1 -one), Sage-217 (l-(2- ((3R.5R, 1 OS, 13 S, 17S)-3-hy droxy-3 , 13-dimethy lhexadecahy dro- 1 H-cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)-lH-pyrazole-4-carbonitrile), and brexanolone (Sage- 547; 1- ((3R, 1 OS, 13 S, 17S)-3-hydroxy-l 0, 13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren- 17- yl)ethan-l-one), or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound of the present disclosure selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage- 217, and brexanolone, or a pharmaceutically acceptable salt thereof to a subject in need thereof [0011] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering CCD-3693, or a pharmaceutically acceptable salt thereof

[0012] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering Co-13-4444, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering ganaxolone, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering is pregnanolone, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering Sage-217, or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering brexanolone, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.

[0018] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea.

[0019] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with restless legs syndrome.

[0020] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a high respiratoiy disturbance index

(RDI).

[0021] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a neurological disease.

[0022] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a circadian rhythm disorder.

[0023] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with pain.

[0024] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with periodic leg movement disorder

(PLMD).

[0025] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with REM behavior disorder.

[0026] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with elderly fragmented sleep.

[0027] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with age-related sleep fragmentation.

[0028] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with post-menopausal sleep disorder.

[0029] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse.

[0030] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse withdrawal.

[0031] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with narcolepsy. [0032] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a mental disorder.

[0033] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with non-restorative sleep.

[0034] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with snoring.

[0035] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with idiopathic hypersomnia.

[0036] Pharmaceutical therapies and methods of using such pharmaceutical therapies are provided herein for sleep fragmentation. Pharmaceutical therapies and methods of using such pharmaceutical therapies are provided for sleep fragmentation in a subject with one or more co- morbid medical condition. In some embodiments, the therapies and methods of using such therapies include pharmaceutical therapies to increase arousal threshold and thereby reduce arousals/microarousals, and the applications of such treatment in a subject that may have one or more of the following medical conditions: a sleep disorder including, but not limited to, obstructive sleep apnea, low-arousal threshold sleep apnea, central sleep apnea, snoring, restless legs syndrome, periodic limb movement disorder (PLMD), non-restorative sleep, narcolepsy, circadian rhythm sleep disorder, elderly sleep fragmentation, post-menopausal sleep

fragmentation, shift work sleep disorder, idiopathic hypersomnia, a psychiatric disorder (e.g., post-traumatic stress disorder, depression, anxiety disorder, bipolar disorder, or schizophrenia), a pain disorder (e.g., nociceptive pain, neuropathic pain, mixed pain, osteoarthritis, lower back pain, postherpetic neuralgia (PHN), fibromyalgia, rheumatoid arthritis, cancer, or post-op pain), substance abuse or substance abuse withdrawal (e.g., opioid abuse, opioid abuse withdrawal, alcoholism, or alcohol withdrawal), a neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, diffuse Lew body disease (DLBD), REM behavior disorder (RBD), Huntington’s disease, a neuromuscular dystonia (e.g., spasmodic torticollis), amyotrophic lateral sclerosis (ALS), or multiple sclerosis), and neurodevelopmental disorders (e.g., autism and schizophrenia).

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0038] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE FIGURES

[0039] FIG. 1 depicts number of wake bouts each hour after administration of CCD-3693, wherein the thin line depicts CCD-3693 administration at 30 mg/kg (PO; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta-cyclodextrin 10% administration at 10 mL/kg (PO; CT- 18, n=12).

[0040] FIG. 2 depicts average sleep bouts after administration of CCD-3693, wherein the thin line depicts CCD-3693 administration at 30 mg/kg (PO; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta-cyclodextrin 10% administration at 10 mL/kg (PO; CT-18, n=12).

[0041] FIG. 3 depicts longest wake bout each hour, wherein the thin line depicts CCD-3693 administration at 30 mg/kg (PO; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta- cyclodextrin 10% administration at 10 mL/kg (PO; CT-18, n=12).

[0042] FIG. 4 depicts number of wake bouts each hour after administration of Co-13-444‘1, wherein the thin line depicts Co-13-4444 administration at 30 mg/kg (PO; CT-18, n=l 1) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=l 1). [0043] FIG. 5 depicts average aligned sleep bout each hour after administration of Co- 13-4444, wherein the thin line depicts Co-13-4444 administration at 30 mg/kg (PO; CT-18, n=l 1) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=l 1).

[0044] FIG. 6 depicts number of wake bouts each hour after administration of ganaxolone , wherein the thin line depicts ganaxolone administration at 15 mg/kg (IP; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta-cyclodextrin 50% administration at 1 mL/kg (IP; CT-18, n=8).

[0045] FIG. 7 depicts average aligned sleep bout each hour after administration of ganaxolone , wherein the thin line depicts ganaxolone administration at 15 mg/kg (IP; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta-cyclodextrin 50% administration at 1 mL/kg (IP; CT-18, n=8).

[0046] FIG. 8 depicts longest aligned wake bout each hour after administration of ganaxolone , wherein the thin line depicts ganaxolone administration at 15 mg/kg (IP; CT-18, n=8) and the thick line depicts 2-hydroxypropyl-beta-cyclodextrin 50% administration at 1 mL/kg (IP; CT-18, n=8).

[0047] FIG. 9 depicts number of wake bouts each hour after administration of pregnanolone, wherein the thin line depicts pregnanolone administration at 30 mg/kg (IP; CT-18, n=12) and the thick line depicts methylcellulose administration at 1 mL/kg (IP; CT-18, n=24).

[0048] FIG. 10 depicts average aligned sleep bout each hour after administration of

pregnanolone, wherein the thin line depicts pregnanolone administration at 30 mg/kg (IP; CT-18, n=12) and the thick line depicts methylcellulose administration at 1 mL/kg (IP; CT-18, n=24).

[0049] FIG. 11 depicts longest aligned wake bout each hour after administration of

pregnanolone, wherein the thin line depicts pregnanolone administration at 30 mg/kg (IP; CT-18, n=12) and the thick line depicts methylcellulose administration at 1 mL/kg (IP; CT-18, n=24).

[0050] FIG. 12 depicts number of wake bouts each hour after administration of Sage-217, wherein the thin line depicts Sage-217 administration at 10 mg/kg (PO; CT-18, n=12) and the thick line methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

[0051] FIG. 13 depicts average aligned sleep bout each hour after administration of Sage-217, wherein the thin line depicts Sage-217 administration at 10 mg/kg (PO; CT-18, n=12) and the thick line methylcellulose administration at 1 mL/kg (PO; CT-18, n=12). [0052] FIG. 14 depicts longest aligned wake bout each hour after administration of Sage-217, wherein the thin line depicts Sage-217 administration at 10 mg/kg (PO; CT-18, n=12) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

[0053] FIG. 15 depicts number of wake bouts each hour after administration of suvorexant, wherein the thin line depicts suvorexant administration at 30 mg/kg (PO; CT-18, n=7) and the thick line depicts TPGS (HY-16388) administration at 1 mL/kg (PO; CT-18, n=9).

[0054] FIG. 16 depicts average aligned sleep bout each hour after administration of suvorexant, wherein the thin line depicts suvorexant administration at 30 mg/kg (PO; CT-18, n=7) and the thick line depicts TPGS (HY-16388) administration at 1 mL/kg (PO; CT-18, n=9).

[0055] FIG. 17 depicts the normalized EEG delta after administration of zolpidem tartrate, wherein the thin line depicts zolpidem tartrate administration at 10 mg/kg (PO; CT-18, n=8) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=9).

[0056] FIG. 18 depicts number of wake bouts each hour after administration of zolpidem tartrate, wherein the thin line depicts zolpidem tartrate administration at 10 mg/kg (PO; CT-18, n=8) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=9).

[0057] FIG. 19 depicts the average aligned sleep bout each hour after administration of zolpidem tartrate, wherein the thin line depicts zolpidem tartrate administration at 10 mg/kg (PO; CT-18, n=8) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=9).

[0058] FIG. 20 depicts REM sleep after administration of zolpidem, wherein the thin line depicts zolpidem administration at 30 mg/kg (PO; n=8) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-5, n=16).

[0059] FIG. 21 depicts Locomotor Activity Intensity (LMAi) after administration of zolpidem, wherein the thin line depicts zolpidem administration at 30 mg/kg (PO; CT-18, n=10) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=10).

[0060] FIG. 22 depicts number of wake bouts each hour after administration of S-zopiclone, wherein the thin line depicts S-zopiclone administration at 10 mg/kg (PO; CT-18, n=13) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=13).

[0061] FIG. 23 depicts average sleep bout each hour after administration of S-zopiclone, wherein (A) depicts S-zopiclone administration at 30 mg/kg (PO; CT-18, n=12); (B) depicts S-zopiclone administration at 10 mg/kg (PO; CT-18, n=10); (C) depicts S-zopiclone administration at 5 mg/kg (PO; CT-18, n=12); (D; thick line) depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

[0062] FIG. 24 depicts the Locomotor Activity Intensity (LMAi) after administration of S- zopiclone, wherein (A) depicts S-zopiclone administration at 30 mg/kg (PO; CT-18, n=12); (B) depicts S-zopiclone administration at 10 mg/kg (PO; CT-18, n=10); (C) depicts S-zopiclone administration at 5 mg/kg (PO; CT-18, n=12); (D; thick line) depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

[0063] Fig. 25 depicts the integrated electromyographic (EMG) after administration of S- zopiclone, wherein the thin line depicts S-zopiclone administration at 10 mg/kg (PO; CT-18, n=13) and the thick line depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

[0064] Fig. 26 depicts the nonREM (NREM) sleep per hour after administration of S-zopiclone, wherein (A) depicts S-zopiclone administration at 30 mg/kg (PO; CT-18, n=12); (B) depicts S- zopiclone administration at 10 mg/kg (PO; CT-18, n=10); (C) depicts S-zopiclone administration at 5 mg/kg (PO; CT-18, n=12); (D; thick line) depicts methylcellulose administration at 1 mL/kg (PO; CT-18, n=12).

DETAILED DESCRIPTION

Definitions

[0065] As used herein,“uninterrupted bouts of sleep” (average sleep bout duration) refers to the average duration of all bouts of uninterrupted sleep that occurred each hour, measured in minutes.“Interruption” of sleep refers to 2 or more consecutive 10 second epochs of

wakefulness.“Interruption” of wake refers to 2 or more consecutive 10 second epochs of sleep. The value for the length of a bout that extends into the subsequent hour is assigned to the hour in which it begins. Analogous quantification is carried out for bouts of wakefulness. Sleep bout length may reflect the human tendency to awaken periodically through the night (such awakenings are normally not recalled), which in turn may be an important factor in determining the restorative value of sleep in a subject (e.g., human). Pre-clinical measures of sleep bout duration are also predictors of soporific efficacy in a subject (e.g., human).

[0066] As used herein,“NREM” and“nonREM ^* refers to non-rapid eye movement sleep stages.

[0067] As used herein,“reduced number of arousals” refers to the reduced number of wake bouts per hour. [0068] As used herein,“REM” refers to the rapid eye movement sleep stage.

[0069] As used herein,“SEM” refers to standard error of the mean.

[0070] As used herein,“CT” refers to circadian time.

[0071] As used herein“sleep consolidation” refers to the measurement of the average sleep bout duration per hour.

[0072] As used herein,“sleep continuity" refers to the measurement of sleep-bout length.

[0073] As used herein, the“depth” of sleep is characterized by EEG slow wave activity, which may subserve sleep continuity or sleep consolidation, which is one of several determinants of sleep quality.

[0074] As used here,“SWA” refers to slow wave activity, which may be exemplified as EEG delta power by use of Fourier analysis.

[0075] As used herein,“LMA intensity” (LMAi) refers to locomotor activity (LMA) counts per minute of EEG-defined wakefulness. This variate allows an assessment of LMA that is independent of the amount of time awake, which may be used to quantify the specificity of a wake- or sleep-promoting effect.

[0076] As used herein,“number of wake bouts” refers to the number of uninterrupted bouts of wakefulness that occurred each hour, measured in minutes. Number of wake bouts are of interest because it may closely reflect the number of arousals from sleep that occur at the time of measurement. Interpreted together, average sleep bout duration and number of wake bouts provide a highly reliable assessment of a drug or novel molecular entity (NME) effect on sleep fragmentation. Drugs that improve sleep fragmentation have been shown to improve the restorative benefits of sleep.

[0077] As used herein, the term“co-morbid” refers to a disease or disorder which is concurrent with a sleep disorder, but may not be the cause, in whole or in part, of the sleep disorder.

[0078] As used herein, the term“pharmaceutically acceptable” refers to compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0079] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0080] As used herein, the term“pharmaceutical composition” is a formulation comprising the compounds of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the subject The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0081] As used herein, the term“preventing,”“prevent,” or“protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0082] As used herein, the term“rat” and“laboratory rat” are used interchangeably.

[0083] It is to be appreciated that references to“treating” or“treatment” include the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. [0084] As used herein, the term“subject" is interchangeable with the term“subject in need thereof ^* , both of which refer to a subject having a disease or having an increased risk of developing the disease. A“subject" includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the mammal is a rat. In some embodiments, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0085] Unless explicitly indicated otherwise, the terms“approximately” and“about ^* are synonymous. In some embodiments,“approximately” and“about ^* refer to the recited amount, value, dose or duration ± 20%, ± 15%, ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1%, or ± 0.5%. In another embodiment,“approximately” and“about” refer to the listed amount or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, or ± 2%. In some embodiments,“approximately” and“about” refer to the listed amount, value, dose, or duration ± 5%. In some embodiments,“approximately” and“about” refer to the listed amount, value, dose, or duration ± 2%. In some embodiments, “approximately” and“about” refer to the listed amount, value, dose, or duration ± 1%.

[0086] In some embodiments, a“compound” is the same as an“active ingredienf ^* , a

“neurosteroid GABAA positive allosteric modulator”, a“neurosteroid allosteric modulator of the GABAA receptor", and a“compound of the present disclosure".

[0087] In some embodiments,“CCD-3693” may also be referred to as HY-10752, 1- ((3R,5R, 1 OS, 13 S, 17S)-3-hydroxy- 13 -methyl-3 -(trifluoromethyl)hexadecahydro- 1 H- ^Q

F.

cy l penta[a] 14henanthrene- 17-y l)ethan- 1 -one (i. e. , ^F l OH H

c o ), or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments,“Co-13-4444” may also be referred to as AL-30011, 1- ((3R,5S,10S,13S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimet hylhexadecahydro-lH- cyclopenta[a]14henanthrene-17-yl)-2-(lH-imidazol-l-yl)ethan- l-one (i.e.,

pharmaceutically acceptable salt thereof.

[0089] In some embodiments,“ganaxolone” may also be referred to as CCD- 1042, 1- ((3R, 1 OS, 13S, 17S)-3-hydroxy-3, 10,13 -trimethy lhexadecahydro- 1 H-

Q,

cy clopenta[a] 14henanthrene- 17-y l)ethan- 1 -one (i. e. , H<5 ), or a pharmaceutically acceptable salt thereof

[0090] In some embodiments,“pregnanolone” may also be referred to as eltanolone, 3a, 5b- tetrahydroprogesterone (3a,5b-THR), 5 P-pregnan-3 a-ol-20-one, CCD-3045, 1- ((3R.5R, 1 OS, 13 S, 17S)-3-hy droxy- 10, 13 -dimethy lhexadecahydro- 1 H-

Q,

HO ^v

cyclopenta[a] 14henanthrene- 17-y l)ethan- 1 -one (i. e. , ), or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments,“Sage-217’ may also be referred to as AL-30006, l-(2- ((3R,5R, 1 OS, 13S, 17S)-3 -hydroxy-3 , 13 -dimethylhexadecahydro- 1 H- cy clopenta[a] 1 Shenanthrene- 17-y l)-2-oxoethy 1)- lH-pyrazole-4-carbonitrile (i. e. ,

pharmaceutically acceptable salt thereof.

[0092] In some embodiments,“brexanolone” may also be referred to as Sage-547, 1-

((3R, 1 OS, 13 S, 17S)-3-hydroxy- 10, 13-dimethylhexadecahydro-lH-cyclopenta[a] 1 Shenanthrene-

O,

17-yl)ethan- 1 -one(i. e. , HO' ).

[0093] In some embodiments, zolpidem may also be referred to as Ambien®, HY-10131 , NJf- dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[l ,2-a]pyridin-3-yl]acetamide (i.e.,

pharmaceutically acceptable salt thereof.

[0094] In some embodiments, zolpidem is a pharmaceutically acceptable salt.

[0095] In some embodiments, zolpidem is zolpidem tartrate.

[0096] In some embodiments, S-zopiclone may also be referred to as Lunesta®, eszopiclone, [(75)-6-(5-chloropyridin-2-yl)-5-oxo-7/f-pyrrolo[3,4-b]pyraz in-7-yl] 4-methylpiperazine- 1 - carboxylate pharmaceutically acceptable salt thereof.

[0097] In some embodiments, suvorexant may also be referred to as Belsomra®, [(7i?)-4-(5- chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4-diazepan-l-yl]-[5-m ethyl-2-(triazol-2-

yl)phenyl]methanone pharmaceutically acceptable salt thereof.

[0098] A neurosteroid allosteric modulator of GABAA receptor, may be characterized as acting at one or more neurosteroid GABAA binding site, and producing a change in chloride flux through ion channels in the synaptic and/or extrasynaptic GABAA macromolecular complex. The facilitation of GABA effects at GABAA receptors by neurosteroid GABAA positive allosteric modulators may improve a sleep disorder as evidenced by a reduced number of arousals, reduced sleep fragmentation, reduced disturbed sleep and/or increased arousal threshold.

Methods of Use

[0099] Sleep fragmentation, a condition in humans characterized by poor sleep consolidation, frequent brief arousals or microarousals (defined by the American Academy of Sleep Medicine as episodes of cortical EEG activation lasting at least 2 seconds and up to 16 seconds in duration and interrupting sleep), and frequent transitions to lighter stages of sleep results in significant daytime impairment that may include impaired attention and concentration, excessive sleepiness, impaired judgement, impaired memory and learning, increased risk of accidents, and secondary morbidity and mortality when sleep fragmentation is a concomitant of pain, sleep disordered breathing, and other disease states. Patients suffering from sleep fragmentation are often unaware of the hundreds of brief arousals that may occur during the night, and primarily complain of severe daytime impairment Sleep fragmentation patients often complain that their sleep is not beneficial, refreshing, or restorative.

[0100] The diagnosis of sleep fragmentation and its methods of treatment must not be equated with insomnia, which is a separate and distinct medical diagnosis. Insomnia is typically characterized by patient awareness and dissatisfaction with their sleep. Most insomnia patients have a hyperarousal disorder that makes it difficult to fall asleep and/or difficult to stay asleep but enables them to function well during the daytime. Insomnia is diagnosed by measuring the latency to persistent sleep, i.e., LPS, (LPS of >30 minutes satisfies the definition of sleep-onset insomnia) and/or measuring the amount of time awake after sleep onset, i.e., WASO (WASO of >50 minutes satisfies the definition of sleep-maintenance insomnia). It is common for insomnia patients, and particularly the elderly, to awaken in the middle of the night and be unable to return to sleep. Unlike patients suffering from sleep fragmentation, insomnia patients are almost always highly aware of their inability to fall asleep or stay asleep at night and complain about their nighttime experience, and typically do not complain about daytime impairment

[0101] An extensive body of research has identified that molecules in a pharmacological class best described as having positive allosteric modulatory activity at Gamma Amino Butyric Acid (GABA) receptor subtype A (GABAA) improve sleep fragmentation as evidenced by reduced number of arousals (measured as reduced number of wake bouts per hour) and increased sleep consolidation (measured by average sleep bout duration per hour).

[0102] Molecules with the requisite GABAA positive allosteric modulator pharmacology may be studied for their effects on EEG sleep-wakefulness, locomotor activity, drink- and food-related activity and body temperature in laboratory rats using an enhanced and expanded version of SCORE-2000 ^® , a sophisticated sleep-wake bioassay and analysis system which shall henceforth be referred to as“SCORE™”. The technology is well suited for sleep-wake efficacy and physiological and behavioral side effect assessment. Associated with this technology is an extensive pharmacological database with standardized sleep-wake, physiological, and behavioral data for over 500 distinct molecules. The standardized nature of the experimental designs, data quality control, and data analysis methods enable direct comparisons between molecules.

Rat and Human Sleep [0103] The present disclosure provides a pre-clinical drug evaluation using rats. Without wishing to be bound by theory, rat sleep and human sleep have all of the necessary fundamental similarities to permit the rat to be used as a preclinical model. As such, compounds that are soporific in a human may have soporific effects in a rat, and compounds that are soporific in a rat may have soporific effects in a human. Both rat and human exhibit robust circadian modulation of sleep tendency and sleep architecture.

[0104] The“homeostatic” control of sleep shares similarity across mammalian species, including humans, in that loss of sleep increases a homeostatic drive for sleep evidenced by a reduction in latency to sleep onset, increase in the depth of sleep that can be reflected by the amount of low- frequency“delta” EEG (“EEG slow waves”) during nonREM, an increase in sleep consolidation as measured by sleep bout duration, or an increase in total sleep time. Sleep deprivation in a subject may cause the subject to fall asleep faster, sleep deeper, sleep more efficiently (e.g., more consolidate of bouts of sleep), or sleep more (e.g., an increase of sleep time) until the

homeostatic drive for sleep becomes adequately discharged through the sleeping process.

[0105] Uninterrupted, well consolidated sleep can determine sleep quality in both a rat and a human. Without wishing to be bound by theory, no matter how much a subject sleeps or what frequency of EEG dominates during sleep, the beneficial work of the sleeping process requires that sleep is not fragmented (interrupted) by frequent arousals.

[0106] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by decreasing the latency to sleep onset, increasing sleep time, increasing the depth and/or consolidation of sleep, reducing arousals, or a combination of the aforementioned effects in a subject, have the same effects in a different subject The compounds of the present disclosure, which affect REM sleep by decreasing the latency to sleep onset effects in a subject, may have the same effects on a subject of a different species. The compounds of the present disclosure, which affect REM sleep by decreasing the latency to sleep onset effects in rats, may have the same effects on a subject of different species. The compounds of the present disclosure, which affect REM sleep by decreasing the latency to sleep onset effects in rats, may have the same effects on a human.

[0107] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing sleep time in a subject, have the same effects on a different subject The compounds of the present disclosure which affect REM sleep by increasing sleep time in a subject, may have the same effects on a subject of a different species. The compounds of the present disclosure which affect REM sleep by increasing sleep time in rats, may have the same effects on a subject of a different species. The compounds of the present disclosure which affect REM sleep by increasing sleep time in rats, may have the same effects on a human.

[0108] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in a subject, have the same effects in a different subject. Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in rats, may have the same effects in a human.

[0109] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in rats, may have the same effects in a human.

[0110] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing the depth or consolidation of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect REM sleep by increasing the depth or consolidation of sleep in a subject may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a human.

[0111] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in a subject, may have the same effects in a subject of a different species.

Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in rats, may have the same effects in a human.

[0112] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in a subject may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in rats, may have the same effects in a human.

[0113] Without wishing to be bound by theory, compounds of the present disclosure which affect REM sleep by reducing arousals in a subject, have the same effects in a different subject. Compounds of the present disclosure which affect REM sleep by reducing arousals in a subject, have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by reducing arousals in rats, have the same effects in a subject of a different species. Compounds of the present disclosure which affect REM sleep by reducing arousals in rats, have the same effects in a human.

[0114] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by decreasing the latency to sleep onset, increasing sleep time, increasing the depth and/or consolidation of sleep, reducing arousals, or a combination of the aforementioned effects in a subject, have the same effects in a different subject The compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects in a subject, may have the same effects on a subject of a different species. The compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects in rats, may have the same effects on a subject of different species. The compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects in rats, may have the same effects on a human. [0115] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing sleep time in a subject, have the same effects on a different subject The compounds of the present disclosure which affect NREM sleep by increasing sleep time in a subject may have the same effects on a subject of a different species. The compounds of the present disclosure which affect NREM sleep by increasing sleep time in rats, may have the same effects on a subject of a different species. The compounds of the present disclosure which affect NREM sleep by increasing sleep time in rats, may have the same effects on a human.

[0116] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in a subject, have the same effects in a different subject. Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in rats, may have the same effects in a human.

[0117] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in rats, may have the same effects in a human.

[0118] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in a subject may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a human.

[0119] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in a subject, have the same effects in a different subject Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in rats, may have the same effects in a human.

[0120] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in a subject, have the same effects in a different subject. Compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in a subject, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in rats, may have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in rats, may have the same effects in a human.

[0121] Without wishing to be bound by theory, compounds of the present disclosure which affect NREM sleep by reducing arousals in a subject, have the same effects in a different subject Compounds of the present disclosure which affect NREM sleep by reducing arousals in a subject, have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by reducing arousals in rats, have the same effects in a subject of a different species. Compounds of the present disclosure which affect NREM sleep by reducing arousals in rats, have the same effects in a human.

[0122] Without wishing to be bound by theory, sleep continuity can be measured as the duration of NREM“bouts” or the duration of REM bouts, or the duration NREM+REM“bouts”, wherein an arousal or bout of wakefulness interrupts the NREM-REM cycle.

[0123] In some embodiments, sleep bout can be comprised of NREM, REM, or NREM+REM [0124] In some embodiments, sleep bout can be comprised of NREM In some embodiments, sleep bout can be comprised of REM. In some embodiments, sleep bout can be comprised of NREM+REM

[0125] In some embodiments, NREM and REM sleep alternate in what may be called the NREM-REM cycle. In some embodiments NREM precedes REM

[0126] In some embodiments, the proportion of time spent in NREM versus REM is the same for different subjects. In some embodiments, the proportion of time spent in NREM versus REM is the same for different subjects of different species. In some embodiments, the proportion of time spent in NREM versus REM is the same for a rat and a subject of a different species. In some embodiments, the proportion of time spent in NREM versus REM is the same for a rat and a human.

[0127] In some embodiments, the proportion of time spent in NREM versus REM is about 5:1.

In some embodiments, the proportion of time spent in NREM versus REM is about 4: 1. In some embodiments, the proportion of time spent in NREM versus REM is about 3: 1. In some embodiments, the proportion of time spent in NREM versus REM is about 2: 1.

[0128] In some embodiments, the proportion of time spent in NREM versus REM is from about 100: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 90: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 80:1 to about 1:1. In some embodiments, the proportion of time spent in NREM versus REM is from about 70: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 60: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 50: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 40: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 30: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 20: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 10:1 to about 1:1. In some embodiments, the proportion of time spent in NREM versus REM is from about 5: 1 to about 1 : 1. In some embodiments, the species is a mouse. In some embodiments, the species is a hoofed animal. In some embodiments, the hoofed animal is a horse or cow. In some embodiments, the species is not a laboratory rat. In some embodiments, the species is not a human. [0129] In some embodiments, hypnotics reduce REM sleep to some degree, and several classes of sleep disorder medicines can strongly suppress REM sleep. Without wishing to be bound by theory, REM sleep suppression may be relevant to learning, memory, and/or psychiatric health.

[0130] Without wishing to be bound by theory, the relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate REM sleep translates from a subject to a different subject. The relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate REM sleep translates from a subject to a subject of a different species. The relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate REM sleep translates from rat to a subject of a different species. The relative effect of some classes of medicines for sleep disorders that either inhibit or stimulate REM sleep may translate from laboratory rats to a human.

[0131] In some embodiments, a class of medicine which may inhibit or stimulate REM or NREM sleep is selected from a sleep therapeutic, a neuropsychiatric antidepressant, and a cardiovascular medicine.

[0132] In some embodiments, a sleep therapeutic is a sedative hypnotic GABAA positive allosteric modulators that binds to the GABAA benzodiazepine receptor. In some embodiments, a neuropsychiatric antidepressant is a selective serotonin reuptake inhibitor (SSRI) or an atypical antipsychotics. In some embodiments, a cardiovascular medicine is a therapeutic that may bind to an alpha-adrenergic receptor.

[0133] There are two differences which may be present between rat and human sleep. First, rats are night-active, whereas humans are day-active. This difference may have no importance per se for testing drug effects on sleep and wakefulness. The timing of the dose relative to the normal sleep period can be relied upon when evaluating drag efficacy on sleep related variables (e.g., inhibition of REM sleep) when comparing rat and human sleep. The difference between rats and humans is sleep-bout length, also referred to as“sleep continuity.” Further, humans may consolidate sleep into a single period per day, interrupted only by short (e.g., less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute) bouts of wakefulness. The abnormal conditions may result in human sleep becoming fragmented, diminishing the restorative benefits of sleep. Rats may have shorter bouts of sleep that occur throughout the 24-hour day (e.g., on average, every 20 minutes, a rat completes a sleep- wake cycle). During darkness (when the rat may be most active), sleep typically occupies about 1/3 of each 20-minute cycle, and REM sleep is rare. During the day (lights-on), the rat typically sleeps about 2/3 of each 20-minute cycle. The polyphasic nature of sleep and shorter spontaneous sleep bout durations in the rat, enables highly sensitive assessments of drug effects, such as those that increase sleep consolidation (sleep bout duration), decrease the number of arousals (number of wake bouts), and a variety of secondary but desirable measures of sleep quality, for example EEG slow wave activity in nonREM sleep, and measures of wake maintenance as measured by wake bout duration. Sleep bout-length may also be a sensitive measure of physiological sleepiness and may be a pre-clinical predictor of soporific efficacy in humans.

Timing of treatment

[0134] Empirical optimization can be performed by assessing sleep-related compounds by administering such compounds at two circadian times of day, CT-18 and CT-5 (Edgar et al, Psychopharmacology, 1991, 105, 374, Edgar et al., J. Pharmacology & Experimental

Therapeutics, 1997, 283, 757; Seidel et al. J. Pharmacology & Experimental Therapeutics 275, 263), wherein CT-0 is defined as lights-on. CT-18 is the mid-point of the activity phase of the rat’s circadian cycle, 6 hours after lights-off, and may be sensitive to soporific drug effects on sleep bout length, although such effects can be observed at both CT-18 and CT-5. CT-5 begins several hours of peak abundance of REM sleep and thus is a sensitive time to reveal drug-related inhibition of REM sleep. Both CT-18 and CT-5 are suitable times of the day for the assessment of drug effects on sleep fragmentation as measured by arousals (number of wake bouts), sleep consolidation (sleep bout duration), as well as assessments of maintenance of wakefulness (wake bout length) and drug-related side effects.

[0135] Preclinical effects observed at either CT-5 (treatments administered at a time of day corresponding to 5 hours after lights-on) and/or CT-18 (treatments administered at a time of day corresponding to 18 hours after lights-on or 6 hours after light-off when animals are housed in a 24 hour light dark cycle consisting of 12-hours of light and 12 hours of dark) are considered sufficient for purposes of identifying compounds which may reduce sleep fragmentation. Biological Assay

[0136] The subject is surgically prepared for EEG and EMG recording and administered an analgesic with an antibiotic, followed by therapeutic delivery via intraperitoneal or oral administration. The sleep and wakefulness may be determined using SCORE™.

[0137] Statistically significant differences between drug and vehicle may be screened using a post-hoc Student’s T-test applied to hourly binned data and adjusted for repeated measures.

[0138] The compounds of the present disclosure exhibit improved sleep fragmentation as assessed by evaluating the sleep architecture and sleep quality endpoints of several neurosteroid molecules with established affinity and functional activity at this target

[0139] In some embodiments, sleep fragmentation is improved by (i) reducing the number of arousals (as measured by the number of wake bouts per hour), or (ii) increasing sleep consolidation (as measured by average sleep bout duration per hour). In some embodiments, sleep fragmentation is improved by (i) reducing the number of arousals (as measured by the number of wake bouts per hour), and (ii) increasing sleep consolidation (as measured by average sleep bout duration per hour). In some embodiments, sleep fragmentation is improved by reducing the number of arousals (as measured by the number of wake bouts per hour. In some embodiments, sleep fragmentation is improved by increasing sleep consolidation (as measured by average sleep bout duration per hour).

Methods of Use

[0140] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder.

[0141] In some embodiments, the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold.

[0142] In some embodiments, the sleep disorder is increased disturbed sleep. In some embodiments, the sleep disorder is increased sleep fragmentation. In some embodiments, the sleep disorder is increased arousals. In some embodiments, the sleep disorder is decreased arousal threshold.

[0143] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound selected from: CCD-3693 (l-((3R,5R,10S,13S,17S)-3-hydroxy-13-methyl-3- (trifluoromethy l)hexadecahydro- 1 H-cy clopenta[a] phenanthren- 17 -yl)ethan- 1 -one), Co-13-4444

(1 -((3R,5S, 1 OS, 13 S, 17S)-3-hydroxy-3-(methoxymethyl)- 10, 13 -dimethylhexadecahy dro- 1 H- cyclopenta[a]phenanthren- 17-yl)-2-( 1 H-imidazol- 1 -yl)ethan- 1 -one), ganaxolone (1-

((3R, 1 OS, 13 S, 17S)-3-hydroxy-3, 10, 13-trimethylhexadecahydro-l H-cyclopenta[a]phenanthren-

17-yl)ethan-l-one), pregnanolone (l-((3R,5R,10S,13S,17S)-3-hydroxy-10,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)etha n-l-one), Sage-217 (l-(2-

((3R,5R, 1 OS, 13 S, 17S)-3-hy droxy-3 , 13 -dimethylhexadecahy dro- 1 H-cyclopenta[a]phenanthren-

17-yl)-2-oxoethyl)-lH-pyrazole-4-carbonitrile), and brexanolone(Sage-547; 1-

((3R, 1 OS, 13 S, 17S)-3-hydroxy-l 0, 13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren- 17- yl)ethan-l-one), or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0144] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of or treating a sleep disorder by administering one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a

pharmaceutically acceptable salt thereof to a subject in need thereof.

[0145] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of a sleep disorder by administering one or more compound selected from: CCD-3693, Co- 13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0146] In some embodiments, the present disclosure provides one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation.

[0147] In some embodiments, the present disclosure provides one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of or treating sleep fragmentation.

[0148] In some embodiments, the present disclosure provides one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of sleep fragmentation.

[0149] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[01 SO] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of or treating sleep fragmentation.

[0151] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of sleep fragmentation.

[0152] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0153] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of or treating sleep fragmentation.

[0154] In some embodiments, the present disclosure provides the use of one or more compound selected from: CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, and brexanolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of sleep fragmentation.

[0155] In some embodiments, the compound is CCD-3693, Co-13-4444, ganaxolone, pregnanolone, Sage-217, or brexanolone, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering CCD-3693, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0157] In some embodiments, the present disclosure provides CCD-3693, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation. [0158] In some embodiments, the present disclosure provides the use of CCD-3693, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0159] In some embodiments, the present disclosure provides the use of CCD-3693, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0160] In some embodiments, the compound is CCD-3693, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, CCD-3693 is administered at a dose between about 0.010 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 0.05 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 0.1 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is

administered at a dose between about 0.5 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 90 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 80 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 70 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 60 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 100 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 90 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 80 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 70 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 60 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 50 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 10 mg/kg and about 60 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 10 mg/kg and about 50 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 10 mg/kg and about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 15 mg/kg and about 60 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 15 mg/kg and about 50 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 15 mg/kg and about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 15 mg/kg and about 30 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 20 mg/kg and about 60 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 20 mg/kg and about 50 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 20 mg/kg and about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose between about 20 mg/kg and about 30 mg/kg.

[0162] In some embodiments, CCD-3693 is administered at a dose of about 0.010 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.015 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.020 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.025 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.05 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.1 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.2 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.3 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.4 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 0.5 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 1 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 2 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 3 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 4 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 5 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 10 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 15 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 20 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 25 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 30 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 35 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 40 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 45 mg/kg. In some embodiments, CCD-3693 is administered at a dose of about 50 mg/kg.

[0163] In some embodiments, the present disclosure shows the effects of an orally bioavailable synthetic analog of pregnanolone, CCD-3693, on the number of arousals and on sleep consolidation.

[0164] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering Co-13-4444, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0165] In some embodiments, the present disclosure provides Co-13-4444, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation.

[0166] In some embodiments, the present disclosure provides the use of Co-13-4444, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0167] In some embodiments, the present disclosure provides the use of Co- 13 -4444, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0168] In some embodiments, the compound is Co- 13-4444, or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, Co-13-4444 is administered at a dose between about 0.010 mg/kg and about 100 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 0.05 mg/kg and about 100 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 0.1 mg/kg and about 100 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 0.5 mg/kg and about 100 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 1 mg/kg and about 100 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 1 mg/kg and about 90 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 1 mg/kg and about 80 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 1 mg/kg and about 70 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 1 mg/kg and about 60 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 5 mg/kg and about 100 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 5 mg/kg and about 90 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 5 mg/kg and about 80 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 5 mg/kg and about 70 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 5 mg/kg and about 60 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 5 mg/kg and about 50 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 5 mg/kg and about 40 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 10 mg/kg and about 60 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 10 mg/kg and about 50 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 10 mg/kg and about 40 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 15 mg/kg and about 60 mg/kg. In some embodiments, Co-13-4444 is

administered at a dose between about 15 mg/kg and about 50 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose between about 15 mg/kg and about 40 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 15 mg/kg and about 30 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 20 mg/kg and about 60 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose between about 20 mg/kg and about 50 mg/kg. In some embodiments, Co-13-4444 is administered at a dose between about 20 mg/kg and about 40 mg/kg. In some embodiments, Co-13-4444 is

administered at a dose between about 20 mg/kg and about 30 mg/kg.

[0170] In some embodiments, Co-13-4444 is administered at a dose of about 0.010 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 0.015 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose of about 0.020 mg/kg. In some

embodiments, Co- 13 -4444 is administered at a dose of about 0.025 mg/kg. In some

embodiments, Co- 13 -4444 is administered at a dose of about 0.05 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose of about 0.1 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 0.2 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose of about 0.3 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 0.4 mg/kg. In some embodiments, Co- 13-4444 is administered at a dose of about 0.5 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose of about 1 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose of about 2 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 3 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 4 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 5 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 10 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 15 mg/kg. In some embodiments, Co- 13 -4444 is administered at a dose of about 20 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 25 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 30 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 35 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 40 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 45 mg/kg. In some embodiments, Co-13-4444 is administered at a dose of about 50 mg/kg.

[0171] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering ganaxolone, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0172] In some embodiments, the present disclosure provides ganaxolone, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation.

[0173] In some embodiments, the present disclosure provides the use of ganaxolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0174] In some embodiments, the present disclosure provides the use of ganaxolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0175] In some embodiments, the compound is ganaxolone, or a pharmaceutically acceptable salt thereof. [0176] In some embodiments, ganaxolone is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, ganaxolone is

administered at a dose between about 0.5 mg/kg and about 50 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 45 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 35 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 1 mg/kg and about 15 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 5 mg/kg and about 25 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 5 mg/kg and about 20 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 5 mg/kg and about 15 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 10 mg/kg and about 25 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 10 mg/kg and about 20 mg/kg. In some embodiments, ganaxolone is administered at a dose between about 10 mg/kg and about 15 mg/kg.

[0177] In some embodiments, ganaxolone is administered at a dose of about 0.010 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.015 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.020 mg/kg. In some

embodiments, ganaxolone is administered at a dose of about 0.025 mg/kg. In some

embodiments, ganaxolone is administered at a dose of about 0.05 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.1 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.2 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.3 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.4 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 0.5 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 1 mg/kg. In some

embodiments, ganaxolone is administered at a dose of about 2 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 3 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 4 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 5 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 10 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 15 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 20 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 25 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 30 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 35 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 40 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 45 mg/kg. In some embodiments, ganaxolone is administered at a dose of about 50 mg/kg.

[0178] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering pregnanolone, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0179] In some embodiments, the present disclosure provides pregnanolone, or a

pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation.

[0180] In some embodiments, the present disclosure provides the use of pregnanolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0181] In some embodiments, the present disclosure provides the use of pregnanolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0182] In some embodiments, the compound is pregnanolone, or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, pregnanolone is administered at a dose between about 0.010 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 0.05 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 0.1 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 0.5 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 90 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 80 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 70 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 60 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 100 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 90 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 80 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 70 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 60 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 50 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 10 mg/kg and about 60 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 10 mg/kg and about 50 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 10 mg/kg and about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 15 mg/kg and about 60 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 15 mg/kg and about 50 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 15 mg/kg and about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 15 mg/kg and about 30 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 20 mg/kg and about 60 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 20 mg/kg and about SO mg/kg. In some embodiments, pregnanolone is administered at a dose between about 20 mg/kg and about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose between about 20 mg/kg and about 30 mg/kg.

[0184] In some embodiments, pregnanolone is administered at a dose of about 0.010 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 0.015 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 0.020 mg/kg. In some

embodiments, pregnanolone is administered at a dose of about 0.025 mg/kg. In some

embodiments, pregnanolone is administered at a dose of about 0.05 mg/kg. In some

embodiments, pregnanolone is administered at a dose of about 0.1 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 0.2 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 0.3 mg/kg. In some embodiments, pregnanolone is

administered at a dose of about 0.4 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 0.5 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 1 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 2 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 3 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 4 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 5 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 10 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 15 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 20 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 25 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 30 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 35 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 40 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 45 mg/kg. In some embodiments, pregnanolone is administered at a dose of about 50 mg/kg.

[0185] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering Sage-217, or a

pharmaceutically acceptable salt thereof to a subject in need thereof.

[0186] In some embodiments, the present disclosure provides Sage-217, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation. [0187] In some embodiments, the present disclosure provides the use of Sage-217, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0188] In some embodiments, the present disclosure provides the use of Sage-217, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0189] In some embodiments, the compound is Sage-217, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, Sage-217 is administered at a dose between about 0.010 mg/kg and about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.05 mg/kg and about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.1 mg/kg and about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.5 mg/kg and about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.5 mg/kg and about 25 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.5 mg/kg and about 20 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.5 mg/kg and about 15 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 0.5 mg/kg and about 10 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 1 mg/kg and about 15 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 1 mg/kg and about 10 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, Sage- 217 is administered at a dose between about 5 mg/kg and about 25 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 5 mg/kg and about 20 mg/kg. In some embodiments, Sage-217 is administered at a dose between about 10 mg/kg and about 15 mg/kg.

[0191] In some embodiments, Sage-217 is administered at a dose of about 0.010 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.015 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.020 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.025 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.05 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.1 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.2 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.3 mg/kg. In some

embodiments, Sage-217 is administered at a dose of about 0.4 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 0.5 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 1 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 2 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 3 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 4 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 5 mg/kg. In some embodiments, Sage- 217 is administered at a dose of about 10 mg/kg. In some embodiments, Sage-217 is

administered at a dose of about 15 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 20 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 25 mg/kg. In some embodiments, Sago-217 is administered at a dose of about 30 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 35 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 40 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 45 mg/kg. In some embodiments, Sage-217 is administered at a dose of about 50 mg/kg.

[0192] In some embodiments, the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering brexanolone, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0193] In some embodiments, the present disclosure provides brexanolone, or a

pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing sleep fragmentation.

[0194] In some embodiments, the present disclosure provides the use of brexanolone, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0195] In some embodiments, the present disclosure provides the use of brexanolone, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing sleep fragmentation.

[0196] In some embodiments, the compound is brexanolone, or a pharmaceutically acceptable salt thereof. [0197] In some embodiments, brexanolone is administered at a dose between about 0.010 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 0.05 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 0.1 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 0.5 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 90 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 80 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 70 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 60 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, brexanolone is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 100 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 90 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 80 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 70 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 60 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 50 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 40 mg/kg. In some embodiments, brexanolone is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, brexanolone is administered at a dose between about 10 mg/kg and about 60 mg/kg. In some embodiments, brexanolone is administered at a dose between about 10 mg/kg and about 50 mg/kg. In some embodiments, brexanolone is administered at a dose between about 10 mg/kg and about 40 mg/kg. In some embodiments, brexanolone is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, brexanolone is administered at a dose between about 15 mg/kg and about 60 mg/kg. In some embodiments, brexanolone is

administered at a dose between about 15 mg/kg and about 50 mg/kg. In some embodiments, brexanolone is administered at a dose between about 15 mg/kg and about 40 mg/kg. In some embodiments, brexanolone is administered at a dose between about 15 mg/kg and about 30 mg/kg. In some embodiments, brexanolone is administered at a dose between about 20 mg/kg and about 60 mg/kg. In some embodiments, brexanolone is administered at a dose between about 20 mg/kg and about 50 mg/kg. In some embodiments, brexanolone is administered at a dose between about 20 mg/kg and about 40 mg/kg. In some embodiments, brexanolone is

administered at a dose between about 20 mg/kg and about 30 mg/kg.

[0198] In some embodiments, brexanolone is administered at a dose of about 0.010 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.015 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.020 mg/kg. In some

embodiments, brexanolone is administered at a dose of about 0.025 mg/kg. In some

embodiments, brexanolone is administered at a dose of about 0.05 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.1 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.2 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.3 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.4 mg/kg. In some embodiments, brexanolone is administered at a dose of about 0.5 mg/kg. In some embodiments, brexanolone is administered at a dose of about 1 mg/kg. In some

embodiments, brexanolone is administered at a dose of about 2 mg/kg. In some embodiments, brexanolone is administered at a dose of about 3 mg/kg. In some embodiments, brexanolone is administered at a dose of about 4 mg/kg. In some embodiments, brexanolone is administered at a dose of about 5 mg/kg. In some embodiments, brexanolone is administered at a dose of about 10 mg/kg. In some embodiments, brexanolone is administered at a dose of about 15 mg/kg. In some embodiments, brexanolone is administered at a dose of about 20 mg/kg. In some embodiments, brexanolone is administered at a dose of about 25 mg/kg. In some embodiments, brexanolone is administered at a dose of about 30 mg/kg. In some embodiments, brexanolone is administered at a dose of about 35 mg/kg. In some embodiments, brexanolone is administered at a dose of about 40 mg/kg. In some embodiments, brexanolone is administered at a dose of about 45 mg/kg. In some embodiments, brexanolone is administered at a dose of about 50 mg/kg.

[0199] In some embodiments, brexanolone is administered at a dose between about 0.010 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.015 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.020 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.025 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.030 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.035 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.040 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.045 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.050 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.055 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.060 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.065 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.070 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.075 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.080 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.085 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.090 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.095 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.10 mg/kg/hour and about 0.15 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.010 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.015 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.020 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.025 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.030 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.035 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.040 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.045 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.050 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.055 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.060 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.065 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.070 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.075 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.080 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.085 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.090 mg/kg/hour and about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose between about 0.095 mg/kg/hour and about 0.10 mg/kg/hour.

[0200] In some embodiments, brexanolone is administered at a dose of about 0.010 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.015 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.020 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.025 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.030 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.035 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.040 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.045 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.050 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.055 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.060 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.065 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.070 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.075 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.080 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.085 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.090 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.095 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.10 mg/kg/hour. In some embodiments, brexanolone is administered at a dose of about 0.15 mg/kg/hour.

[0201] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered parenterally. In some embodiments, the compound is administered transdermally. In some embodiments, the compound is administered subcutaneously. In some embodiments, the compound is administered intravenously.

[0202] In some embodiments, a compound of the present disclosure is not suvorexant, zolpidem, or S-zopiclone, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, a compound of the present disclosure is not suvorexant, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, a compound of the present disclosure is not zolpidem, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, a compound of the present disclosure is not S-zopiclone, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is caused by or co-morbid with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.

[0207] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.

[0208] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with sleep apnea, restless legs syndrome, high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.

[0209] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea.

[0210] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by sleep apnea.

[0211] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is co-morbid with sleep apnea.

[0212] In some embodiments, sleep apnea is obstructive sleep apnea.

[0213] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with or without a concomitant apnea.

[0214] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with a concomitant apnea. [0215] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with or without a concomitant hypopnea.

[0216] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with a concomitant hypopnea.

[0217] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with or without concomitant acute hemoglobin desaturation.

[0218] In some embodiments, sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with concomitant acute hemoglobin desaturation.

[0219] In some embodiments, sleep apnea is central sleep apnea.

[0220] In some embodiments, sleep apnea is low-arousal threshold sleep apnea.

[0221] In some embodiments, sleep apnea is hypopnea.

[0222] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with restless legs syndrome.

[0223] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by restless legs syndrome.

[0224] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with restless legs syndrome.

[0225] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a high respiratory disturbance index

(RDI).

[0226] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a high respiratory disturbance index (RDI).

[0227] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a high respiratory disturbance index (RDI).

[0228] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with or without a concomitant apnea.

[0229] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with a concomitant apnea.

[0230] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with or without a concomitant hypopnea.

[0231] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with a concomitant hypopnea.

[0232] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with or without concomitant acute hemoglobin desaturation.

[0233] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with concomitant acute hemoglobin desaturation.

[0234] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with or without concomitant hemoglobin desaturation.

[0235] In some embodiments, the RDI is associated with an elevated respiratory event related arousal (RERA) with concomitant hemoglobin desaturation.

[0236] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a neurological disease. [0237] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a neurological disease.

[0238] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a neurological disease.

[0239] In some embodiments, the neurological disease is a neurodegenerative disease.

[0240] In some embodiments, the neurodegenerative disease is Lewy body disease (i.e., Lewy body dementia). In some embodiments, the Lewy body disease is diffuse.

[0241] In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is a synucleinopathy.

[0242] In some embodiments, a synucleinopathy is Alzheimer’s disease, Parkinson’s disease, or Lewy body dementia. In some embodiments, a synucleinopathy is Alzheimer’s disease. In some embodiments, a synucleinopathy is Parkinson’s disease. In some embodiments, a synucleinopathy is dementia with Lewy bodies. In some embodiments, a synucleinopathy is multiple system atrophy.

[0243] In some embodiments, the neurological disease is a neurodevelopmental disease. In some embodiments, the neurodevelopmental disease is autism. In some embodiments, the neurological disease is a muscular dystonia. In some embodiments, the dystonia is neuromuscular dystonia. In some embodiments, the neuromuscular dystonia is spasmodic torticollis.

[0244] In some embodiments, the neurological disease is multiple sclerosis (MS).

[0245] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a circadian rhythm disorder. [0246] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a circadian rhythm disorder.

[0247] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a circadian rhythm disorder.

[0248] In some embodiments, the circadian rhythm disorder is advanced sleep-wake phase disorder. In some embodiments, the circadian rhythm disorder is irregular sleep-wake rhythm disorder. In some embodiments, the circadian rhythm disorder is jet lag. In some embodiments, the circadian rhythm disorder is shift work sleep disorder. In some embodiments, the circadian rhythm disorder is delayed sleep phase syndrome. In some embodiments, the circadian rhythm disorder is non-24 hour rhythm disorder.

[0249] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with pain.

[0250] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is caused by pain.

[0251] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with pain.

[0252] In some embodiments, the pain is selected from an inflammatory pain, a nociceptive pain, a neuropathic pain, a mixed nociceptive and neuropathic pain, a post-operative pain, a postherpetic pain, a traumatic pain, a phantom-limb pain, a fibromyalgia, a back pain, a cancer pain, and an osteoarthritic pain. [0253] In some embodiments, the pain is an inflammatory pain. In some embodiments, the inflammatory pain is arthritis. In some embodiments, the arthritis is rheumatoid arthritis. In some embodiments, the arthritis is osteoarthritis.

[0254] In some embodiments, the pain is a nociceptive pain. In some embodiments, the nociceptive pain is acute. In some embodiments, the nociceptive pain is chronic. In some embodiments, the nociceptive pain is caused by a cancer therapy. In some embodiments, the nociceptive pain is caused by a surgery.

[0255] In some embodiments, the pain is a neuropathic pain. In some embodiments, the neuropathic pain is chronic. In some embodiments, the neuropathic pain is acute. In some embodiments, the neuropathic pain is back pain. In some embodiments, the neuropathic pain is caused by a spinal cord injury. In some embodiments, the neuropathic pain is caused by multiple sclerosis. In some embodiments, the neuropathic pain is caused by a stroke. In some

embodiments, the neuropathic pain is caused by diabetes. In some embodiments, the neuropathic pain is caused by a metabolic condition.

[0256] In some embodiments, the pain is a mixed nociceptive and neuropathic pain.

[0257] In some embodiments, the pain is a post-operative pain.

[0258] In some embodiments, the pain is a post-herpetic pain.

[0259] In some embodiments, the pain is a traumatic pain. In some embodiments, traumatic pain is caused by causalgia.

[0260] In some embodiments, the pain is a phantom-limb pain.

[0261] In some embodiments, the pain is a fibromyalgia.

[0262] In some embodiments, the pain is a back pain. In some embodiments, the pain is a low back pain.

[0263] In some embodiments, the pain is a cancer pain. In some embodiments, the cancer pain is cancer. In some embodiments, the cancer pain is caused by a tumor. In some embodiments, the cancer pain is caused by a cancer treatment. In some embodiments, the cancer pain is caused by chemotherapy. In some embodiments, the cancer pain is radiation therapy. In some

embodiments, the cancer pain is caused by surgery.

[0264] In some embodiments, the pain is an osteoarthritic pain.

[0265] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with periodic leg movement disorder

(PLMD).

[0266] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by periodic leg movement disorder (PLMD).

[0267] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with periodic leg movement disorder (PLMD).

[0268] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with REM behavior disorder.

[0269] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by REM behavior disorder.

[0270] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with REM behavior disorder.

[0271] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with elderly fragmented sleep.

[0272] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by elderly fragmented sleep. [0273] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with elderly fragmented sleep.

[0274] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with age-related sleep fragmentation.

[0275] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by age-related sleep fragmentation.

[0276] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with age-related sleep fragmentation.

[0277] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is caused by or co-morbid with post-menopausal sleep disorder.

[0278] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by post-menopausal sleep disorder.

[0279] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with post-menopausal sleep disorder.

[0280] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse.

[0281] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by substance abuse.

[0282] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with substance abuse.

[0283] In some embodiments, the substance abuse is opioid abuse or alcoholism. In some embodiments, the substance abuse is opioid abuse. In some embodiments, the substance abuse is alcoholism.

[0284] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse withdrawal.

[0285] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by substance abuse withdrawal.

[0286] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with substance abuse withdrawal.

[0287] In some embodiments, the substance abuse withdrawal is opioid withdrawal or alcohol withdrawal. In some embodiments, the substance abuse withdrawal is opioid withdrawal. In some embodiments, the substance abuse is alcohol withdrawal.

[0288] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with narcolepsy.

[0289] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by narcolepsy.

[0290] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with narcolepsy.

[0291] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a mental disorder.

[0292] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a mental disorder.

[0293] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is co-morbid with a mental disorder.

[0294] In some embodiments, the mental disorder is depression, major depressive disorder, post- traumatic stress disorder, anxiety disorder, bipolar disorder, or schizophrenia.

[0295] In some embodiments, the mental disorder is depression. In some embodiments, the mental disorder is major depressive disorder. In some embodiments, the mental disorder is post- traumatic stress disorder. In some embodiments, the mental disorder is anxiety disorder. In some embodiments, the mental disorder is bipolar disorder. In some embodiments, the mental disorder is schizophrenia.

[0296] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with non-restorative sleep.

[0297] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by non-restorative sleep.

[0298] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with non-restorative sleep.

[0299] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with snoring.

[0300] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by snoring.

[0301] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject wherein the sleep disorder is co-morbid with snoring.

[0302] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with idiopathic hypersomnia.

[0303] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by idiopathic hypersomnia. [0304] In some embodiments, the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with idiopathic hypersomnia.

[0305] In some embodiments, compounds of the present disclosure may also facilitate sleep continuity. In some embodiments, the sleep continuity is an increase in depth of sleep as measured by EEG slow wave activity. In some embodiments, the sleep continuity is an increase in arousal threshold as measured by a wake bout length. In some embodiments, the sleep continuity is a reduction in maintenance of wakefulness as measured by a wake bout length.

[0306] In some embodiments, the number of arousals is decreased by up to about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment.

[0307] In some embodiments, CCD-3693 alleviates a symptom of, treats, or prevents a sleep disorder.

[0308] In some embodiments, CCD-3693 reduces sleep fragmentation . In some embodiments, CCD-3693 decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep consolidation (e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment).

[0309] In some embodiments, CCD-3693 reduces wake bout length.

[0310] In some embodiments, Co-13-4444 alleviates a symptom of, treats, or prevents a sleep disorder.

[0311] In some embodiments, Co- 13 -4444 reduces sleep fragmentation. In some embodiments, Co- 13-4444 decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment), and increases sleep consolidation (e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment).

[0312] In some embodiments, ganaxolone alleviates a symptom of, treats, or prevents a sleep disorder. [0313] In some embodiments, ganaxolone reduces sleep fragmentation. In some embodiments, ganaxolone decreases the number of arousals (e.g., about 3-fold reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment), and increases sleep consolidation (e.g., about 5-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment).

[0314] In some embodiments, compounds of the present disclosure may improve other measures of sleep quality indicative of molecules that facilitate sleep continuity as demonstrated by increased depth of sleep as measured by EEG slow wave activity or increased arousal threshold and reduced maintenance of wakefulness as measured by a wake bout length.

[0315] In some embodiments, ganaxolone (CCD- 1042) reduces wake bout length.

[0316] In some embodiments, pregnanolone alleviates a symptom of, treats, or prevents a sleep disorder.

[0317] In some embodiments, pregnanolone reduces sleep fragmentation. Pregnanolone is also known as eltanolone, and is a naturally occurring neuroactive steroid that is endogenously biosynthesized from progesterone. In some embodiments, pregnanolone decreases the number of arousals (e.g., about 3-fold reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment), and increases sleep consolidation (e.g., about >10-fold increase in average sleep bout duration per hour post-treatment relative to vehicle treatment).

[0318] In some embodiments, pregnanolone facilitates sleep continuity to increase arousal threshold and reduce maintenance of wakefulness as measured by wake bout length.

[0319] In some embodiments, Sage-217 alleviates a symptom of, treats, or prevents a sleep disorder.

[0320] In some embodiments, Sage-217 reduces sleep fragmentation. In some embodiments, Sage-217 decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep

consolidation (e.g., about 8-fold increase in average sleep bout duration per hour post-treatment relative to vehicle treatment).

[0321] In some embodiments, Sage-217 facilitates sleep continuity to increase arousal threshold and reduce maintenance of wakefulness as measured by a wake bout length.

[0322] In some embodiments, brexanolone alleviates a symptom of, treats, or prevents a sleep disorder. [0323] In some embodiments, compounds of the present disclosure produce improvements in sleep fragmentation and differentiate from drugs that are routinely prescribed (and comprise pharmacological standard of care) for insomnia. In some embodiments, standard of care agents for insomnia are, for example, but not limited to, the orexin antagonists suvorexant (Belsomra®), and the non-benzodiazepine, benzodiazepine receptor dependent GABAA allosteric modulators zolpidem (Ambien®) and eszopiclone (Lunesta®), which do not adequately improve the requisite preclinical measures of sleep fragmentation.

[0324] In some embodiments, the orexin 0X1 /OX2 receptor antagonist suvorexant fails to improve sleep fragmentation at 3 mg/kg, 10 mg/kg, and 30 mg/kg. In some embodiments, suvorexant does not reduce the number of arousals as measured by the number of wake bouts per hour, but instead, increases the number of arousals. In some embodiments, suvorexant produces small improvements in sleep consolidation at the highest dose (30 mg/kg) as measured by average sleep bout duration per hour post-treatment

[0325] In some embodiments, zolpidem, at doses sufficient to produce increases in soporific efficacy as measured by EEG slow wave activity (EEG delta power in nonREM sleep), fails to reduce the number of arousals as measured by the number of wake bouts per hour and fails to produce improvement in sleep consolidation as measured by average sleep bout duration per hour. Zolpidem can produce sedative effects (up to and including non-responsiveness of the subject); however, increasing the dose of zolpidem may be complicated by a short kinetic half- life and can be contraindicated due to significant unwanted side effects including, but not limited to, severe REM sleep inhibition, severe motor coordination impairment, memory impairment, rebound insomnia, and other unwanted adverse effects, or a combination thereof.

[0326] In some embodiments, S-zopiclone (marketed as Lunesta®) fails to reduce the number of arousals as measured by the number of wake bouts per hour and produces only small

improvements in sleep consolidation as measured by average sleep bout duration per hour. In some embodiments, the doses of S-zopiclone (i.e., from about 5 mg/kg to about 30 mg/kg) do not increase sleep consolidation above the levels exhibited during the baseline rest phase (lights-on; circadian time 0:00-12:00 prior to treatment). While the immediate sedative hypnotic effects of S-zopiclone can increase with dose, driving additional soporific efficacy with high doses is contraindicated due to dose-dependent unwanted side effects. In some embodiments, doses of S- zopiclone (i.e., from about 5 mg/kg to about 30 mg/kg) decrease Locomotor Activity Intensity (LMAi), reflecting undesirable dose-dependent and disproportional motor impairment during wakefulness. In some embodiments, S-zopiclone also dose-dependently inhibits REM sleep, which may be important for memory and learning. In some embodiments, standard of care insomnia drugs (e.g., zolpidem and S-zopiclone) can also reduce muscle tone, which is not only important for ambulation (e.g., getting up from sleep to use the bathroom), but also could have unwanted consequences for subjects diagnosed with or at risk for obstructive sleep apnea. In some embodiments, relaxation of upper airway muscles is an undesirable side effect as it could worsen obstructive sleep apnea and its comorbid health risks. Direct electromyographic assessment of nuchal muscle tone may reveal unwanted myorelaxation (decrease in muscle electrical activity) after treatment with S-zopiclone. The improvement in nonREM sleep time induced by S-zopiclone can be followed by an undesirable dose-dependent rebound interference in sleep that would not enable improvement in sleep fragmentation.

EXAMPLES

[0327] The following examples illustrate the disclosure. These examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the methods of the present disclosure. While particular embodiments of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

Abbreviations

[0328] The following abbreviations are used in the examples, which follow. This list is not meant to be an all-inclusive list of abbreviations used in the application as additional standard abbreviations, which are readily understood by those skilled in the art, can also be used in the examples.

C Celsius

EEC Electro- encephalograph

EMG electromyograph

g grams

HPfJCD (2-hydroxypropyl)-P-cyclodextrin

Hz hertz

kg kilograms

mL milliliters Example 1. Experimental details and methods for determining sleep continuity, wakefulness, number of arousals, locomotor activity, and soporific efficacy

Animal preparation rats

[0329] Adult, male Wistar rats (approximately 270 g at time of surgery, Charles River

Laboratories) were anesthetized (2% isoflourane in 95/5 oxygen) and surgically prepared with a cranial implant that permitted EEG and EMG recording. Body temperature and locomotor activity were monitored via a miniature transmitter (Minimitter Series 4000 E-Mitter, Bend, OR) surgically placed in the abdomen during the same anesthetic event the cranial portion was implanted. The cranial implant consisted of stainless steel screws (2 frontal [+3.9 AP from bregma, ±2.0 ML] and 2 occipital [-6.4 AP, ±5.5 ML]) for EEG recording. Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All leads were soldered to a miniature connector (Microtech, Boothwyn, PA) and gas sterilized with ethylene oxide prior to surgery. The implant assembly was affixed to the skull by the combination of the EEG recording screws, cyanoacrylate applied between the hermetically sealed implant connector and skull, and dental acrylic. An analgesic (buprinorphine 0.3 mg/kg IP) was administered pre-operatively and daily SC for 2 days post-surgery. An antibiotic was administered before surgery (chloramphenicol 40 mg/kg IM) and for 7-10 days after surgery (Clavamox b.i.d.). At least three weeks were allowed for surgical recovery prior to any data collection.

Recording environment

[0330] Rats were housed individually within specially modified Nalgene ^® microisolator cages equipped with an ultra-low-torque slip-ring commutator and a custom polycarbonate filter-top riser. These cages were located within separate, ventilated compartments of a stainless steel sleep-wake recording chamber. Food and water were available ad libitum and the ambient temperature was 23±1° C. A 24-hourlight-dark cycle (LD 12: 12) was maintained throughout the study using fluorescent light Light intensity averaged 35-40 lux at mid-level inside the cage. Relative humidity averaged 50% approximately. Animals were undisturbed for two days before and after each treatment.

Automated data collection

[0331] Sleep and wakefulness were determined using SCORE™— a microcomputer-based sleep-wake and physiological monitoring system. Validation of the SCORE™ sleep stage identification algorithm in rodents and utility in pre-clinical drug evaluation have been previously described (Van Gelder etal. 1991; Edgar etal. Psychopharmacology 1991, 105, 374; J. Pharmacology & Experimental Therapeutics 1997, 283, 757; Seidel etal. J Pharmacology & Experimental 'Therapeutics 275, 263; J. Pharmacology & Experimental Therapeutics, 285,

1073). For the studies described herein, the system monitored amplified EEG (x 10,000, bandpass 1-30 Hz; initial digitization rate 400 Hz [Grass Corp., Quincy, MA]), integrated EMG (bandpass 10-100 Hz, RMS integration), and telemetered body temperature and non-specific locomotor activity (LMA), and drink- and food-related activity, from up to 150 rodents simultaneously. Arousal states were classified on-line as NREM sleep, REM sleep, wake, or theta-dominated wake every 10 seconds using EEG period and amplitude feature extraction and ranked membership algorithms. Individually taught EEG-arousal-state templates and EMG criteria differentiated states of arousal. LMA and drink-related activity were automatically recorded as counts per minute, and body temperature was recorded each minute. LMA was detected in both horizontal and vertical planes by a customized telemetry receiver (ER4000, Minimitter, Bend, OR) beneath the cage. Drink-related activity and food-related activity were detected by beam break sensors closely situated around recessed access portals to the lixit and the food bin, respectively. The beam break area for the food bin was, however, relatively large, and these data have not been validated as an endpoint for food consumption per se. Telemetry measures (LMA and body temperature) were not part of the SCORE arousal-state determination algorithm; thus, sleep-scoring and telemetry data were concurrent but independent measures. In addition to frequent on-line inspection of the EEG and EMG signals, quality control of the data was assured by expert analysts with a minimum of 4 years of experience using a proprietaiy suite of programs (SCOREVIEW™, Hypnion, Inc., Lexington, MA) that allowed data quality of all variables to be flexibly scrutinized at the level of (i) individual visual examination of raw EEG and EMG signals, (ii) individual hourly mean timeseries, and (Hi) group mean times eries, using a combination of graphical and statistical assessments. An integrated relational database was updated with data quality control decisions for each individual treatment, and this database controlled all subsequent use of these data. Complete, digitized raw EEG and integrated EMG data have been written to CD-R and are permanently archived for all treatments.

Treatments and drug preparation

[0332] Drug dose, route of administration, and timing of administration were described for each compound and variable within the data exemplifications. Where applicable, methylcellulose vehicle was prepared as a sterile 0.25% solution of methylcellulose (15 centipoise, Sigma, St. Louis, MO., USA). HRbOO (American Maise Products, Indianapolis, IN) vehicle was initially prepared as a 50% stock solution (w/v in 0.9% NaCl) and then further diluted with 0.9% NaCl to achieve percent solutions as reported for respective studies. Intraperitoneal administration was delivered at a volume of 1 mL/kg. Oral dosing was at a volume of up to 10 ml/kg.

[0333] Drugs were weighed using a Metier AX205 analytical balance (d=0.01 mg). Compound was mixed with vehicle using a sterile 2 mL ground glass pestle and mortar until completely dissolved, and then transferred to a sterile Vacutainer (red top) tube. Solutions were agitated immediately before being drawn into a syringe. To administer the treatment, each rat was removed from its cage for about 60-90 seconds to be weighed and treated (the home cage is the recording cage in SCORE™ systems). Note that this procedure caused no prior sleep loss, unlike cases in which the animal must first be acclimated to a special recording chamber. Rats in this experiment lived permanently in their“home cage” within the recording chamber. Prior sleep loss— for instance, the“acclimation” commonly used by other investigators— significantly influences the measurement of sleep-wakefulness responses to drugs (Edgar et al.

Psychopharmacology 1991, 105, 374; Meltzer & Serpa, Drug Dev. Res., 1988, 14, 151).

Study design

[0334] The standard recording duration for SCORE data was not less than 30 hours before and after treatment The 30 hours pre-treatment baseline recording was itself preceded by at least 24 hours in which the animal was undisturbed in the home/recording cage. Rats were randomly assigned to treatments in parallel groups. Some rats received more than one active treatment, in which cases at least 7 days“washout” elapsed between each treatment.

Statistical Analysis

[0335] Statistically significant differences between drag and vehicle were screened using a post- hoc Student’s T-test applied to hourly binned data and adjusted for repeated measures.

Figure formats and graphics conventions

[0336] With reference to FIG. 1-26, two types of time-series plots are depicted. Post-treatment detail plots the first five hours post-treatment. Variables were computed in 5-minute bins, aligned to the minute of treatment. The first time bin, labeled 0, represents the first 5 minutes post treatment Pre- and post-treatment time series plot ±30 hours before and after CT-18 treatments (or 29 hours before and 31 hours after CT-5 treatments). Treatment occurred at the beginning of the hour marked by an arrow. Variables were computed in hourly bins unless denoted otherwise in the text figure descriptions or Figure legend.

[0337] The following graphics convention have been used: All data are plotted as group mean ± SEM. The gray shaded area encompasses the vehicle treatment mean ± SEM Along the x-axis, time of treatment is marked by a triangle unless noted otherwise. Along the x-axis, light/dark bars indicate lights on/off.

Example 2. CCD-3693 effect on sleep continuity, wakefulness, number of arousals, locomotor activity, and soporific efficacy

CCD-3693 reduced the number of arousals

[0338] The neurosteroid GABAA positive allosteric modulator CCD-3693 administered orally to Wistar rats (N=8) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), reduced the number of arousals (as indicated by the arrow), as demonstrated by a reduction in the number of wake bouts per hour post-treatment relative to vehicle control.

Number of wake bouts plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 1).

CCD-3693 produces robust increases sleep continuity/consolidation at CT-18

[0339] The neurosteroid GABAA positive allosteric modulator CCD-3693 administered orally to Wistar rats (N=8) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (as indicated by the arrow), as measured by the average sleep bout duration per hour. Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (CCD-3693 N=8; Vehicle N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant post-treatment difference from methylcellulose vehicle control within the initial 6 hours post-treatment are indicated by asterisk (PO.05). 24 hour light- dark cycle (LD 12:12) indicated on the abscissa. At 30 mg/kg, the highest dose tested, CCD- 3693 increased the average sleep bout duration over 30 minutes per hour, which was

approximately 5-fold greater than that spontaneously observed during the usual circadian rest phase (circadian time 0:00-12:00; vertical arrow) during the pre-treatment baseline (FIG. 2). CCD-3693 reduces maintenance of wakefulness

[0340] The neurosteroid GABAA positive allosteric modulator CCD-3693 administered to Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), decreased wake bout length (a measure of maintenance of wakefulness, and indirect measure of arousal threshold and the latency to return to sleep; as indicated by the arrow), as measured by the average wake bout duration per hour. Longest wake bout duration was calculated as the mean duration of the single longest wake bouts initiated in a given hour for an individual animal, plotted as the population (N=8) hourly mean ± SEM 30 hours before

(baseline) and after treatment Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 3).

Example 3. Co- 13-4444 effect on arousals and sleep continuity

Co-13-4444 reduces the number of arousals

[0341] The neurosteroid GABAA positive allosteric modulator Co-13-4444 administered orally to Wistar rats (N=l 1) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), reduced the number of arousals (as indicated by the arrow), as demonstrated by a reduction in the number of wake bouts per hour post-treatment relative to vehicle control. Number of wake bouts are plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control is indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa. Co-13-4444 is labeled “AL-30011” (FIG. 4).

Co-13-4444 produces robust increases sleep continuity/consolidation at CT-18

[0342] The neurosteroid GABAA positive allosteric modulator Co-13-4444 administered orally to Wistar rats (N=l 1) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (as indicated by the arrow), as measured by the average sleep bout duration per hour. Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (Co-13-4444 (labeled“AL-30011”) N=11; Vehicle N=l l) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant post-treatment difference from methylcellulose vehicle control within the initial 6 hours post-treatment are indicated by asterisk (P<0.05). 24 hour light-dark cycle (LD 12:12) indicated on the abscissa. At 30 mg/kg, the highest dose tested, Co- 13-4444 increased the average sleep bout duration over 90 minutes, which was approximately 10-fold greater than that spontaneously observed during the usual circadian rest phase (circadian time 0:00-12:00; vertical arrow) during the pre-treatment baseline

(FIG. 5).

Example 4. Ganaxolone effect on arousals, sleep continuity, and wakefulness

Ganaxolone reduces number of arousals

[0343] The neurosteroid GABAA positive allosteric modulator ganaxolone (CCD- 1042) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), produced a 3 -fold reduction in the number of arousals (as indicated by the arrow), as measured by the number of wake bouts, as compared to vehicle control treatment. Number of wake bouts are plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control is indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 6).

Ganaxolone increases sleep continuity/consolidation

[0344] The neurosteroid GABAA positive allosteric modulator ganaxolone (CCD- 1042) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation as demonstrated by the approximately 5- fold increase (as indicated by the arrow) in average sleep bout duration per hour post-treatment relative to vehicle control treatment The robust sleep consolidating effect of ganaxolone was approximately 3 times greater (illustrated by vertical arrow) than the circadian peak for this measure during the undisturbed baseline circadian rest phase (circadian time 0:00-12:00).

Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (N=8) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant difference from

methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 7).

Ganaxolone reduces maintenance of ' wakefulness

[0345] The neurosteroid GABAA positive allosteric modulator ganaxolone (CCD- 1042) administered to Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), decreased wake bout length (a measure of maintenance of wakefulness, and indirect measure of arousal threshold and latency to return to sleep; as indicated by the arrow), as measured by the average wake bout duration per hour. Longest wake bout duration was calculated as the mean duration of the single longest wake bouts initiated in a given hour for an individual animal, plotted as the population (N=8) hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa

(FIG. 8).

Example 5. Pregnanolone effect on arousals, sleep continuity, and wakefulness

Pregnanolone reduces number of arousals

[0346] The neurosteroid GABAA positive allosteric modulator pregnanolone (CCD-3045) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), produced a 3 -fold reduction in the number of arousals (as indicated by the arrow), as measured by the number of wake bouts, as compared to vehicle control treatment. Number of wake bouts are plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control is indicated by asterisk. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa (FIG. 9).

Pregnanolone increases sleep continuity/consolidation

[0347] The neurosteroid GABAA positive allosteric modulator pregnanolone (CCD-3045) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation as demonstrated by the >10-fold increase in average sleep bout duration per hour post-treatment (as indicated by the arrow) relative to vehicle control treatment. The robust sleep consolidating effect of pregnanolone was

approximately 7 times greater (illustrated by vertical arrow) than the circadian peak for this measure during the undisturbed baseline circadian rest phase (circadian time 0:00-12:00).

Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from

methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa (FIG. 10). Pregnanolone reduces maintenance of wakefulness

[0348] The neurosteroid GABAA positive allosteric modulator pregnanolone (CCD-3045) administered to Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), decreased wake bout length (a measure of maintenance of wakefulness, and indirect measure of arousal threshold and latency to return to sleep; as indicated by the arrow), as measured by the average wake bout duration per hour. Longest wake bout duration was calculated as the mean duration of the single longest wake bouts initiated in a given hour for an individual animal, plotted as the population (N=8) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 11).

Example 6. Sage-217 effect on arousals, sleep continuity, and wakefulness

Sage-217 reduces number of arousals

[0349] The neurosteroid GABAA positive allosteric modulator Sage-217 (AL-30006) orally administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), produced up to a 50% reduction in the number of arousals (as indicated by the arrow), as measured by the number of wake bouts, as compared to vehicle control treatment Number of wake bouts are plotted as the population (N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant difference from

methylcellulose vehicle control is indicated by asterisk. 24 hour light-dark cycle (LD 12:12) is indicated on the abscissa (FIG. 12).

Sage-217 increases sleep continuity/consolidation

[0350] The neurosteroid GABAA positive allosteric modulator Sage-217 (AL-30006) orally administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation as demonstrated by the > 10-fold increase in average sleep bout duration per hour post-treatment (as indicated by the arrow) relative to vehicle control treatment. The robust sleep consolidating effect of Sage-217 was approximately 7 times greater than the circadian peak for this measure during the undisturbed baseline circadian rest phase (circadian time 0:00-12:00). Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in each hour for an individual animal, plotted as the population (N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment.

Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 13).

Sage-217 reduces maintenance of wakefidness

[0351] The neurosteroid GABAA positive allosteric modulator Sage-217 (AL-30006) administered to Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), decreased wake bout length (a measure of maintenance of wakefulness, and indirect measure of arousal threshold and latency to return to sleep; as indicated by the arrow), as measured by the average wake bout duration per hour. Longest wake bout duration was calculated as the mean duration of the single longest wake bouts initiated in each hour for an individual animal, plotted as the population (N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa (FIG. 14).

Example 7. Suvorexant effect on arousals and sleep continuity

Effect of suvorexant on the number of arousals

[0352] The orexin OX1/OX2 antagonist suvorexant (LSN 3046965, HY-16387) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), failed to reduce the number of arousals (as indicated by the arrow), as measured by the number of wake bouts. Instead, suvorexant slightly increased the number of wake bouts. Number of wake bouts plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from vehicle control (TPGS) indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 15).

Effect of suvorexant on sleep continuity/consolidation at CT-18

[0353] The orexin OX1/OX2 antagonist standard of care sedative hypnotic suvorexant (HY- 16387) administered to Wistar rats at CT-5 (5 hours after light-on; time of treatment indicated by the triangle on the abscissa), produced a weak increase in sleep consolidation (statistical trend 0.05<P<1), as measured by the average sleep bout duration per hour (weak effect observed in the first two hours post-treatment; as indicated by the arrow). Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (N=12) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 16).

Example 8. Zolpidem effect on EEG slow wave activity, arousals, sleep continuity, and REM sleep

Zolpidem soporific efficacy as measured by EEG slow wave activity

[0354] The standard of care treatment for insomnia, zolpidem, administered to Wistar rats (N=8) at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa) increased EEG slow wave activity in nonREM sleep, as measured by the normalized (percent change from baseline; as indicated by the arrow) EEG delta power during nonREM sleep per hour. Normalized EEG delta power (power in the EEG at frequencies of 0.5-4.0 Hz, computed using Fourier analysis) is plotted in this example as the population (N=17) hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 17).

Soporific doses of zolpidem fail to significantly reduce the number of arousals

[0355] The insomnia standard of care, zolpidem, administered at a dose that has robust soporific efficacy as measured by EEG slow wave activity (Fig. 16) failed to reduce the number of arousals as measured by the number of wake bouts per hour. Zolpidem is a GABAA positive allosteric modulator acting at the benzodiazepine binding site on GABAA. In this example, zolpidem (HY-10131) was administered to Wistar rats (N=8) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa). Number of wake bouts plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from vehicle control (methylcellulose) indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 18).

Effect of zolpidem on sleep continuity/consolidation at CT-18

[0356] At a dose sufficient to produce robust soporific efficacy as measured by EEG slow wave activity (see Fig. 16), the benzodiazepine receptor mediated GABAA positive allosteric modulator, zolpidem (HY-10131), administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), produced a weak increase in sleep consolidation (statistical trend 0.0S<P<.1), as measured by the average sleep bout duration per hour (weak effect observed in the first two hours post-treatment; as indicated by the arrow). Average sleep bout duration was calculated as the mean duration of all sleep bouts initiated in a given hour for an individual animal, plotted as the population (N=8) hourly mean ± SEM 30 hours before (baseline) and after treatment Statistically significant difference from

methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 19).

Zolpidem inhibits REM sleep

[0357] The GABAA positive allosteric modulator, zolpidem (HY-10131) administered to Wistar rats (N=16) at CT-5 (5 hours after light-on; time of treatment indicated by the triangle on the abscissa), inhibited REM sleep (as indicated by the arrow), as measured by the percent REM sleep that occurred per hour. The magnitude of REM sleep inhibition increases with dose, and is severe in this zolpidem 30 mg/kg example. Data are plotted as the population hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 20).

Zolpidem interferes with locomotor activity

[0358] The GABAA positive allosteric modulator sedative hypnotic, zolpidem (HY-10131), administered to Wistar rats (N=10) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), inhibited Locomotor Activity Intensity (LMAi), as measured by the counts of locomotor activity per minute of wakefulness (as indicated by the arrow), averaged hourly for each animal. LMAi reveals changes in motor activity (movements) that are disproportionate from that normally observed during wakefulness. Hypoactivity during wakefulness, as shown here, is indicative of motor coordination impairment due to the well documented myorelaxant properties of zolpidem and related sedative hypnotics. The magnitude of undesirable motor impairment (reduction in LMAi) increases with dose, and is evident 4-5 hours post-treatment in this zolpidem 30 mg/kg example. Data are plotted as the population hourly mean ± SEM 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control indicated by asterisk. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa (FIG. 21). Example 9. S-zopidone effect on arousals, sleep continuity, locomotor activity, musde tone, and sleep rebound disturbance

S-zopiclone failed to reduce the number of arousals

[0359] The insomnia standard of care, S-zopiclone, administered to Wistar rats (N=13) at CT-18 (6 hours after light-off) failed to reduce the number of arousals (as indicated by the arrow), as measured by the number of wake bouts per hour post-treatment. Number of wake bouts are plotted as hourly mean ± SEM 30 hours before (baseline) and after treatment (triangle on the abscissa). Statistically significant difference from vehicle control (methylcellulose) is indicated by asterisk. 24 hour light-dark cycle (LD 12:12) is indicated on the abscissa (FIG. 22).

Effect of S-zopiclone on sleep continuity/consolidation at CT-18

[0360] Three doses of S-zopiclone (5 mg/kg. 10 mg/kg and 30 mg/kg) administered to Wistar rats (N=10-12) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), produced a weak increase in sleep consolidation that was statistically significant in the first treatment hour for the highest dose (30 mg/kg), as measured by the average sleep bout duration per hour (as indicated by the arrow). Effect on sleep consolidation was not dose proportional. Data are plotted as the population mean ± SEM each hour for 30 hours before (baseline) and after treatment. Statistically significant difference from methylcellulose vehicle control are indicated by asterisk. 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG. 23).

S-zopiclone dose-dependenlly interferes with locomotor activity

[0361] The insomnia standard of care sedative hypnotic s-zopiclone, administered to Wistar rats (N=10-12) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), inhibited Locomotor Activity Intensity (LMAi) as measured by the counts of locomotor activity per minute of wakefulness (as indicated by the arrow), averaged hourly for each animal. LMAi reveals whether changes in motor activity (movements) are disproportionate from that normally observed during wakefulness. A disproportionate reduction in locomotor activity during wakefulness, as shown here, is indicative of motor impairment likely due to the myorelaxant properties of s-zopiclone (see also FIG. 25; as indicated by the arrow). The magnitude of undesirable motor impairment (reduction in LMAi) increases with dose, and is especially evident 1-6 hours post-treatment in the s-zopiclone 10 mg/kg and 30 mg/kg treatment groups. Data are plotted as the population mean ± SEM on an hourly basis for 30 hours before (baseline) and after treatment Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12: 12) indicated on the abscissa (FIG. 24).

S-zopiclone decreases muscle tone as measured by electromyogram (EMG)

[0362] The insomnia standard of care sedative hypnotic s-zopiclone, administered to Wistar rats (N=13) at CT-18 (6 hours after light-off), decreased EMG activity as measured by root-mean- square analysis of EMG power in 5 minute intervals (treatment occurred at time zero; as indicated by the arrow). Data are plotted as population mean ± SEM. Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa. Reduction in EMG tone is considered an undesirable feature that could worsen the risk of upper airway occlusion in subjects with obstructive sleep apnea, or slips and falls while under the influence of this drug (FIG. 25).

S-zopiclone soporific effects are followed by rebound sleep disturbance

[0363] The insomnia standard of care sedative hypnotic s-zopiclone, administered to Wistar rats (N=10-12) at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), initially increased the amount of nonREM (NREM) sleep post-treatment (as indicated by the arrow), but these initial soporific effects were followed by an interval of sleep interference (labeled as“rebound” in FIG. 26) characterized by a reduction in sleep time, and corresponded with other markers of sleep disturbance such as concomitant reductions in sleep bout durations during the next circadian sleep phase (circadian time 0:00-12:00; also see FIG. 23). Latent sleep disturbance is a highly undesirable feature of drugs intended to treat sleep fragmentation. Data are plotted as the population mean ± SEM on an hourly basis for 30 hours before (baseline) and after treatment Statistically significant differences from methylcellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12:12) indicated on the abscissa (FIG. 26).

EQUIVALENTS

[0364] The details of one or more embodiments of the disclosure are set forth in the

accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0365] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.