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1. (WO2019050903) METHODS FOR TREATING SLEEP DISORDERS, SLEEP DISTURBANCES, AND RELATED SYMPTOMS USING AMINOSTEROL COMPOSITIONS
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WHAT IS CLAIMED

1. A method of treating or preventing a sleep disorder, sleep disturbance, or related symptom in a subject comprising administering to the subject a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial effect.

2. The method of claim 1, further comprising:

(a) determining a dose of an aminosterol or a pharmaceutically acceptable salt or derivative thereof for the subject, wherein the aminosterol dose is determined based on the effectiveness of the aminosterol dose in improving or resolving a sleep disorder, sleep

disturbance, or related symptom being evaluated,

(b) followed by administering the aminosterol dose to the subject for a period of time, wherein the method comprises:

(i) identifying a sleep disorder, sleep disturbance, or related symptom to be evaluated;

(ii) identifying a starting aminosterol dose for the subject; and

(iii) administering an escalating dose of the aminosterol to the subject over a period of time until an effective dose for the sleep disorder, sleep disturbance, or related symptom being evaluated is identified, wherein the effective dose is the aminosterol dose where improvement or resolution of the sleep disorder, sleep disturbance, or related symptom is observed, and fixing the aminosterol dose at that level for that particular sleep disorder, sleep disturbance, or related symptom in that particular subject.

3. The method of claim 1 or 2, wherein the composition is administered orally, intranasally, or a combination thereof.

4. The method of any one of claims 1-3, wherein the composition is administered orally and:

(a) the starting aminosterol dose ranges from about 1 mg up to about 175 mg/day;

(b) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof for the subject following escalation is fixed at a range of from about 1 mg up to about 500 mg/day; and/or

(c) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is escalated in about 25 mg increments.

5. The method of any one of claims 1-3 wherein the composition is administered

intranasally and:

(a) the starting dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof ranges from about 0.001 mg to about 3 mg/day;

(b) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof for the subject following escalation is fixed at a range of from about 0.001 mg up to about 6 mg/day;

(c) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof for the subject following escalation is a dose which is subtherapeutic when given orally or by injection; and/or

(d) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is escalated in increments of about 0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 mg.

6. The method of any one of claims 1-5, wherein:

(a) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is escalated every about 3 to about 5 days;

(b) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is escalated every about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days;

(c) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is escalated about lx/week, about 2x/week, about every other week, or about lx/month;

(d) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is given once per day, every other day, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other week, or every few days;

(e) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative

thereof is given for a few weeks, followed by skipping a few weeks, followed by restarting aminosterol treatment;

(f) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is incrementally reduced after the fixed dose of aminosterol or a pharmaceutically acceptable salt or derivative thereof has been administered to the subject for a period of time;

(g) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is varied plus or minus a defined amount to enable a modest reduction or increase in the fixed dose;

(h) the dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is varied plus or minus a defined amount to enable a modest reduction or increase in the fixed dose, and the fixed aminosterol dose is increased or decreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%; and/or

(i) the starting dose of the aminosterol or a pharmaceutically acceptable salt or derivative thereof is higher if the symptom being evaluated is severe.

7. The method of any one of claims 2-6, wherein the sleep disorder, sleep disturbance, or related symptom to be evaluated is selected from the group consisting of:

(1) total sleep time;

(2) total number of hours of uninterrupted sleep, per day;

(3) sleep efficiency;

(4) presence or frequency of a change in sleeping patterns;

(5) presence or frequency of a change in Circadian rhythm;

(6) developing a normal Circadian (i.e., diurnal) rhythm;

(7) presence of a sleep-wake cycle that is not 24 hours;

(8) sleeping at night rather than during the day, when night would is the preferred sleeping period;

(9) presence and/or frequency of awakenings during sleep period;

(10) presence and/or frequency of nonrestorative sleep;

(11) presence and/or frequency of a difficulty maintaining sleep;

(12) presence and/or frequency of sleep fragmentation;

(13) presence and/or frequency of hallucinations during sleep period;

(14) presence and/or frequency of thrashing or limb movement during sleep period;

(15) presence and/or frequency of nightmares and/or vivid dreams;

(16) presence and/or frequency of delayed sleep onset;

(17) presence and/or frequency of day time sleepiness;

(18) presence and/or frequency of clinical or sub-clinical "sleep attacks";

(19) cognitive impairment and/or improvement in memory as a result of better memory consolidation during sleep;

(20) presence and/or frequency of disturbances in sleep architecture;

(21) time of awakening following sleep period, with a later time correlated with improved sleep;

(22) presence and/or frequency of sleep problems;

(23) presence and/or frequency of sleep disturbances and/or sleep disruption;

(24) REM disturbed sleep;

(25) presence and/or frequency of apnea;

(26) presence and/or frequency of narcolepsy;

(27) poor psychomotor coordination;

(28) presence and/or frequency of headaches;

(29) presence and/or frequency of gastrointestinal distress;

(30) presence and/or frequency of insomnia;

(31) presence and/or frequency of parasomnias;

(32) diurnal skin temperature oscillations;

(33) a symptom from the Horne-Ostberg Morningness-Eveningness Questionnaire

(MEQ) selected from the group consisting of difficulty waking up in the morning, difficulty falling asleep at night, falling asleep earlier than normal at night, dependence on alarm to wake in morning, lack of alertness in morning, appetite upon waking in morning, feeling tired after waking in the morning, going to bed later than normal when subject has no commitments the following day, inability to fall back to sleep upon waking in the morning, lack of willingness to engage in physical activity in the morning, and lack of willingness to engage in cognitively challenging tasks in the morning;

(34) a symptom from the Epworth Sleepiness Scale (ESS) selected from the group

consisting of dozing or sleeping when sitting and reading, dozing or sleeping when watching television (TV), dozing or sleeping when sitting while inactive in public, dozing or sleeping when riding as a passenger in a car for greater than 1 hour, dozing or sleeping when lying down in the afternoon, dozing or sleeping when talking to another person, dozing or sleeping when sitting quietly after lunch, and dozing or sleeping when driving and stopped in traffic;

(35) REM behavior disorder (RBD);

(36) circadian rhythm dysfunction;

(37) Restless leg syndrome;

(38) jet lag;

(39) hypersomnia; and/or

(40) personal judgement of restful sleep.

8. The method of any one of claims 1-7, wherein:

(a) administration of the composition decreases the occurrence of at least one symptom of the sleep disorder or sleep disturbance;

(b) progression or onset of the sleep disorder, sleep disturbance or related symptom is slowed, halted, or reversed over a defined time period following administration of the composition, as measured by a medically-recognized technique, tool or scale; and/or

(c) the sleep disorder, sleep disturbance or related symptom is positively impacted by administration of the composition, as measured by a clinically-recognized technique, tool or scale.

9. The method of claim 8, wherein:

(a) the progression or onset of the sleep disorder, disturbance or related symptom is slowed, halted, or reversed by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as measured by a medically-recognized technique, tool or scale; and/or

(b) the positive impact on the sleep disorder, disturbance, or related symptom is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%), at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%>, at least about 90%, at least about 95%, or at least about 100%, as measured using a clinically recognized scale, tool, or technique.

10. The method of any one of claims 1-9, wherein the sleep disorder, disturbance or related symptom:

(a) comprises a dyssomnia, parasomnia, and/or circadian rhythm sleep disorder;

(b) comprises a loss of diurnal rhythm (Circadian rhythm);

(c) comprises a delay in sleep onset, sleep fragmentation, REM-behavior disorder (RBD), sleep-disordered breathing including snoring and apnea, day-time sleepiness, micro-sleep episodes, narcolepsy, hallucinations, hypersomnia, Restless leg syndrome (RLS), Periodic limb movement disorder (PLMD), insomnia, gastrointestinal distress, headache, narcolepsy, REM disturbed sleep, clinical or sub-clinical "sleep attacks", thrashing or limb movement during sleep period, nonrestorative sleep, awakenings during sleep period, cognitive impairment, sleep problems, poor psychomotor coordination, bruxism, catathrenia, cataplexy, sleep walking, Delayed sleep phase disorder (DSPD), advanced sleep phase disorder (ASPD), non-24-hour sleep-wake disorder (non-24) in the sighted or in the blind, irregular sleep wake rhythm, Shift work sleep disorder (SWSD), Hypopnea syndrome, Idiopathic hypersomnia, Kleine-Levin syndrome, sleep terror disorder, nocturia, sleep paralysis, somniphobia, or any combination thereof; and/or

(d) comprises or is associated with a neurodegenerative disorder or disease.

11. The method of claim 10, wherein: :

(a) the loss of diurnal rhythm is caused by dysfunction of the suprachiasmatic nucleus, and administration of the composition reverses the dysfunction of the suprachiasmatic nucleus, restores the diurnal rhythm, and treats the sleep disorder, sleep disturbance, or related symptom;

(b) the loss of diurnal rhythm is caused by dysfunction of the enteric nervous system, and administration of the composition reverses the dysfunction of the enteric nervous system, restores the diurnal rhythm, and treats the sleep disorder, sleep disturbance, or related symptom;

(c) the loss of diurnal rhythm is caused by dysfunction of the olfactory nervous system, and administration of the composition reverses the dysfunction of the olfactory nervous system, restores the diurnal rhythm, and treats the sleep disorder, sleep disturbance, or related symptom;

(d) the loss of diurnal rhythm is caused by visual loss, and administration of the composition reverses the dysfunction of the circadian rhythm caused by visual loss;

(e) the loss of diurnal rhythm is caused by jet lag, and administration of the composition reverses the dysfunction of circadian rhythm caused by jet lag; and/or

(f) the loss of diurnal rhythm is caused by night-shift work, and administration of the composition reverses the dysfunction of the circadian rhythm caused by night-shift work.

12. The method of claim 10, wherein:

(a) treating the sleep disorder, sleep disturbance, or related symptom prevents or delays the onset or progression of the neurodegenerative disorder; and/or

(b) the neurodegenerative disorder is selected from the group consisting of

Parkinson's disease, Alzheimer's disease, Huntington's chorea and/or Disease, schizophrenia, multiple sclerosis, dementia, degenerative processes associated with aging, dementia of aging, multi-system atrophy (MSA), fronto-temporal dementia, autism, progressive nuclear palsy, Guadeloupian Parkinsonism, spinocerebellar ataxia, Amyotorphic Lateral Sclerosis (ALS), Friedreich's ataxia, vascular dementia, Lewy Body dementia or disease, spinal muscular atrophy, supranuclear palsy, fronto temperal dementia, neuropathy of diabetes, peripheral sensory neuropathy, cerebral palsy, epilepsy, diabetic neuropathy, and depression.

13. The method of any one of claims 1-12, wherein:

(a) the method results in a positive change in the sleeping pattern of the subject;

(b) the method results in a positive change in the sleeping pattern of the subject, wherein the positive change is defined as an increase in the total amount of sleep obtained of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%;

(c) the method results in a positive change in the sleeping pattern of the subject, and the positive change is defined as a percent decrease in the number of awakenings during the night selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%;

and/or

(d) as a result of the method the subject obtains the total number of hours of sleep recommended by a medical authority for the age group of the subject.

14. The method of any one of claims 1-13, wherein the aminosterol:

(a) is isolated from the liver of Squalus acanthias;

(b) is squalamine or a pharmaceutically acceptable salt thereof;

(c) is a squalamine isomer or derivative;

(d) is aminosterol 1436 or a pharmaceutically acceptable salt thereof;

(e) is an aminosterol 1436 isomer or derivative;

(f) comprises a sterol nucleus and a polyamine attached at any position on the sterol, such that the molecule exhibits a net charge of at least + 1;

(g) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least + 1;

(h) is a derivative of squalamine or aminosterol 1436 modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof;

(i) is a derivative of a natural aminosterol modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof;

(j) is a synthetic aminosterol; or

(k) is a derivative modified to include one or more of the following:

(i) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain;

(ii) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and/or

(iii) substitution of one or more ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system.

15. The method of claim 14, wherein the aminosterol is squalamine or a pharmaceutically acceptable salt thereof or aminosterol 1436 or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-15, wherein the aminosterol is a phosphate salt.

17. The method of any one of claims 1-16, wherein the composition further comprises one or more of the following: (a) an aqueous carrier; (b) a buffer; (c) a sugar; and/or (d) a polyol compound.

18. The method of any one of claims 1-17, wherein:

(a) each aminosterol dose is taken on an empty stomach, optionally within two hours of the subject waking; and/or

(b) no food is taken after about 60 to about 90 minutes of taking the aminosterol dose.

19. The method of any one of claims 1-18, wherein the aminosterol or a pharmaceutically acceptable salt or derivative thereof is administered in combination with at least one additional active agent to achieve either an additive or synergistic effect.

20. The method of claim 19, wherein:

(a) the additional active agent is administered via a method selected from the group consisting of concomitantly, as an admixture, separately and simultaneously or concurrently, and separately and sequentially;

(b) the additional active agent is a different aminosterol from that administered in the method of any one of claims 1-19;

(c) the method comprises a first aminosterol which is aminosterol 1436 or a pharmaceutically acceptable salt or derivative thereof administered intranasally and a second aminosterol which is squalamine or a salt or derivative thereof administered orally;

(d) the additional active agent is an active agent used to treat sleep disorders, sleep disruption, or a related symptom;

(e) the additional active agent is selected from the group consisting of an orexin receptor antagonist such as suvorexant (Belsomra®), supplements such as melatonin, valerian, 5-htp, magnesium or glycine; a benzodiazepine such as clonazepam (Klonopin®), diazepam (Valium®), chlorodiazepoxide (Librium®), flurazepam (Dalmine®); and/or a Z-drug such as zopiclone (Imovane®), zaleplon (Sonata®) and Zolpidem (Ambien®).

21. The method of any one of claims 1-20, wherein the subject is a human.

22. A composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, for use in a method of treating or preventing a sleep disorder, sleep disturbance, or related symptom in a subject.

23. The composition of claim 22, for use in a method according to any one of claims 1-21.