WO2024095158A1 - Dosage d'agonistes du récepteur de type 2 de l'orexine - Google Patents

Dosage d'agonistes du récepteur de type 2 de l'orexine Download PDF

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WO2024095158A1
WO2024095158A1 PCT/IB2023/060969 IB2023060969W WO2024095158A1 WO 2024095158 A1 WO2024095158 A1 WO 2024095158A1 IB 2023060969 W IB2023060969 W IB 2023060969W WO 2024095158 A1 WO2024095158 A1 WO 2024095158A1
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agonist
plasma concentration
orexin
awakening
receptor agonist
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Haruhide Kimura
Hiroe HARA
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Takeda Pharmaceutical Company Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Narcolepsy is a severe neurological sleep disorder characterized by excessive daytime sleepiness (EDS).
  • EDS daytime sleepiness
  • narcolepsy may be accompanied by a sudden loss of muscle tone and mobility (cataplexy).
  • Narcolepsy accompanied by cataplexy is known as narcolepsy type 1 (NT1); narcolepsy in the absence of cataplexy is known as narcolepsy type 2 (NT2).
  • NT1 narcolepsy type 1
  • NT2 narcolepsy in the absence of cataplexy
  • other symptoms include hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation), which together comprise the narcolepsy symptom pentad.
  • stimulants e.g. modafinil
  • antidepressants e.g. clomipramine
  • sodium oxybate and pitolisant may be used to treat both EDS and cataplexy.
  • these drugs are known to have side effects such as insomnia, rebound symptom, and the potential for drug abuse (Trends in Pharmacol. Sci., Vol. 27, No. 7, 368-374, (2006)).
  • Orexin hypercretin is a neuropeptide produced in particular neurons located sparsely in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptors, which are G protein-coupled receptors mainly present in the brain. There are two known subtypes of the orexin receptor, type 1 (OX1R) and type 2 (OX2R). Both orexin A and orexin B bind to OX2R with similar affinity (Cell, Vol. 92, 573-585, (1998)).
  • orexin-producing neurons are localized in the vicinity of the feeding center, and intraventricular administration of orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide involved in the regulation of feeding behavior.
  • canine narcolepsy is caused by a genetic variation of orexin type 2 receptor (Cell, Vol. 98, 365-376, (1999)) and researchers turned their attention to the role of orexin in controlling sleep and wakefulness.
  • Other studies have shown that narcolepsy type 1 is associated with the irreversible loss of orexin producing neurons, and therefore agonists targeting orexin type 2 receptor (0X2R) have been thought to represent a promising treatment for NT1.
  • OX2R agonists at wake-promoting dosages to subjects diagnosed with narcolepsy type 1 has shown to improve daytime symptoms such as excessive sleepiness and cataplexy (J Sleep Res. 32(5):el3878. (2023), N Engl J Med. 389(4):309-321. (2023)).
  • Administration of OX2R agonists at dosage levels which are significantly less than arousal-promoting dosage levels (i.e., at “low dose”), as well as the therapeutic effect of such low dose administration, are not known.
  • This invention provides a method of treating narcolepsy type 1 in a human in need thereof, the method comprising administering to the human a dosage form comprising an orexin type 2 receptor agonist, wherein the dosage form provides a blood plasma concentration of the agonist after administration at or below a maximum non-awakening plasma concentration of the agonist over a dosing interval.
  • One aspect of the invention provides a method as described above in which the blood plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains between about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum non-awakening plasma concentration of the agonist over a dosing interval.
  • Another aspect of the invention provides a method as described above in which the dosing interval for the orexin type 2 receptor agonist is one day, two days, one week, two weeks, four weeks, six weeks or eight weeks.
  • a further aspect of the invention provides a method as described above which improves one or more nighttime symptoms of NT1 selected from fragmented sleep, sleep paralysis and hallucinations, and improves one or more daytime symptoms of NT1 selected from fragmented wakefulness and cataplexy symptom.
  • An additional aspect of the invention provides a method as described above in which the dosage form comprises a sustained release formulation.
  • the sustained release formulation may be a depot formulation for subcutaneous administration of the OX2R agonist or an infusion system designed to provide continuous subcutaneous delivery of the OX2R agonist.
  • Another aspect of the invention provides a method as described above in which the blood plasma concentration of the orexin type 2 receptor agonist is selected by: i) determining the non-awakening plasma concentration of the orexin type 2 receptor agonist that does not provide an arousal response in a human; and ii) determining a dose of the orexin type 2 receptor agonist that will provide a blood plasma concentration which is at or below the maximum non-awakening plasma concentration.
  • the arousal response may be determined by measuring sleep latency in one or more subjects diagnosed with narcolepsy type 1.
  • a further aspect of the invention provides a method as described above in which the blood plasma concentration of the orexin type 2 receptor agonist is selected by: i) determining the maximum non-awakening concentration of the orexin type 2 receptor agonist that does not provide an arousal response in a human; ii) determining an amount of 0X2R agonist that provides the maximum nonawakening concentration of the agonist; and iii) selecting a dose of the 0X2R agonist that will provide a level of the agonist that is at or below the maximum non-awakening plasma concentration of the agonist.
  • the arousal response may be determined by measuring sleep latency in one or more subjects diagnosed with narcolepsy type 1.
  • An additional aspect of the invention provides a method as described above in which the orexin type 2 receptor agonist is selected from N-((2S,3S)-l-(2-hydroxy-2- methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yljmethanesulfonamide; N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-
  • FIG. 1 shows wakefulness times detected by EEG/EMG recording in NT1 model mice following administration of Compound B.
  • FIG. 2 shows the time-course blood plasma concentration in NT1 model mice following administration of Compound B.
  • FIG. 3 shows wakefulness times detected by EEG/EMG recording in NT1 model mice following administration of Compound A.
  • FIG. 4 shows the time-course blood plasma concentration in NT1 model mice following administration of Compound A.
  • FIG. 5 shows wakefulness times detected by EEG/EMG recording in cynomolgus monkeys following administration of Compound A.
  • FIG. 6 shows the time-course blood plasma concentration in cynomolgus monkeys following administration of Compound A.
  • FIG. 7 shows the time-course blood plasma (BP) concentration of Compound A at a dose that provides BP concentration at or below non-awakening concentration.
  • FIG. 8 shows observed episodes of sleep/wakefulness of mice following administration of Compound A.
  • FIG. 9 shows wakefulness times detected by EEG/EMG recording in NT1 model mice following administration of Compound D.
  • FIG. 10 shows the time-course BP concentration in NT1 model mice following administration of Compound D.
  • FIG. 11 shows the time-course BP concentration of Compound D at a dose that provides BP concentration below non-awakening concentration.
  • FIG. 12 shows observed episodes of sleep/wakefulness of mice following administration of Compound D.
  • FIG. 13 shows wakefulness times detected by EEG/EMG recording in NT1 model mice following administration of Compound B.
  • FIG. 14 shows the time-course BP concentration in NT1 model mice following administration of Compound B.
  • FIG. 15 shows the time-course BP concentration of Compound B at a dose that provides BP concentration below non-awakening concentration.
  • FIG. 16 shows observed episodes of sleep/wakefulness of mice following administration of Compound B.
  • FIG. 17 shows wakefulness times detected by EEG/EMG recording in NT1 model mice following administration of Compound E.
  • FIG. 18 shows the time-course BP concentration in NT1 model mice following administration of Compound E.
  • FIG. 19 shows the time-course BP concentration of Compound E at a dose that provides BP concentration below non-awakening concentration.
  • FIG. 20 shows observed episodes of sleep/wakefulness of mice following administration of Compound E.
  • FIG. 21 shows wakefulness times detected by EEGZEMG recording in NT1 model mice following administration of Compound F.
  • FIG. 22 shows the time-course BP concentration in NT1 model mice following administration of Compound F.
  • FIG. 23 shows the time-course BP concentration of Compound F at a dose that provides BP concentration below non-awakening concentration.
  • FIG. 24 shows observed episodes of sleep/wakefulness of mice following administration of Compound F.
  • compositions and uses disclosed herein include the use of an OX2R agonist at non-awakening plasma concentration thereof.
  • the blood plasma concentration of the substance increases for a time, reaches a maximum concentration and then decays. Consequently, the medicinal effect of the substance generally follows its blood plasma concentration.
  • an OX2R agonist administered to promote arousal in subjects having NT1 once the blood plasma concentration of the agonist exceeds the maximum non-awakening concentration, the subjects experience marginal arousal, which is followed by full arousal once the concentration exceeds a certain threshold (the arousal-promoting concentration).
  • Certain OX2R agonists have been shown to produce potent efficacy in wakefulness when the blood plasma concentration of the OX2R agonist exceeds the arousal-promoting concentration in subjects having NT1.
  • the present invention relates to the use of an orexin type 2 receptor (OX2R) agonist at a non-awakening concentration in a subject (e.g. mammal).
  • the present invention also relates to a method of administering an OX2R agonist to a subject (e.g. mammal) in need thereof at a dose that provides a blood plasma concentration of the agonist after administration at or below the maximum non-awakening blood plasma concentration thereof.
  • the present invention also relates to a method of treatment of narcolepsy type 1 (NT1) in a subject (e.g.
  • the blood plasma concentration of an 0X2R agonist after administration is about 1/20 to about 1/1 of the maximum nonawakening concentration of the agonist over the dosing interval.
  • the present invention also relates to a dosing regimen for treatment of NT1 in a subject (e.g. mammal) by administering a first 0X2R agonist at a dose sufficient to bring the plasma blood concentration of the 0X2R agonist above the non-awakening blood plasma concentration, preferably above the arousal-promoting concentration, and administering a second 0X2R agonist, which may be the same or different than the first 0X2R agonist, at a dose sufficient to provide a blood plasma concentration at or below the maximum non-awakening concentration.
  • a dosing regimen for treatment of NT1 in a subject e.g. mammal
  • the current approach for treating NT1 with 0X2R agonists aims to induce and promote arousal of NT1 subjects, and therefore the dose needs to exceed the maximum non-awakening blood plasma concentration and to reach the arousal-promoting concentration.
  • the present invention focuses on the effect of 0X2R agonists at non-awakening blood plasma concentration. Continuous or repeated administration of 0X2R agonist at non-awakening blood plasma concentration unexpectedly improves multiple daytime and nighttime symptoms in a subject with narcolepsy type 1.
  • the use of 0X2R agonists of the present invention is expected to provide a new method and strategy for treating NT1 and other sleep-related symptoms. Further the use of 0X2R agonists of the present invention is expected to have fewer side effects as compared to the use of the agonists in arousal-promoting concentration.
  • the methods, compositions and uses of this disclosure may be directed to [1] the use of an orexin type 2 receptor agonist in a subject (e.g. mammal) at a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [2] the use of an orexin type 2 receptor agonist in a subject (e.g. mammal) at a dose that provides a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [3] a method comprising the administration of an orexin type 2 receptor agonist to a subject (e.g. mammal) at a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [4] a method of administration of an orexin type 2 receptor agonist to a subject (e.g. mammal) at a dose which provides a blood plasma concentration that is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [5] a method of treating narcolepsy type 1 in a subject (e.g. mammal), wherein the method comprises administering to the subject an orexin type 2 receptor agonist at a dose that provides a blood plasma concentration after administration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [6] a method of treating symptoms of excessive sleepiness and/or cataplexy episodes during active phase (generally daytime), and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase (generally nighttime) in a subject (e.g. mammal), wherein the method comprises administering to the subject an orexin type 2 receptor agonist at a dose that provides a blood plasma concentration after administration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist.
  • Excessive sleepiness can also occur in individuals who do not have deficiency of orexin.
  • This disclosure is also directed to treating diseases, disorders, and/or symptoms of excessive sleepiness that are not associated with reduced orexin level.
  • the methods, compositions and uses of this disclosure may be directed to [7] the use of an orexin type 2 receptor agonist in a subject (e.g. mammal) at a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of narcolepsy type 1 in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [8] the use of an orexin type 2 receptor agonist in a subject (e.g.
  • a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the OX2R agonist for the treatment of symptoms of excessive sleepiness and/or cataplexy episodes during active phase, and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [9] a method of administration of an orexin type 2 receptor agonist to a subject (e.g. mammal) at a dose that provides a blood plasma concentration after administration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of narcolepsy type 1 in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [10] a method of administration of an orexin type 2 receptor agonist to a subject (e.g. mammal) at a dose that provides a blood plasma concentration after administration which is at or below the maximum non-awakening plasma concentration of the agonist for the treatment of symptoms of excessive sleepiness and/or cataplexy episodes during active phase, and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase in the subject.
  • a subject e.g. mammal
  • a dose that provides a blood plasma concentration after administration which is at or below the maximum non-awakening plasma concentration of the agonist for the treatment of symptoms of excessive sleepiness and/or cataplexy episodes during active phase, and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [11] the method of administration of [9] or [10], wherein the orexin type 2 receptor agonist is administered in a sustained-release formulation.
  • the methods, compositions and uses of this disclosure may be directed to [12] the method of administration of [9] or [10], wherein the orexin type 2 receptor agonist is administered in an oral formulation.
  • the methods, compositions and uses of this disclosure may be directed to [13] repeated or continuous use of an orexin type 2 receptor agonist in a subject (e.g. mammal) at a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of narcolepsy type 1 in the subject.
  • a subject e.g. mammal
  • a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of narcolepsy type 1 in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [14] repeated or continuous use of an orexin type 2 receptor agonist in a subject (e.g. mammal) at a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of symptoms of excessive sleepiness and/or cataplexy episodes during active phase, and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase in the subject.
  • a subject e.g. mammal
  • a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the 0X2R agonist for the treatment of symptoms of excessive sleepiness and/or cataplexy episodes during active phase, and/or sleep fragmentation and/or sleep paralysis/hallucination during sleep phase in the subject.
  • the methods, compositions and uses of this disclosure may be directed to [15] a method of treating narcolepsy type 1 in a human in need thereof, the method comprising: administering to the human a dosage form comprising an orexin type 2 receptor agonist, wherein the dosage form provides a blood plasma concentration of the 0X2R agonist after administration which is at or below the maximum non-awakening plasma concentration of the agonist over a dosing interval.
  • the dosing interval for the orexin type 2 receptor agonist is one day (once daily), two days (once every other day), a week (once per week), two weeks (once every two weeks), four weeks (once every four weeks), six weeks (once every six weeks), or eight weeks (once every eight weeks).
  • [0063] In one embodiment, [20] the method according to [15], wherein the blood plasma concentration of the orexin type 2 receptor agonist after administration reaches about one- fifth, one-quarter, one-third, or a half of the maximum non-awakening plasma concentration of the orexin type 2 receptor agonist. [0064] In one embodiment, [21] the method according to [15], wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches the maximum non-awakening concentration thereof.
  • sustained release formulation is a depot formulation for subcutaneous administration.
  • the orexin type 2 receptor agonist is selected from N-((2S,3S)-l-(2- hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide; N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy- 2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide; methyl (2R,3 S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate; N- ⁇ (2S,3R)-4,4-difluoro-l
  • the orexin type 2 receptor agonist is N-((2S,3S)-l-(2-hydroxy-2- methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.
  • the orexin type 2 receptor agonist is selected from 4-(5-cyclopropyl-l,2,4- oxadiazol-3-yl)-N- ⁇ (lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-l-yl]cyclohexyl ⁇ -4- methylpiperidine-1 -carboxamide and N- ⁇ (lR,6S)-2,2-difluoro-6-[4-(propan-2- yl)piperazin-l-yl]cyclohexyl ⁇ -4- ⁇ 5-[(lS,2S)-2-fluorocyclopropyl]-l,2,4-oxadiazol-3-yl ⁇ - 4-methylpiperidine-l -carboxamide; or a pharmaceutically acceptable salt or hydrate thereof.
  • the orexin type 2 receptor agonist is selected from (R)-2-cyclopropyl-2- ((lR,3S,5S)-3-((3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8- azabicyclo[3.2.1]octan-8-yl)acetamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5- fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3- methylbutaneamide; (R)-2-((lR,3R,5S)-3-((3S,4R)-l-(5-chloropyrimidin-2-yl)
  • the orexin type 2 receptor agonist is N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa- l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-5 3 - yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.
  • the blood plasma concentration of the orexin type 2 receptor agonist is selected by: i) determining a non-awakening plasma concentration of the orexin type 2 receptor agonist that does not provide an arousal response in a human; and ii) determining a dose of the orexin type 2 receptor agonist that will provide a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the agonist determined in i).
  • [39] the method according to embodiments [37] or [38], wherein the arousal response can be determined by measuring sleep latency in one or more humans diagnosed with narcolepsy type 1.
  • the methods, compositions and uses of this disclosure may be directed to [41] the use of an orexin type 2 receptor agonist in a human, at a blood plasma concentration that is at or below the maximum non-awakening plasma concentration of the agonist, in combination with an additional orexin type 2 receptor agonist at a blood plasma concentration that is above the maximum non-awakening plasma concentration of the additional 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [42] a method of treatment of narcolepsy type 1 in a subject (e.g. mammal), the method comprising: i) acute treatment for an NT1 symptom which administering an orexin type 2 receptor agonist to the subject at a blood plasma concentration that is above the maximum non-awakening concentration of the 0X2R agonist; ii) followed by maintenance treatment comprising repeatedly or continuously administering the OX2R agonist to the subject at a blood plasma concentration that is at or below the maximum non-awakening concentration of the 0X2R agonist.
  • the methods, compositions and uses of this disclosure may be directed to [43] an orexin type 2 receptor agonist which is selected from compounds described in any of WO 2019/027058, WO2017/135306, W02020/158958, W02021/107023, W02022/014680, W02020/167701, W02020/167706, WO2021/026047, W02022/040070, W02022/094012, W02022/040058, W02022/109117, WO 2022/119888, WO 2022/132696, WO2022/051583, WO2022/051596, and WO2021/108628.
  • an orexin type 2 receptor agonist which is selected from compounds described in any of WO 2019/027058, WO2017/135306, W02020/158958, W02021/107023, W02022/014680, W02020/167701, W02020/167706, WO2021/026047, W02022/040070, W02022/
  • the methods, compositions and uses of this disclosure may be directed to [44] a pharmaceutical composition which comprises an orexin type 2 receptor agonist at a dose which provides a blood plasma concentration of the agonist at or below the maximum non-awakening plasma concentration over a dosing interval.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about 1/20 of the maximum non-awakening plasma concentration.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about 1/10 of the maximum non-awakening plasma concentration.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about 1/5 of the maximum non-awakening plasma concentration.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about 1/3 of the maximum non-awakening plasma concentration.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about 1/2 of the maximum non-awakening plasma concentration.
  • the dose of orexin type 2 receptor agonist according to [44] provides a blood plasma concentration which is not less than about the maximum non-awakening plasma concentration.
  • the methods, compositions and uses of this disclosure may be directed to [51] a dose of an orexin type 2 receptor agonist for administration to a human, wherein the dose is in a range of about 1 mg to about 5 mg.
  • the methods, compositions and uses of this disclosure may be directed to [52] a method of administering an orexin type 2 receptor agonist to a mammal in need thereof, wherein the method comprises maintaining the average blood plasma concentration of the agonist in the mammal which is less than about 100 ng/mL, less than about 50 ng/mL, less than about 30 ng/mL, less than about 10 ng/mL, less than about 5 ng/mL, less than about 3 ng/mL, or less than about 1 ng/mL, but greater than 0 ng/mL over the dosing interval.
  • Another aspect of the present invention relates to [53] a method of producing a dosage form for treatment of NT1 in a human in need thereof, which comprises an orexin type 2 receptor agonist in an amount of about 1 mg to about 5 mg, wherein the dosage form is a sustained release formulation for injection.
  • Another aspect of the present invention relates to [54] the use of an orexin type 2 receptor agonist in manufacturing a dosage form for treatment of NT1 in a human in need thereof, wherein the agonist provides a blood plasma concentration after administration which is at or below the maximum non-awakening concentration of the agonist, and the dosage form is a sustained release formulation for injection.
  • the amount of the orexin type 2 receptor agonist in the dosage form is about 1 mg to about 5 mg.
  • the methods, compositions and uses of this disclosure may be directed to [56] a pharmaceutical composition comprising an orexin type 2 receptor agonist at a dose which provides a blood concentration after administration at or below the maximum non-awakening plasma concentration in a subject (i.e. mammal).
  • the methods, compositions and uses of this disclosure may be directed to [57] a method of treating narcolepsy type 1 in a human in need thereof by administering an orexin type 2 receptor agonist, which method comprises i) obtaining the maximum non-awakening plasma concentration of the agonist in the human; ii) selecting a dose of the agonist that provides blood plasma concentration at or below the maximum non-awakening plasma concentration in the human; and iii) administering the dose of the agonist selected in ii) repeatedly or continuously to the human.
  • the methods, compositions and uses of this disclosure may be directed to [58] a method of treating narcolepsy type 1 in a human in need thereof by administering an orexin type 2 receptor agonist, which method comprises i) obtaining the maximum non-awakening plasma concentration of the agonist in the human; ii) selecting a plasma concentration at or below the maximum non-awakening plasma concentration in the human; and iii) administering the agonist at a dose that provides the plasma concentration selected in ii) repeatedly or continuously to the human.
  • the methods, compositions and uses of this disclosure may be directed to [59] a method of producing a pharmaceutical composition for treatment of narcolepsy type 1 (NT1) in a human in need thereof comprising an orexin type 2 receptor agonist, wherein the method comprises: i) determining the maximum nonawakening concentration of the orexin type 2 receptor agonist in human with NT1; ii) selecting a dose of the agonist that provides blood plasma concentration at or below the maximum non-awakening plasma concentration in human with NT1; iii) combining the unit dose of the agonist and pharmaceutically acceptable carriers to formulate the pharmaceutical composition.
  • the methods, compositions and uses of this disclosure may be directed to [60] the use according to [1], which is for reducing sleep fragmentation during the dark phase in an NT1 patient by about 10% to about 20%.
  • the methods, compositions and uses of this disclosure may be directed to [61] the use according to [1], which is for reducing cataplexy -like symptoms during light phase in an NT1 patient by about 15% to about 50%.
  • the methods and uses disclosed herein may treat narcolepsy type 1 in a subject in need thereof.
  • the methods and uses disclosed herein may also treat symptoms such as excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation).
  • treating narcolepsy type 1 may comprise reducing or alleviating one or more symptoms of narcolepsy type 1.
  • the one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation).
  • the one or more symptoms of narcolepsy type 1 is selected from excessive daytime sleepiness (EDS), cataplexy (including cataplexy-like symptom) in active phase, and sleep fragmentation during sleep phase.
  • EDS excessive daytime sleepiness
  • cataplexy including cataplexy-like symptom
  • sleep fragmentation during sleep phase may also treat comorbidities of narcolepsy type 1, such as obesity, type 2 diabetes, cardiovascular diseases, apnea during sleep, mood disorders, anxiety, attention-deficit hyperactivity disorder (ADHD), restless leg syndrome, sleep parasomnias and the like.
  • ADHD attention-deficit hyperactivity disorder
  • Narcolepsy may be diagnosed by diagnostic criteria generally used in the field, e.g., the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (Current Medical Research and Opinion, 32: 10, 1611-1622, (2016)). Additionally, nighttime sleep will be improved, for example, by reducing the number of waking incidents during the sleep cycle.
  • the methods and uses disclosed herein may increase wakefulness, and/or decrease and/or treat excessive sleepiness, and/or decrease occurrence of cataplexy episodes in a subject in need thereof during active phase.
  • excessive sleepiness as used herein is also known as excessive daytime sleepiness (EDS) or excessive need for sleep (ENS).
  • wakefulness, excessive sleepiness, cataplexy symptom, sleep fragmentation, and/or sleep paralysis/hallucinations is determined by known method such as using any one or more of electroencephalogram (EEG), electromyogram (EMG), Maintenance Wakefulness Test (MWT), polysomnography, and the like (Sleep, Vol. 45, Issue 8, zsac091, (2022)).
  • EEG electroencephalogram
  • EMG electromyogram
  • MTT Maintenance Wakefulness Test
  • polysomnography and the like
  • MWT is quantified by EEG optionally combined with EMG.
  • An electroencephalogram is a test that detects electrical activity in the brain using small, metal discs or electrodes attached to the scalp.
  • wakefulness and/or decrease of sleepiness is determined by using the multiple sleep latency test (MSLT) or the Oxford Sleep Resistance (OSLER) test.
  • the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS) or the Stanford Sleepiness Scale.
  • KSS Karolinska Sleepiness Scale
  • ESS Epworth Sleepiness Scale
  • Stanford Sleepiness Scale Stanford Sleepiness Scale.
  • treating excessive sleepiness may comprise reducing or alleviating one or more symptoms of excessive sleepiness.
  • the one or more symptoms of excessive daytime sleepiness may be selected from drowsiness, languor, inertness, fatigue, sluggishness.
  • the subject suffers from the diseases or disorders or symptoms associated with excessive sleepiness.
  • the subject is a sleep-deprived subject, a subject with excessive sleepiness, a subject with disruptive regular sleep cycle, or a subject with a need to decrease sleepiness.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.
  • the term “administration” of an agent to a subject includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and the administration by another. Administration of an 0X2R agonist for treatment purpose in this invention is generally long-term, continuous, chronic, and/or repetitive. “After administration” of an 0X2R agonist in the present invention means a certain time period elapses from the administration of the 0X2R agonist to a subject. Generally, this means from about 24 to about 48 hours after the initial administration.
  • the term “dosage form” or “pharmaceutical composition” means a composition containing a drug molecules.
  • the dosage form include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet), capsule (including soft capsule, microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g., orally disintegrable films, oral mucosa-adhesive film) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., transdermal absorption type preparation, ointment, lotion, adhesive preparation), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like.
  • oral preparations such as tablet (including
  • the compound and medicament of the present invention can be respectively safely administered orally or parenterally (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion).
  • parenterally e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion.
  • release control preparation e.g., sustained-release microcapsule
  • the term “effective amount” or “therapeutically effective amount” refers to a quantity of a compound sufficient to achieve a desired effect or a desired therapeutic effect.
  • the amount of the compound administered to the subject may depend on the type and severity of the disease or symptom and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • modulate refers positively or negatively alter.
  • Exemplary modulations include an about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100% change.
  • the term “increase” refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.
  • the term “reduce” refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.
  • 0X2R agonist refers to a drug or substance, such as a small molecule, that activates 0X2R.
  • 0X2R is a G-protein coupled receptor (GPCR) which interacts with Gq class of heterotrimeric G proteins and P-arrestins.
  • GPCR G-protein coupled receptor
  • Orexin-A and Orexin-B peptides are known to increase calcium mobilization (Cell, Vol. 92, 573-585, (1998)) and promote recruitment of P-arrestins (J. Biol. Chem. Vol. 286, No. 19, 16726-16733, (2011)) in OX2R-expressed recombinant cells.
  • OX2R agonists such as Danavorexton and YNT-185 have also been shown to increase calcium mobilization and promote recruitment of P-arrestins (Pharmacol. Biochem. Behav.,187 (2019), 172794; Proc. Natl Acad. Sci. USA., 114(22), 5731-5736, (2017)). Therefore, OX2R agonistic activity of drug candidates may be evaluated by calcium mobilization assays or P-arrestin recruitment assays using OX2R-expressed cells.
  • arousal means the status of a subject is near complete wakefulness which is examined by known measures such as Maintenance of Wakefulness Test (MWT) and EEG/EMG recordings.
  • MTT Maintenance of Wakefulness Test
  • EEG/EMG recordings EEG/EMG recordings
  • blood plasma concentration refers to a concentration of a pharmaceutical substance in blood plasma derived from a subject blood collected at certain time point.
  • Blood plasma concentration after administration in the present invention means the blood plasma concentration of the pharmaceutical substance at the time point about 24 hours or later following to administration of the substance.
  • Average blood plasma concentration means average of blood plasma concentrations of different time points 24 hours or later following the administration of a pharmaceutical substance in a subject.
  • non-awakening plasma concentration or “nonawakening concentration” refer to a plasma concentration of an orexin type 2 receptor agonist that will not induce arousal in a subject.
  • Non-awakening plasma concentration can be identified by conducting a multiple-dose study. Such study may be conducted as part of preclinical and clinical PK/PD studies during drug development.
  • the “maximum non-awakening plasma concentration” is the highest concentration above which marginal arousal effect occurs.
  • the phrase “at or below the maximum non-awakening plasma concentration” of an OX2R agonist means the plasma concentration of the OX2R agonist in a subject is larger than 0 (zero) and the same or less than the maximum non-awakening plasma concentration.
  • the plasma concentration of the OX2R agonist in a subject over a dosing interval is at or below the maximum non-awakening plasmatic concentration, but not less than about 1/20, about 1/12, about 1/10, about 1/8, about 1/5, or about 1/3 of the maximum non-awakening concentration of the agonist.
  • the average plasma concentration of an 0X2R agonist can be about 1/20, about 1/10, about 1/8, about 1/5, about 1/4, about 1/3, about 1/2, or 1/1 of the maximum non-awakening concentration of the agonist, + 5%.
  • the average plasma concentration of the 0X2R agonist, at or below the maximum non-awakening plasma concentration is about 1/60, 1/40 1/36, 1/30, 1/20/ or 1/10 of the arousal-promoting plasma concentration.
  • the term “arousal-promoting concentration” of an 0X2R agonist refers to a threshold blood plasma concentration of the agonist which provides nearly complete wakefulness effect (i.e. maintenance of wakefulness for more than 75% in 10 min-bins.) in a subject.
  • Certain 0X2R agonists have been shown to produce potent efficacy in wakefulness when the blood plasma concentration of the 0X2R agonist exceeded its arousal-promoting concentration in NT1 subjects.
  • the arousal-promoting concentration of an 0X2R agonist is significantly higher than the maximum nonawakening concentration of the 0X2R agonist.
  • the determination of blood plasma concentration can be performed with measures known to the skilled person in the art, including high-performance liquid chromatography-tandem mass spectrometry.
  • the level is typically expressed as ng of analyte/mL.
  • a maximum non-awakening concentration and an arousal-promoting concentration of an 0X2R agonist in a subject can be determined by combining timeseries measurement of blood plasma concentration with recording of nighttime and/or daytime sleep and awake patterns in the subject by known methods including EEG/EMG recording and actigraphy.
  • EEG/EMG recording and actigraphy When detecting the maximum non-awakening concentration or arousal-promoting concentration of an 0X2R agonist in a non-NTl subject, the measurement is performed during night time when autogenic orexin-A level of the subject is generally low.
  • actigraphy refers to methods using miniaturized computerized wristwatch-like devices to monitor and collect data generated by movements. Most actigraphs contain an analogue system to detect movements. In some devices, a piezo-electric beam detects movement.
  • treatment includes improvement, reduction, alleviation, or amelioration of one or more symptoms associated with a disease.
  • the methods and uses disclosed herein may improve one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations; and/or improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy.
  • improvements can be assessed using any one or more of MWT, MALT, EEG, or EMG, by comparing the conditions before and after administration of an 0X2R agonist to the subject, or by comparing the conditions between subjects administered placebo and administered an 0X2R agonist.
  • an 0X2R agonist of the present invention improves night time sleep fragmentation of NT1 patients as indicated by reducing the number of episodes of wakefulness during sleep phase (dark phase) by about 10% to about 20%, and/or increasing NREM sleep duration during the light phase by 10% to about 30%.
  • the term “dosing interval” refers to the time between administrations of an OX2R agonists to a subject.
  • the dosing interval of an OX2R agonist may depend on the pharmacokinetic profiles of the OX2R agonist as well as the dosage form of the OX2R agonist in a manner known to the person skilled in the art.
  • the preferable dosing interval may be once a week, once every two weeks, once every four weeks, once every six weeks or once every eight weeks, among others.
  • the term “subject” refers to a mammal including human, bovine, horse, dog, cat, monkey, mouse, and rat, and preferably refers to a human.
  • pharmaceutically acceptable substances refer to those substances which are suitable for administration to subjects.
  • light phase refers to the active phase or daytime for human and monkey, and sleep phase or nighttime for mice.
  • dark phase refers to the sleep phase or nighttime for human and monkey, and active phase or daytime for mice.
  • the methods, compositions, and uses in this invention are characterized in that the blood plasma concentration of an orexin type 2 receptor (0X2R) agonist in a subject is at or below the maximum non-awakening plasma concentration of the agonist.
  • the blood plasma concentration of the 0X2R agonist in the subject is at or below the maximum non-awakening plasma concentration of the agonist when measured at 24 hours or later after administration.
  • an initial release of the 0X2R agonist may continue for about 24 hours to about 48 hours following administration, and the plasma concentration of the 0X2R agonist may rise above the maximum non-awakening concentration, but does not reach the arousal-promoting concentration.
  • the blood plasma concentration of the 0X2R agonist is at or below the maximum non-awakening concentration, it is larger than 0 (zero) and is the same as, or less than, the maximum nonawakening plasma concentration.
  • the plasma concentration of the 0X2R agonist in a subject is about 1/20 to 1/1, about 1/12 to 1/1, about 1/10 to 1/1, about 1/8 to 1/1, about 1/5 to 1/1, or about 1/3 to 1/1 of the maximum non-awakening concentration of the agonist.
  • the 0X2R agonist is administered over multiple dosing intervals in a subject for the treatment of NT1 and/or sleep-related symptoms, and throughout each dosing interval, the plasma concentration of the agonist is at or below the maximum non-awakening plasma concentration of the agonist.
  • the terms “repeated,” “repetitive,” “repeatedly,” “continued,” “continuously,” “chronic,” “chronically,” or “long-term” means the 0X2R agonist is administered over multiple dosing intervals.
  • the 0X2R agonist is administered to a subject by repeated oral administration or by infusion administration, or by using a slow-release formulation or a sustained-release formulation of the 0X2R agonist.
  • the suitable formulation may be selected based on the characteristics of the OX2R agonist.
  • a sustained-release or slow- release formulation may be particularly useful for administering an OX2R agonist having a short half-life (i.e., less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours).
  • the dose of an 0X2R agonist may be determined by i) identifying the maximum non-awakening concentration of the 0X2R agonist in a subject (e.g. by using EEG), and then ii) identifying the dose of the 0X2R agonist that achieves the maximum nonawakening concentration after administration.
  • the person skilled in the art in the pharmaceutical industry can select a dose that is lower than the dose determined in the step ii).
  • the blood plasma concentration of an 0X2R agonist that is at or below the maximum non-awakening plasma concentration of the agonist in a human is about 0.01 ng/mL to about 1 mg/mL, about 0.03 ng/mL to about 300 ng/mL, about 0.05 ng/mL to about 100 ng/mL, about 0.08 ng/mL to about 50 ng/mL, or about 1 ng/mL to about 30 ng/mL.
  • the dose of an 0X2R agonist that provides a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the agonist in a human is about 0.1 mg to about 50 mg, about 0.5 mg to about 30 mg, or about 1 mg to about 20 mg.
  • treating narcolepsy type 1 may comprise reducing or alleviating one or more symptoms of narcolepsy type 1.
  • the one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS) and cataplexy.
  • Narcolepsy may be diagnosed by diagnostic criteria generally used in the field, e.g., the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Additionally, nighttime sleep is expected to be improved, for example, by reducing the number of waking incidents during the sleep cycle.
  • the methods and uses disclosed herein may increase wakefulness and/or decrease excessive sleepiness in a subject in need thereof.
  • wakefulness and/or decrease of excessive sleepiness is determined by electroencephalogram (EEG) and/or electromyogram (EMG). These tests can also be employed to determine a threshold concentration for potent arousal and a non-awakening concentration for a particular 0X2R agonist.
  • wakefulness and/or decrease of sleepiness is determined by using the Maintenance Wakefulness Test (MWT) with EEG, optionally combined with EMG.
  • MTT Maintenance Wakefulness Test
  • An electroencephalogram (EEG) is a test that detects electrical activity in the brain, for example, by using small, metal discs or electrodes attached to the scalp.
  • wakefulness and/or decrease of sleepiness is determined by using the multiple sleep latency test (MSLT) or the Oxford Sleep Resistance (OSLER) test.
  • MSLT multiple sleep latency test
  • OSLER Oxford Sleep Resistance
  • the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS) or the Stanford Sleepiness Scale.
  • actigraphy can be employed to study the effects of an 0X2R agonist on sleep and wake patterns.
  • actigraphy refers to methods using miniaturized computerized wristwatch-like devices to monitor and collect data generated by movements. Most actigraphs contain an analogue system to detect movements. In some devices, a piezo-electric beam detects movement. See, Sadeh et al., Sleep Medicine Reviews 6(2); 113-124 (2002).
  • the methods and uses disclosed herein may decrease excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) rating in a subject in need thereof.
  • KSS Karolinska Sleepiness Scale
  • the KSS rating is improved 1, 2, 3, 4, or 5 or more ratings.
  • the subject has a KSS rating of 1, 2, 3, 4, or 5 after treatment.
  • the methods and uses disclosed herein may comprise performing one or more tests to quantify a subject’s sleepiness.
  • the test is selected from the multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), and the Oxford Sleep Resistance (OSLER) test.
  • MSLT multiple sleep latency test
  • MTT maintenance of wakefulness test
  • OSLER Oxford Sleep Resistance
  • the test is MWT.
  • the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, Ullanlinna Narcolepsy Scale (UNS), Work Limitations Questionnaire (WLQ), SF-8 (subset of SF-36 questionnaire) or a combination of these tests.
  • the methods and uses disclosed herein comprise administering an OX2R agonist to a subject in need thereof.
  • the OX2R agonist is administered orally.
  • the OX2R agonist is administered non-orally.
  • the non-oral administration is intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration.
  • the non-oral administration is intravenous administration.
  • the non-oral administration is subcutaneous administration.
  • the plasma concentration for an OX2R agonist represents an average plasma concentration for a group of treated subjects and the time period of 1 hour or more begins at any time point following administration. As long as the average plasma concentration for a group of treated subjects meets the condition, “about XX ng/mL or more for a period of about 1 hour or more,” the plasma concentration for an individually treated subject may deviate from the condition.
  • OX2R agonists of the present invention is used, administered over multiple dosing intervals.
  • an OX2R agonist of the present invention may be administered once daily, every other day, once a week, twice a week, bi-weekly, monthly, or bi-monthly.
  • the methods of treating NT1 of the present invention may further comprise combining the administration of an OX2R agonist at or below the maximum nonawakening plasma concentration with administration of an additional OX2R agonist at a dose to induce arousal plasma concentration.
  • the additional OX2R agonist and the OX2R agonist may be different or the same.
  • the additional OX2R agonist may be administered to a subject in need to provide acute treatment of NT1 symptom, followed by administration of the OX2R agonist to provide maintenance treatment. Between the administrations of the two OX2R agonists, there may be a dosing interval of 1 to 5 days depending on the clearance profile of the additional 0X2R agonist.
  • Useful 0X2R agonist for the methods, uses, or compositions of the present invention is a chemical molecule (compound) having OX2R agonist activity.
  • Such compound may be selected from among known compounds or from newly designed/synthesized compounds.
  • a compound having shorter half-life i.e. less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours is particularly useful when formulating it in a slow-release dosage form.
  • OX2R agonist is N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2- ((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound A herein).
  • Compound A is described in WO 2019/027058.
  • OX2R agonist is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound B or danavorexton herein).
  • Compound B is described in WO2017/135306.
  • OX2R agonist is N-((2S,3S)-2-((2,3'-difluorobiphenyl-3- yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound C herein).
  • Compound C is described in WO 2019/027058.
  • OX2R agonist is N- ⁇ (2S,3R)-4,4-difluoro-l-(2-hydroxy-2- methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3- yljmethanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound D herein).
  • Compound D is described in W02020/158958
  • Useful OX2R agonists include JZP441/DSP-0187, ALKS2680, and E2086. [0150] Useful OX2R agonists are described in PCT Published Appl. No.
  • W02021/107023 which is fully incorporated by reference herein, and include the following compounds and their pharmaceutically acceptable salts and hydrates: 4-(5- cyclopropyl-l,2,4-oxadiazol-3-yl)-N- ⁇ (lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin- l-yl]cy c lohexyl ⁇ -4-methylpiperidine-l-carboxamide represented by the following formula (I):
  • W02022/014680 which is fully incorporated by reference herein, and include the following compounds and their pharmaceutically acceptable salts and hydrates: (R)-2- cyclopropyl-2-((lR,3S,5S)-3-((3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4- yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide represented by the following formula (III):
  • ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3;
  • T is CR1R2 or O
  • W is CR4R5 or O
  • U is CR 6 R 7 ;
  • X is CRSR 9 ;
  • V is CR 3 or N
  • Y is NR10, O or absent
  • R is halogen or deuterium; p is 0, 1, 2, 3, or 4; and m is 1, 2, 3, or 4;
  • Ri, R2, R4, and Rs are each, independently, selected from the group consisting of H, halogen, and deuterium; or, alternatively, R2 and Rs together with the carbon atoms to which they are attached, form a single bond;
  • R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R 3 and Ri, together with the carbon atoms to which they are attached, form a C 3 -Cscycloalkyl; or, alternatively, R 3 and R4, together with the carbon atoms to which they are attached, form a C 3 -Cs cycloalkyl;
  • Re, R7, R 8 , R9, and R11 are each, independently, selected from the group consisting of H, halogen, and deuterium;
  • Rio is selected from the group consisting of H, unsubstituted Ci-C 3 alkyl, and Ci- C 3 alkyl substituted with one or more halogen atoms; and each R12 and RI 3 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted Ci-C 3 alkyl, and Cl-C 3 alkyl substituted with one or more halogen atoms; and R12 and RB are, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C i-Csalkyl, and Ci-Csalkyl substituted with one or more halogen atoms.
  • Examples of suitable OX2R agonists described in W02019/027058 include N- ((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)- cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide represented by the following formula (VII): or a pharmaceutically acceptable salt thereof (also referred to as Compound E herein); and N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,l)-piperidina-l(l,2)-benzena-2(l,4)- cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide represented by the following formula (VIII): or a pharmaceutically acceptable salt or hydrate
  • the OX2R agonist may exist as a pharmaceutically acceptable salt.
  • such salts include a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like.
  • the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like.
  • Examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert- butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N- dibenzylethylenediamine and the like.
  • Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like.
  • Examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • the OX2R agonist may exist as a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate).
  • the OX2R agonist may exist as a pharmaceutically acceptable cocrystal or cocrystal salt.
  • the cocrystal or cocrystal salt means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability).
  • the cocrystal or cocrystal salt may be produced by known methods.
  • the pharmaceutical composition comprises pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.
  • Examples of the dosage form of the aforementioned pharmaceutical composition include tablet (including sugar-coated tablet, film-coated tablet, orally disintegrating tablet), capsule (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like, which can be respectively safely administered orally or non-orally (e.g., topical, rectal, intravenous administration).
  • These preparations may be a release control preparation such as an immediate-release preparation, a sustained-release preparation and the like.
  • the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for non-oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for transdermal administration.
  • a pharmaceutical composition comprises (a) an orexin type 2 receptor (OX2R) agonist; and (b) one or more pharmaceutically acceptable carriers that are capable of providing a sustained release of the OX2R agonist at or below the maximum non-awakening plasma concentration.
  • OX2R orexin type 2 receptor
  • the pharmaceutical composition provides an average plasma concentration of the OX2R agonist after administration of about 0.01 ng/mL to about 1 mg/mL, about 0.03 ng/mL to about 300 ng/mL, about 0.05 ng/mL to about 100 ng/mL, about 0.08 ng/mL to about 50 ng/mL, or about 1 ng/mL to about 30 ng/mL.
  • EXAMPLE 1 Determination of arousal-promoting plasma concentration of an OX2R agonist in NT1 model mice.
  • Orexin/ataxin-3 mice of C57BL/6J background Neuron, 30(2), 345-54, (2001) were provided by the University of Tsukuba. Mice were housed under laboratory conditions (12 h light/dark cycles). Implantation of electroencephalogram (EEG) and electromyogram (EMG) electrodes and EEGZEMG recordings were performed as described previously (Pharmacol. Biochem. Behav., (2019)187, 172794).
  • Compound B (1 mg/kg at a volume of 10 mL/kg of body weight) was suspended in 0.5% (w/v) methylcellulose (MC) in saline and was subcutaneously administered to mice at zeitgeber time (ZT) 12 or ZT 5 (start of the lights-on period is ZT0).
  • EEGZEMG were recorded using VitalRecorder (Kissei Comtec Co, Ltd, Nagano, Japan) and locomotor activity was measured using an infrared activity sensor (Biotex, Kyoto, Japan). SleepSign (Kissei Comtec) was used to classify sleep/wakefulness states in 4-sec epochs.
  • Each stage was characterized as follows: (1) wakefulness, low-amplitude EEG and high-voltage EMG activities or locomotion score; (2) NREM sleep, high-amplitude slow EEG and low- voltage EMG activities; and (3) REM sleep, theta-dominated EEG an- EMG atonia. A total of 4 - 5 animals were used.
  • Compound B produced potent arousal (defined as maintenance of wakefulness for more than 75% in 10 min-bins) up to 70 min and 90 min after administration during the dark (administered at ZT12) (FIG. 1 left) and light (administered at ZT5) (FIG. 1 right) phase, respectively.
  • FIG. 2 which shows the time-course blood plasma concentration of Compound B, the arousal-promoting concentration of Compound B in the mice was estimated to be about 20-40 ng/mL.
  • EXAMPLE 2 Determination of non-awakening plasma concentration of an OX2R agonist in NT1 model mice.
  • mice J Neurosci., 34(19), 6495-509, (2014).
  • Orexin-tTA mice with a C57BL/6J genetic background were obtained from Nagoya University.
  • Orexin-tTA mice were crossed with TetO diphtheria toxin A (DTA) mice (B6.Cg-Tg(tetO-DTA)lGfi/J, The Jackson Laboratory, Bar Harbor, ME, USA) to generate orexin-tTA;TetO DTA mice. Mice were housed under laboratory conditions (12 h light/dark cycles).
  • EEG electroencephalogram
  • EMG electromyogram
  • EEGZEMG were recorded using VitalRecorder (Kissei Comtec Co, Ltd, Nagano, Japan) and locomotor activity was measured using an infrared activity sensor (Biotex, Kyoto, Japan).
  • SleepSign Karl (Kissei Comtec) was used to classify sleep/wakefulness states in 4-sec epochs. Each stage was characterized as follows: (1) wakefulness, low-amplitude EEG and high-voltage EMG activities or locomotion score; (2) NREM sleep, high-amplitude slow EEG and low-voltage EMG activities; and (3) REM sleep, theta-dominated EEG and EMG atonia. A total of 8 animals were used. Results are shown in FIG. 3.
  • the minimum effective dose of Compound A to produce arousal (defined as maintenance of wakefulness for more than 75% in 10 min-bins) was 10 mg/kg.
  • the plasma concentration of Compound A at 10 mg/kg at the last time-point when it produced potent arousal (110-min after administration) was 1128.9 ng/mL (FIG. 4).
  • the peak plasma concentration of Compound A at 1 mg/kg which produced negligible wakepromoting effects was 371.6 ng/mL(FIG. 4). Therefore, the margin between the arousalpromoting and non-awaking plasma concentration was determined to be 3.04 times (around 3 times).
  • EXAMPLE 3 Determination of non-awakening plasma concentration of an OX2R agonist in monkeys.
  • Compound A was suspended in 0.5% (w/v) methylcellulose (MC) in distilled water (Fujifilm Wako pure chemical Co., Osaka, Japan), and was orally administered to monkeys (3, 10 mg/kg at a volume of 5 mL/kg of body weight) at zeitgeber time (ZT) 12 (start of the lights-off period is ZT12). 3 mg/kg of Compound A was selected as a dose that provides potential maximum non-awakening concentration of Compound A. Cortical electroencephalogram (EEG), electromyogram (EMG) and locomotor activity were recorded using Dataquest ART software (Data Sciences International Inc.).
  • EEG Cortical electroencephalogram
  • EMG electromyogram
  • locomotor activity were recorded using Dataquest ART software (Data Sciences International Inc.).
  • SleepSign (Kissei Comtec) was used to classify sleep/wakefulness states in 20-sec epochs. Wakefulness was determined by the presence of locomotor activity and/or EMG signals in the absence of high-amplitude slow wave EEG. A total of 8 animals were used.
  • HPLC-MS high-performance liquid chromatography -tandem mass spectrometry
  • EXAMPLE 4 Determination of arousal -promoting plasma concentration and maximum non-awakening concentration of an OX2R agonist in human.
  • SRD Phase I single rising dose
  • the arousalpromoting plasma concentration of Compound B in individuals with NT1 was determined to be around the average plasma exposure level of Compound B at 11.2 mg, which is 20 ng/mL (Proc. Natl Acad. Sci. USA., 119(35), e2207531119, (2022)).
  • the maximum non-awakening dose of Compound B in individuals with NT1 was selected to be around one-third of the arousal-promoting concentration (20 ng/mL), which is about 7 ng/mL.
  • EXAMPLE 5 Efficacy of an OX2R agonist at or below non-awakening plasma concentration
  • mice J Neurosci., 34(19), 6495-509, (2014).
  • Orexin-tTA mice with a C57BL/6J genetic background were obtained from Nagoya University.
  • Orexin-tTA mice were crossed with TetO diphtheria toxin A (DTA) mice (B6.Cg-Tg(tetO-DTA)lGfi/J, The Jackson Laboratory, Bar Harbor, ME, USA) to generate orexin-tTA; TetO DTA mice. Mice were housed under laboratory conditions (12 h light/dark cycles).
  • EEG electroencephalogram
  • EMG electromyogram
  • Compound A was solubilized in 40% Captisol/0.1% Polysorbate 80 in distilled water at 7.5 mg/mL (Dose 1) and 17.5 mg/mL (Dose 2) and was loaded into Alzet osmotic pump (Alzet model 2002, Muromachi).
  • the pumps were submerged in 0.9% saline and were incubated at 37°C for at least 16 h before implantation in mice.
  • the pump was inserted from a small incision made in the skin behind the neck of mice. Plasma samples were obtained on day 1, 4, 7, 15 days after implantation of the pump and the concentrations of Compound A in the plasma was quantified with high-performance liquid chromatography-tandem mass spectrometry.
  • the experiment consisted of four groups: wild-type (WT) mice (also referred to as Non-Tg) treated with vehicle (implanted with pumps filled with vehicle), orexin- tTA;TetO DTA mice treated with vehicle, and orexin-tTA;TetO DTA mice (also referred to as Tg) treated with Compound A at Dose 1 and Dose 2.
  • WT wild-type mice
  • orexin-tTA;TetO DTA mice treated with vehicle
  • orexin-tTA;TetO DTA mice also referred to as Tg treated with Compound A at Dose 1 and Dose 2.
  • Compounds were administered by infusion using an osmotic pump as described above.
  • the sleep stages were analyzed by EEG/EMG recordings on day 14 after implantation of the pump.
  • SleepSign (Kissei Comtec) was used to classify sleep/wakefulness states in 4-sec epochs as wakefulness, non-rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep, and to calculate the total time, the number of episodes and the duration of each sleep stage. Effects during the dark and light phase were analyzed in 12 h-bins. The scores of the WT mice treated with vehicle or the orexin-tTA;TetO DTA mice treated by Compound A (Dose 1 or Dose 2) were compared with orexin-tTA;TetO DTA mice treated with vehicle by a Dunnet-type multiple comparison test. A total of 14 to 16 mice were used for each treatment group.
  • Orexin-tTA;TetO DTA mice treated with vehicle showed significantly increased fragmentation of wakefulness during the day and significantly increased fragmentation of sleep during the night compared with the WT mice treated with vehicle, as indicated by the increased episode number and reduced episode duration of wakefulness during the dark phase, and increased episode number and reduced episode duration of NREM sleep during the light phase.
  • Treatment of orexin-tTA;TetO DTA mice by Compound A at two plasma concentrations significantly reduced the number of episodes and increased the duration of wakefulness during the dark phase, and significantly reduced the number of episodes and increased the duration of NREM sleep during the light phase compared with the orexin- tTA;TetO DTA mice treated with vehicle.
  • DREM Direct transitions from wakefulness to REM sleep
  • REM REM sleep
  • DREM was analyzed as described previously (Proc. Natl Acad. Sci USA., 119(35):e2207531119, (2022)). Briefly, DREM was defined according to the following criteria: an abrupt episode of EMG atonia lasting for more than 20 seconds, lack of locomotor activity, predominance of theta EEG activity, and wakefulness lasting for more than 40 seconds before the episode.
  • Orexin-tTA;TetO DTA mice treated with the doses of Compound A which provides plasma concentration at or below the non-awakening plasma concentration after administration showed significantly fewer mean number of DREM episodes compared with the vehicle-treated orexin-tTA;TetO DTA mice during the dark and light phase.
  • the doses of Compound A improved cataplexy symptoms in orexin- tTA;TetO DTA mice during the dark and light phase.
  • EXAMPLE 6 Efficacy of an OX2R agonist below non-awakening plasma concentration
  • Compound D was solubilized in 20% Captisol/0.1% Polysorbate 80 in distilled water at 2 mg/mL and was loaded into Alzet osmotic pump (Alzet model 2004, Muromachi). The pumps were submerged in 0.9% saline and were incubated at 37°C for at least 40 h before implantation to mice. The pump was inserted from a small incision made in the skin behind the neck of mice. Plasma samples were obtained on day 1, 2, 5, 7, 14, 21, 28 days after implantation of the pump and the concentrations of Compound D in the plasma were quantified with high-performance liquid chromatography -tandem mass spectrometry. [0194] The plasma concentrations of Compound D were maintained at doses below the non-awakening concentration (around 40 and 60 ng/mL) between 7 and 28 days after implantation of the pump (FIG. 11).
  • the experiment consisted of three groups: wild-type (WT) mice treated with vehicle (implanted with pumps filled with vehicle), orexin-tTA;TetO DTA mice treated with vehicle, and orexin-tTA;TetO DTA mice treated with infusion of Compound D.
  • WT mice wild-type mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with infusion of Compound D were compared with orexin-tTA;TetO DTA mice treated with vehicle by a Dunnet-type multiple comparison test on treatment day 28. A total of 8 to 12 mice were used for each treatment group.
  • Treatment of orexin-tTA;TetO DTA mice by infusion of Compound D at or below the maximum non-awakening plasma concentration significantly reduced the number of episodes and increased the duration of wakefulness during the dark phase, and significantly reduced the number of episodes and increased the duration of NREM sleep during the light phase compared with the orexin-tTA;TetO DTA mice treated with vehicle.
  • Orexin-tTA;TetO DTA mice treated with infusion of Compound D at or below the maximum non-awakening plasma concentration showed significantly fewer mean number of DREM episodes compared with the vehicle-treated orexin-tTA;TetO DTA mice during the dark and light phase.
  • Example 7 Efficacy of an OX2R agonist below non-awakening plasma concentration
  • Compound B was solubilized in 20% Captisol/0.1% Polysorbate 80 in distilled water at 1.3 mg/mL and was loaded into Alzet osmotic pump (Alzet model 2004, Muromachi). The pumps were submerged in 0.9% saline and were incubated at 37°C for at least 40 h before implantation to mice. The pump was inserted from a small incision made in the skin behind the neck of mice. Plasma samples were obtained on day 1, 4, 7, 14, 21, 28 days after implantation of the pump and the concentrations of Compound B in the plasma were quantified with high-performance liquid chromatography -tandem mass spectrometry.
  • the experiment consisted of three groups: wild-type (WT) mice treated with vehicle (implanted with pumps filled with vehicle), orexin-tTA;TetO DTA mice treated with vehicle, and orexin-tTA;TetO DTA mice treated with infusion of Compound B.
  • WT mice wild-type mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with infusion of Compound B were compared with orexin-tTA;TetO DTA mice treated with vehicle by a Dunnet-type multiple comparison test on treatment day 28. A total of 8 to 12 mice were used for each treatment group.
  • Treatment of orexin-tTA;TetO DTA mice by infusion of Compound B at or below the maximum non-awakening plasma concentration significantly reduced the number of episodes and increased the duration of wakefulness during the dark phase, and significantly reduced the number of episodes and increased the duration of NREM sleep during the light phase compared with the orexin-tTA;TetO DTA mice treated with vehicle.
  • Orexin-tTA;TetO DTA mice treated with infusion of Compound B at or below the maximum non-awakening plasma concentration showed significantly fewer mean number of DREM episodes compared with the vehicle-treated orexin-tTA;TetO DTA mice during the dark and light phase.
  • Example 8 Efficacy of an 0X2R agonist below non-awakening plasma concentration
  • Compound E was solubilized in 20% Captisol/0.1% Polysorbate 80 in distilled water at 1 mg/mL and was loaded into Alzet osmotic pump (Alzet model 2004, Muromachi). The pumps were submerged in 0.9% saline and were incubated at 37°C for at least 40 h before implantation to mice. The pump was inserted from a small incision made in the skin behind the neck of mice. Plasma samples were obtained on day 4, 7, 14, 28 days after implantation of the pump and the concentrations of Compound E in the plasma were quantified with high-performance liquid chromatography -tandem mass spectrometry.
  • the experiment consisted of three groups: wild-type (WT) mice treated with vehicle (implanted with pumps filled with vehicle), orexin-tTA;TetO DTA mice treated with vehicle, and orexin-tTA;TetO DTA mice treated with infusion of Compound E.
  • WT mice wild-type mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with vehicle orexin-tTA;TetO DTA mice treated with infusion of Compound E.
  • the scores of the WT mice treated with vehicle or the orexin-tTA;TetO DTA mice treated by infusion of Compound E were compared with orexin-tTA;TetO DTA mice treated with vehicle by a Dunnet-type multiple comparison test on treatment day 14. A total of 8 to 12 mice were used for each treatment group.
  • Compound F was solubilized in 20% Captisol/0.1% Polysorbate 80 in distilled water at 3 mg/mL and was loaded into Alzet osmotic pump (Alzet model 2004, Muromachi). The pumps were submerged in 0.9% saline and were incubated at 37°C for at least 40 h before implantation to mice. The pump was inserted from a small incision made in the skin behind the neck of mice. Plasma samples were obtained on day 4, 7, 14, 28 days after implantation of the pump and the concentrations of Compound F in the plasma were quantified with high-performance liquid chromatography -tandem mass spectrometry.
  • the experiment consisted of three groups: wild-type (WT) mice treated with vehicle (implanted with pumps filled with vehicle), orexin-tTA;TetO DTA mice treated with vehicle, and orexin-tTA;TetO DTA mice treated with infusion of Compound F.
  • WT mice wild-type mice treated with vehicle
  • orexin-tTA;TetO DTA mice treated with vehicle orexin-tTA;TetO DTA mice treated with infusion of Compound F.
  • the scores of the WT mice treated with vehicle or the orexin-tTA;TetO DTA mice treated by infusion of Compound F were compared with orexin-tTA;TetO DTA mice treated with vehicle by a Dunnet-type multiple comparison test on treatment day 14. A total of 8 to 12 mice were used for each treatment group.
  • EXAMPLE 10 Formulation of a sustained release formulation of an OX2R agonist
  • Microcapsule powders comprising of 1), 2), and 3) were formulated using inwater drying method (O/W) as described in W003/002092. The total amount of 1) and 2) were dissolved in di chloromethane, then added to an aqueous phase to make an emulsion. Microcapsules were obtained during emulsification and were collected after evaporating di chloromethane. Collected microcapsules were washed and lyophilized with the whole amount of 3) to give rise to microcapsule powders. The obtained microcapsule powders (45.63 mg) were dispersed in diluent (0.12 mL) and administered to rats by subcutaneous administration. It was confirmed that the formulation using the microcapsule achieved sustained release of compound B over a 4-week period.
  • O/W inwater drying method
  • a range includes each individual member.
  • a group having 1 to 3 cells refers to groups having 1, 2, or 3 cells.
  • a group having 1 to 5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

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Abstract

L'invention concerne des utilisations d'un agoniste du récepteur de type 2 de l'orexine (OX2R) à des concentrations de non-éveil. L'invention concerne également des compositions et des procédés d'administration d'un agoniste d'OX2R à un sujet (par exemple, un mammifère) en ayant besoin à une dose qui fournit une concentration dans le plasma sanguin de l'agoniste d'OX2R qui est inférieure ou égale à la concentration maximale dans le plasma sanguin de non-éveil de l'agoniste d'OX2R. L'invention concerne également des compositions et des méthodes de traitement de la narcolepsie de type 1 (NT1) chez un sujet en ayant besoin par maintien de la concentration de plasma sanguin d'un agoniste de l'OX2R après l'administration qui est inférieure ou égale à la concentration maximale de non-éveil de l'agoniste de l'OX2R.
PCT/IB2023/060969 2022-10-31 2023-10-31 Dosage d'agonistes du récepteur de type 2 de l'orexine WO2024095158A1 (fr)

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Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002092A2 (fr) 2001-06-29 2003-01-09 Takeda Chemical Industries, Ltd. Composition a liberation controlee et procede de production de cette composition
WO2017135306A1 (fr) 2016-02-04 2017-08-10 Takeda Pharmaceutical Company Limited Composé de pipéridine substituée et son utilisation
US20190040010A1 (en) * 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2020158958A1 (fr) 2019-01-31 2020-08-06 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2020167701A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
WO2021048822A1 (fr) * 2019-09-13 2021-03-18 Takeda Pharmaceutical Company Limited Tak-925 destiné à être utilisé dans le traitement de la narcolepsie
US20210155636A1 (en) * 2019-11-25 2021-05-27 Alkermes, Inc. Substituted Macrocyclic Compounds and Related Methods of Treatment
WO2021107023A1 (fr) 2019-11-27 2021-06-03 大日本住友製薬株式会社 Dérivé de cycloalkyl urée
WO2022014680A1 (fr) 2020-07-17 2022-01-20 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pipéridine substitué et son application
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine
WO2022040058A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine cyclopentapyrrole
WO2022051583A1 (fr) 2020-09-03 2022-03-10 Orexia Therapeutics Limited Dérivés hétérocycliques substitués par un benzyle moyen cycle ou macrocyclique et leurs utilisations en tant qu'agonistes du récepteur de l'orexine 2
WO2022051596A1 (fr) 2020-09-03 2022-03-10 Orexia Therapeutics Limited Dérivés hétérocycliques bicycliques et leurs utilisations en tant qu'agonistes du récepteur de l'orexine 2
US20220081441A1 (en) * 2019-11-27 2022-03-17 Sumitomo Dainippon Pharma Co., Ltd. Cycloalkylurea derivative
WO2022094012A1 (fr) 2020-11-02 2022-05-05 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine d'urée macrocyclique
WO2022109117A1 (fr) 2020-11-23 2022-05-27 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type 3-amino pyrrolidine et pipéridine macrocyclique
WO2022119888A1 (fr) 2020-12-03 2022-06-09 Merck Sharp & Dohme Corp. Agonistes 3-hétéroaryl pyrrolidine et pipéridine des récepteurs de l'orexine
WO2022132696A1 (fr) 2020-12-16 2022-06-23 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine d'urée

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002092A2 (fr) 2001-06-29 2003-01-09 Takeda Chemical Industries, Ltd. Composition a liberation controlee et procede de production de cette composition
WO2017135306A1 (fr) 2016-02-04 2017-08-10 Takeda Pharmaceutical Company Limited Composé de pipéridine substituée et son utilisation
US20190040010A1 (en) * 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2019027058A1 (fr) 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2020158958A1 (fr) 2019-01-31 2020-08-06 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2020167701A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
WO2021048822A1 (fr) * 2019-09-13 2021-03-18 Takeda Pharmaceutical Company Limited Tak-925 destiné à être utilisé dans le traitement de la narcolepsie
WO2021108628A1 (fr) 2019-11-25 2021-06-03 Alkermes, Inc. Composés macrocycliques substitués et méthodes de traitement associées
US20210155636A1 (en) * 2019-11-25 2021-05-27 Alkermes, Inc. Substituted Macrocyclic Compounds and Related Methods of Treatment
US20220081441A1 (en) * 2019-11-27 2022-03-17 Sumitomo Dainippon Pharma Co., Ltd. Cycloalkylurea derivative
WO2021107023A1 (fr) 2019-11-27 2021-06-03 大日本住友製薬株式会社 Dérivé de cycloalkyl urée
WO2022014680A1 (fr) 2020-07-17 2022-01-20 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pipéridine substitué et son application
US11479552B2 (en) * 2020-07-17 2022-10-25 Eisai R&D Management Co., Ltd. Substituted piperidine compounds and their use
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine
WO2022040058A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine cyclopentapyrrole
WO2022051596A1 (fr) 2020-09-03 2022-03-10 Orexia Therapeutics Limited Dérivés hétérocycliques bicycliques et leurs utilisations en tant qu'agonistes du récepteur de l'orexine 2
WO2022051583A1 (fr) 2020-09-03 2022-03-10 Orexia Therapeutics Limited Dérivés hétérocycliques substitués par un benzyle moyen cycle ou macrocyclique et leurs utilisations en tant qu'agonistes du récepteur de l'orexine 2
WO2022094012A1 (fr) 2020-11-02 2022-05-05 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine d'urée macrocyclique
WO2022109117A1 (fr) 2020-11-23 2022-05-27 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type 3-amino pyrrolidine et pipéridine macrocyclique
WO2022119888A1 (fr) 2020-12-03 2022-06-09 Merck Sharp & Dohme Corp. Agonistes 3-hétéroaryl pyrrolidine et pipéridine des récepteurs de l'orexine
WO2022132696A1 (fr) 2020-12-16 2022-06-23 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine d'urée

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
"The Cambridge Dictionary of Science and Technology", 1988
CELL, vol. 92, 1998, pages 573 - 585
CELL, vol. 98, 1999, pages 437 - 451
CNS DRUGS, vol. 27, 2013, pages 83 - 90
CURRENT MEDICAL RESEARCH AND OPINION, vol. 32, no. 10, 2016, pages 1611 - 1622
ELECTROENCEPHALOGR. CLIN. NEUROPHYSIOL., vol. 53, no. 6, 1982, pages 658 - 661
EVANS REBECCA: "Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 119, no. 35, 22 August 2022 (2022-08-22), pages 1 - 10, XP093050145, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436334/pdf/pnas.202207531.pdf> DOI: 10.1073/pnas.2207531119 *
EXP. NEUROL., vol. 217, no. 1, 2009, pages 46 - 54
HALEMARHAM: "The Harper Collins Dictionary of Biology", 1991, SPRINGER VERLAG
J NEUROSCI., vol. 34, no. 19, 2014, pages 6495 - 509
J SLEEP RES., vol. 32, no. 5, 2023, pages e13878
J. BIOL. CHEM., vol. 286, no. 19, 2011, pages 16726 - 16733
J. MED. CHEM., vol. 58, 2015, pages 7931 - 7937
N ENGL J MED., vol. 389, no. 4, 2023, pages 309 - 321
NAT REV DIS PRIMERS, vol. 3, 2017, pages 16100
NEURON, vol. 30, no. 2, 2001, pages 345 - 54
NEURON, vol. 38, 2003, pages 715 - 730
PHARMACOL. BIOCHEM. BEHAV., vol. 187, 2019, pages 172794
PROC. NATL ACAD. SCI USA., vol. 119, no. 35, 2022, pages e2207531119
PROC. NATL ACAD. SCI. USA, vol. 101, 2004, pages 4649 - 4654
PROC. NATL ACAD. SCI. USA., vol. 114, no. 22, 2017, pages 5731 - 5736
PROC. NATL ACAD. SCI. USA., vol. 119, no. 35, 2022, pages e2207531119
PROC. NATL ACAD. SCI., vol. 119, no. 35, 2002, pages e2207531119
SADEH ET AL., SLEEP MEDICINE REVIEWS, vol. 6, no. 2, 2002, pages 113 - 124
SINGLETON ET AL.: "Dictionary of Microbiology and Molecular Biology", 1994
SLEEP, vol. 45, 2022, pages 091
THER. ADV. NEUROL. DISORD., vol. 12, 2019, pages 1 - 12
THORPY MICHAEL J.: "Recently Approved and Upcoming Treatments for Narcolepsy", CNS DRUGS, vol. 34, no. 1, 1 January 2020 (2020-01-01), AUCKLAND, NZ, pages 9 - 27, XP055791029, ISSN: 1172-7047, Retrieved from the Internet <URL:http://link.springer.com/article/10.1007/s40263-019-00689-1/fulltext.html> DOI: 10.1007/s40263-019-00689-1 *
TRENDS IN PHARMACOL. SCI., vol. 27, no. 7, 2006, pages 368 - 374
YUKITAKE HIROSHI ET AL: "TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice", PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, ELSEVIER, US, vol. 187, 22 October 2019 (2019-10-22), XP085903575, ISSN: 0091-3057, [retrieved on 20191022], DOI: 10.1016/J.PBB.2019.172794 *

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